Human Immunodeficiency Virus (HIV): Difference between revisions

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Latest revision as of 21:45, 22 September 2017

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2], Alejandro Lemor, M.D. [3]

Overview

AIDS is caused by the human immunodeficiency virus (HIV). HIV is a retrovirus classified into the family of Retroviridae and the sub family orthoretroviridae.^[1]. Two main subspecies of HIV exist: HIV-1, and HIV-2. HIV-1 is composed of two copies of single-stranded RNA enclosed by a conical capsid comprising the viral protein p24. The genome consists of several major genes that code for structural and functional proteins. These include the gag, pol, env, tat, and nef genes. The genome and proteins of HIV have been the subject of extensive research since the discovery of the virus in 1983. It is a well known fact that no two HIV genomes are the same, not even from the same person, causing some to speculate that HIV is a "quasispecies" of a virus.^[2] A major requirement for all retroviruses is reverse transcriptase that transcribes the viral RNA into double-stranded DNA and integrase that integrates this newly formed DNA into the host genome.

Taxonomy

HIV 1 and HIV 2 are classified into the family of Retroviridae and sub family orthoretroviridae.^[1]
Retrovirus are enveloped RNA viruses which requires a DNA intermediate to replicate.
HIV 1 and HIV 2 belongs to the genus Lentivirus (Lentus which in latin means slow)
The retrovirus rely on enzyme reverse transcriptase to transcribe their genome from RNA to DNA.
Integrase incorporates the DNA into the host DNA and becomes a part of cellular DNA replicating with it.

Origin

Both HIV-1 and HIV-2 are of primate origin. The origin of HIV-1 is the Central Common Chimpanzee (Pan troglodytes troglodytes) found in southern Cameroon.^[3]
It is believed that HIV-2 originated from the Sooty Mangabey (Cercocebus atys), an Old World monkey of Guinea Bissau, Gabon, and Cameroon.
Most experts believe that HIV probably transferred to humans as a result of direct contact with primates, for instance during hunting or butchery.^[4]

Structure

Figure 1. Diagram of HIV - By US National Institute of Health

HIV is different in structure from other retroviruses. It is around 120 nm in diameter (120 billionths of a meter; around 60 times smaller than a red blood cell) and roughly spherical.
HIV-1 is composed of two copies of single-stranded RNA enclosed by a conical capsid comprising the viral protein p24, typical of lentiviruses (Figure 1). The RNA component is 9749 nucleotides long. This is in turn surrounded by a plasma membrane of host-cell origin. The single-strand RNA is tightly bound to the nucleocapsid proteins, p7 and enzymes that are indispensable for the development of the virion, such as reverse transcriptase and integrase. The nucleocapsid (p7 and p6) associates with the genomic RNA (one molecule per hexamer) and protects the RNA from digestion by nucleases. A matrix composed of an association of the viral protein p17 surrounds the capsid, ensuring the integrity of the virion particle. Also enclosed within the virion particle are Vif, Vpr, Nef, p7 and viral protease (Figure 1). The envelope is formed when the capsid buds from the host cell, taking some of the host-cell membrane with it. The envelope includes the glycoproteins gp120 and gp41.
Recently, an Anglo-German team compiled a 3D structure of HIV by combining multiple images. It is hoped that this new information would contribute to scientific understanding of the virus, and help in the creation of a cure. Oxford University's Professor Stephen D. Fuller said the 3D map would assist in understanding how the virus grows. ^[5] The validity of this work remains a matter of debate ^[6], with a conflicting model produced by another team led by Florida State University Professor Kenneth Roux in the US ^[7].

Genome organization

HIV has several major genes coding for structural proteins that are found in all retroviruses, and several nonstructural ("accessory") genes that are unique to HIV. The gag gene provides the basic physical infrastructure of the virus, and pol provides the basic mechanism by which retroviruses reproduce, while the others help HIV to enter the host cell and enhance its reproduction. Though they may be altered by mutation, all of these genes except tev exist in all known variants of HIV; see Genetic variability of HIV.

gag (Group-specific Antigen): codes for p24, the viral capsid; p6 and p7, the nucleocapsid proteins; and p17, a matrix protein.

pol: Codes for viral enzymes, the most important of which are reverse transcriptase, integrase, and protease which cleaves the proteins derived from gag and pol into functional proteins.

env (for "envelope"): Codes for the precursor to gp120 and gp41, proteins embedded in the viral envelope which enable the virus to attach to and fuse with target cells.

tat, rev, nef, vif, vpr, vpu: Each of these genes codes for a single protein with the same names; see Tat, Rev, Nef, Vif, Vpr, Vpu.

tev: This gene is only present in a few HIV-1 isolates. It is a fusion of parts of the tat, env, and rev genes, and codes for a protein with some of the properties of Tat, but little or none of the properties of Rev.

Protein function

Gag

These proteins are encoded by the gag gene, and provide structural elements of the virus.

p24

p24 makes up the viral capsid.
When a Western blot test is used to detect HIV infection, p24 is one of the three major proteins tested for, along with gp120/gp160 and gp41.

p6, p7, and p17

p6 and p7 provide the nucleocapsid.
p17 provides a protective matrix.

Pol

Reverse transcriptase

Common to all retroviruses, this enzyme transcribes the viral RNA into double-stranded DNA.

Integrase

This enzyme integrates the DNA produced by reverse transcriptase into the host's genome.

Protease

A protease is any enzyme that cuts proteins into segments. HIV's gag and pol genes do not produce their proteins in their final form, but as larger combination proteins; the specific protease used by HIV cleaves these into separate functional units. Protease inhibitor drugs block this step.

Env

The env gene does not actually code for gp120 and gp41, but for a precursor to both, gp160. During HIV reproduction, the host cell's own enzymes cleave gp160 into gp120 and gp41. See Replication cycle of HIV.

gp120

Exposed on the surface of the viral envelope, the glycoprotein gp120 binds to the CD4 receptor on any target cell that has such a receptor, particularly the helper T-cell. See HIV tropism and Replication cycle of HIV.
Since CD4 receptor binding is the most obvious step in HIV infection, gp120 was among the first targets of HIV vaccine research. These efforts have been hampered by its chemical properties, which make it difficult for antibodies to bind to gp120; also, it can easily be shed from the virus due to its loose binding with gp41.

gp41

The glycoprotein gp41 is non-covalently bound to gp120, and provides the second step by which HIV enters the cell. It is originally buried within the viral envelope, but when gp120 binds to a CD4 receptor, gp120 changes its conformation causing gp41 to become exposed, where it can assist in fusion with the host cell.
Fusion inhibitor drugs such as enfuvirtide block the fusion process by binding to gp41.

Transactivators

Tat

Stands for "Trans-Activator of Transcription". Tat consists of between 86 and 101 amino acids depending on the subtype.^[8] Tat helps HIV reproduce by compensating for a defect in its genome: the HIV RNA initially has a hairpin-structured portion which prevents full transcription occurring. However, a small number of RNA transcripts will be made, which allow the Tat protein to be produced. Tat then binds to and phosphorylates cellular factors, eliminating the effect of the hairpin RNA structure and allowing transcription of the HIV DNA.^[9] This itself increases the rate of transcription, providing a positive feedback cycle. This in turn allows HIV to have an explosive response once a threshold amount of Tat is produced, a useful tool for defeating the body's response. Tat also appears to play a more direct role in the HIV disease process. The protein is released by infected cells in culture, and is found in the blood of HIV-1 infected patients.^[10] It can be absorbed by cells that are not infected with HIV, and can act directly as a toxin producing cell death via apoptosis in uninfected "bystander" T cells, assisting in progression toward AIDS.^[11] By interacting with the CXCR4 receptor, Tat also appears to encourage the reproduction of less virulent M-tropic strains of HIV early in the course of infection, allowing the more rapidly pathogenic T-tropic strains to emerge later.^[10]

Rev

**Rev-mediated HIV mRNA transport.** Rev (red) binds the Rev response element (RRE, blue) to mediate export of unspliced and singly spliced mRNA from the nucleus to the cytoplasm. - De I, Vossman, CC BY 2.5, https://commons.wikimedia.org/w/index.php?curid=2401724

Stands for "Regulator of Virion". This protein allows fragments of HIV mRNA that contain a Rev Response Unit (RRE) to be exported from the nucleus to the cytoplasm. In the absence of the rev gene, RNA splicing machinery in the nucleus quickly splices the RNA so that only the smaller, regulatory proteins can be produced; in the presence of rev, RNA is exported from the nucleus before it can be spliced, so that the structural proteins and RNA genome can be produced. Again, this mechanism allows a positive feedback loop to allow HIV to overwhelm the host's defenses, and provides time-dependent regulation of replication (a common process in viral infections)^[12]

Vpr

Stands for "Viral Protein R". Vpr, a 96 amino acid 14-kDa protein, plays an important role in regulating nuclear import of the HIV-1 pre-integration complex, and is required for virus replication in non-dividing cells such as macrophages. Vpr also induces cell cycle arrest and apoptosis in proliferating cells, which can result in immune dysfunction.^[13]^[14]
Vpr is also immunosuppressive due to its ability to sequester a proinflammatory transcriptional activator in the cytoplasm. HIV-2 contains both a Vpr protein and a related (by sequence homology) Vpx protein (Viral Protein X). Two functions of Vpr in HIV-1 are split between Vpr and Vpx in HIV-2, with the HIV-2 Vpr protein inducing cell cycle arrest and the Vpx protein required for nuclear import.

Other regulatory proteins

Nef

Stands for "Negative Regulatory Factor". The expression of Nef early in the viral life cycle ensures T cell activation and the establishment of a persistent state of infection, two basic attributes of HIV infection. Nef also promotes the survival of infected cells by downmodulating the expression of several surface molecules important in host immune function. These include major histocompatibility complex-I (MHC I) and MHC II present on antigen presenting cells (APCs) and target cells, CD4 and CD28 present on CD4+ T cells. One group of patients in Sydney were infected with a nef-deleted virus and took much longer than expected to progress to AIDS.^[15]
A nef-deleted virus vaccine has not been trialed in humans and has failed in nonhuman animals.HIV-1 Nef-induced FasL induction and bystander killing requires p38 MAPK activation.

Vif

Stands for "Viral infectivity factor". Vif is a 23-kilodalton protein that is essential for viral replication.^[12] Vif inhibits the cellular protein, APOBEC3G, from entering the virion during budding from a host cell by targeting it for proteasomal degredation. Vif hijacks the cellular Cullin5 E3 ubiquitin ligase in order to target APOBEC3G for degradation. In the absence of Vif, APOBEC3G causes hypermutation of the viral genome, rendering it dead-on-arrival at the next host cell. APOBEC3G is thus a host defence to retroviral infection which HIV-1 has overcome by the acquisition of Vif.

Vpu

Stands for "Viral Protein U". Vpu is involved in viral budding, enhancing virion release from the cell.

Tropism

HIV tropism refers to the cell type that the human immunodeficiency virus (HIV) infects and replicates in. HIV tropism of a patient's virus is measured by the Trofile assay.
HIV can infect a variety of cells such as CD4+ helper T-cells and macrophages that express the CD4 molecule on their surface. HIV-1 entry to macrophages and T helper cells is mediated not only through interaction of the virion envelope glycoproteins (gp120) with the CD4 molecule on the target cells but also with its chemokine coreceptors.
Macrophage (M-tropic) strains of HIV-1, or non-syncitia-inducing strains (NSI) use the beta-chemokine receptor CCR5 for entry and are thus able to replicate in macrophages and CD4+ T-cells ^[16]. The normal ligands for this receptor, RANTES, macrophage inflammatory protein (MIP)-1-beta and MIP-1-alpha, are able to suppress HIV-1 infection in vitro. This CCR5 coreceptor is used by almost all primary HIV-1 isolates regardless of viral genetic subtype.
T-tropic isolates, or syncitia-inducing (SI) strains replicate in primary CD4+ T-cells as well as in macrophages and use the alpha-chemokine receptor, CXCR4, for entry ^[16]. The alpha-chemokine, SDF-1, a ligand for CXCR4, suppresses replication of T-tropic HIV-1 isolates. It does this by down regulating the expression of CXCR4 on the surface of these cells.
Viruses that use only the CCR5 receptor are termed R5, those that only use CXCR4 are termed X4, and those that use both, X4R5. However, the use of coreceptor alone does not explain viral tropism, as not all R5 viruses are able to use CCR5 on macrophages for a productive infection ^[16].
HIV can also infect a subtype of dendritic cells ^[17], MDC-1, which probably constitute a major reservoir that maintains infection when T helper cell numbers have declined to extremely low levels.

Replication cycle

Image obtained from AIDSinfo.org http://aidsinfo.nih.gov/education-materials/fact-sheets/19/73/the-hiv-life-cycle

Steps in the HIV Replication Cycle

Fusion of the HIV cell to the host cell surface.
HIV RNA, reverse transcriptase, integrase, and other viral proteins enter the host cell.
Viral DNA is formed by reverse transcription.
Viral DNA is transported across the nucleus and integrates into the host DNA.
New viral RNA is used as genomic RNA and to make viral proteins.
New viral RNA and proteins move to cell surface and a new, immature, HIV virus forms.
The virus matures by protease releasing individual HIV proteins.

Schematic representation of the key structural features of HIV-1 entry into T cells. The two bottom images show alternate models for entry into cells. - By Rachid Sougrat, Alberto Bartesaghi, Jeffrey D. Lifson, Adam E. Bennett, Julian W. Bess, Daniel J. Zabransky, Sriram Subramaniam - Sougrat R, Bartesaghi A, Lifson JD, et al (May 2007). "Electron tomography of the contact between T cells and SIV/HIV-1: implications for viral entry". PLoS Pathog. 3 (5): e63. PMID 17480119. doi:10.1371/journal.ppat.0030063Direct link to image: http://www.plospathogens.org/article/showImageLarge.action?uri=info%3Adoi%2F10.1371%2Fjournal.ppat.0030063.g008, CC BY 2.5, https://commons.wikimedia.org/w/index.php?curid=4198856

The HIV replication cycle - By Translated by Raul654 - Originally from GFDL image Image:Hiv gross german.png, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=32862

Entry to the cell

HIV enters macrophages and CD4⁺ T cells by the adsorption of glycoproteins on its surface to receptors on the target cell followed by fusion of the viral envelope with the cell membrane and the release of the HIV capsid into the cell.^[18]^[19]
Entry to the cell begins through interaction of the trimeric envelope complex (gp160 spike, discussed above) and both CD4 and a chemokine receptor (generally either CCR5 or CXCR4, but others are known to interact) on the cell surface.^[18]^[19] The gp160 spike contains binding domains for both CD4 and chemokine receptors.^[18]^[19] The first step in fusion involves the high-affinity attachment of the CD4 binding domains of gp120 to CD4. Once gp120 is bound with the CD4 protein, the envelope complex undergoes a structural change, exposing the chemokine binding domains of gp120 and allowing them to interact with the target chemokine receptor.^[18]^[19] This allows for a more stable two-pronged attachment, which allows the N-terminal fusion peptide gp41 to penetrate the cell membrane.^[18]^[19] Repeat sequences in gp41, HR1 and HR2 then interact, causing the collapse of the extracellular portion of gp41 into a hairpin. This loop structure brings the virus and cell membranes close together, allowing fusion of the membranes and subsequent entry of the viral capsid.^[18]^[19]
Once HIV has bound to the target cell, the HIV RNA and various enzymes, including reverse transcriptase, integrase, ribonuclease and protease, are injected into the cell.^[18]
HIV can infect dendritic cells (DCs) by this CD4-CCR5 route, but another route using mannose-specific C-type lectin receptors such as DC-SIGN can also be used.^[20] DCs are one of the first cells encountered by the virus during sexual transmission. They are currently thought to play an important role by transmitting HIV to T cells once the virus has been captured in the mucosa by DCs.^[20]

Replication and transcription

Once the viral capsid enters the cell, an enzyme called reverse transcriptase liberates the single-stranded (+)RNA from the attached viral proteins and copies it into a complementary DNA.^[21] This process of reverse transcription is extremely error-prone and it is during this step that mutations may occur. Such mutations may cause drug resistance. The reverse transcriptase then makes a complementary DNA strand to form a double-stranded viral DNA intermediate (vDNA). This vDNA is then transported into the cell nucleus. The integration of the viral DNA into the host cell's genome is carried out by another viral enzyme called integrase.^[21]
This integrated viral DNA may then lie dormant, in the latent stage of HIV infection.^[21] To actively produce the virus, certain cellular transcription factors need to be present, the most important of which is NF-κB (NF kappa B), which is upregulated when T cells become activated.^[22] This means that those cells most likely to be killed by HIV are those currently fighting infection.
In this replication process, the integrated provirus is copied to mRNA which is then spliced into smaller pieces. These small pieces produce the regulatory proteins Tat (which encourages new virus production) and Rev. As Rev accumulates it gradually starts to inhibit mRNA splicing.^[23] At this stage, the structural proteins Gag and Env are produced from the full-length mRNA. The full-length RNA is actually the virus genome; it binds to the Gag protein and is packaged into new virus particles.
HIV-1 and HIV-2 appear to package their RNA differently; HIV-1 will bind to any appropriate RNA whereas HIV-2 will preferentially bind to the mRNA which was used to create the Gag protein itself. This may mean that HIV-1 is better able to mutate (HIV-1 infection progresses to AIDS faster than HIV-2 infection and is responsible for the majority of global infections).

Assembly and release

The final step of the viral cycle, assembly of new HIV-1 virons, begins at the plasma membrane of the host cell. The Env polyprotein (gp160) goes through the endoplasmic reticulum and is transported to the Golgi complex where it is cleaved by protease and processed into the two HIV envelope glycoproteins gp41 and gp120. These are transported to the plasma membrane of the host cell where gp41 anchors the gp120 to the membrane of the infected cell.
The Gag (p55) and Gag-Pol (p160) polyproteins also associate with the inner surface of the plasma membrane along with the HIV genomic RNA as the forming virion begins to bud from the host cell.
Maturation either occurs in the forming bud or in the immature virion after it buds from the host cell. During maturation, HIV proteases cleave the polyproteins into individual functional HIV proteins and enzymes. The various structural components then assemble to produce a mature HIV virion.^[24] This cleavage step can be inhibited by protease inhibitors. The mature virus is then able to infect another cell.

Genetic variability

HIV differs from many viruses in that it has very high genetic variability. This diversity is a result of its fast replication cycle, with the generation of 10⁹ to 10¹⁰ virions every day, coupled with a high mutation rate of approximately 3 x 10^-5 per nucleotide base per cycle of replication and recombinogenic properties of reverse transcriptase.^[25]
This complex scenario leads to the generation of many variants of HIV in a single infected patient in the course of one day.^[25] This variability is compounded when a single cell is simultaneously infected by two or more different strains of HIV. When simultaneous infection occurs, the genome of progeny virions may be composed of RNA strands from two different strains. This hybrid virion then infects a new cell where it undergoes replication. As this happens, the reverse transcriptase, by jumping back and forth between the two different RNA templates, will generate a newly synthesized retroviral DNA sequence that is a recombinant between the two parental genomes.^[25] This recombination is most obvious when it occurs between subtypes.^[25]
The closely related simian immunodeficiency virus (SIV) exhibits a somewhat different behavior: in its natural hosts, African green monkeys and sooty mangabeys, the retrovirus is present in high levels in the blood, but evokes only a mild immune response,^[26] does not cause the development of simian AIDS,^[27] and does not undergo the extensive mutation and recombination typical of HIV.^[28] By contrast, infection of heterologous hosts (rhesus or cynomologus macaques) with SIV results in the generation of genetic diversity that is on the same order as HIV in infected humans; these heterologous hosts also develop simian AIDS.^[29] The relationship, if any, between genetic diversification, immune response, and disease progression is unknown.
Three groups of HIV-1 have been identified on the basis of differences in env: M, N, and O.^[30] Group M is the most prevalent and is subdivided into eight subtypes (or clades), based on the whole genome, which are geographically distinct.^[31] The most prevalent are subtypes B (found mainly in North America and Europe), A and D (found mainly in Africa), and C (found mainly in Africa and Asia); these subtypes form branches in the phylogenetic tree representing the lineage of the M group of HIV-1. Coinfection with distinct subtypes gives rise to circulating recombinant forms (CRFs). In 2000, the last year in which an analysis of global subtype prevalence was made, 47.2% of infections worldwide were of subtype C, 26.7% were of subtype A/CRF02_AG, 12.3% were of subtype B, 5.3% were of subtype D, 3.2% were of CRF_AE, and the remaining 5.3% were composed of other subtypes and CRFs.^[32] Most HIV-1 research is focused on subtype B; few laboratories focus on the other subtypes.^[33]
The genetic sequence of HIV-2 is only partially homologous to HIV-1 and more closely resembles that of SIV than HIV-1.

The phylogenetic tree of the SIV and HIV (click on image for a detailed description). - By Kuiken, C., Foley, B., Hahn, B., Marx, P., McCutchan, F., Mellors, J. W., Mullins, J., Wolinsky, S. & Korber, B. (1999). A compilation and analysis of nucleic acid and amino acid sequences. In Human Retroviruses and AIDS. Los Alamos, New Mexico: Theoretical Biology and Biophysics Group, Los Alamos National Laboratory. - Theoretical Biology and Biophysics Group, Los Alamos National Laboratory.http://www.hiv.lanl.gov/content/sequence/HIV/COMPENDIUM/99compendium.htmlhttp://www.hiv.lanl.gov/content/sequence/HIV/COMPENDIUM/1999/1/intro.pdf, Public Domain, https://commons.wikimedia.org/w/index.php?curid=3915158

Map showing HIV-1 subtype prevalence. The bigger the pie chart, the more infections are present. - By The original uploader was Grcampbell at English WikipediaLater version(s) were uploaded by Renegadeviking, Emmojo666 at en.wikipedia.(Original text: en.User:Grcampbell) - Based on Osmanov S, Pattou C, Walker N, Schwardlander B, Esparza J; WHO-UNAIDS Network for HIV Isolation and Characterization. (2002) Estimated global distribution and regional spread of HIV-1 genetic subtypes in the year 2000. J Acquir Immune Defic Syndr. 29(2):184-90., CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=3745709

References

↑ ^1.0 ^1.1 "HIV monograph" (PDF).
↑ WainHobson, S., 1989. HIV genome variability in vivo. AIDS 3: supp 1; 139.
↑ Keele BF, van Heuverswyn F, Li YY; et al. (2006). "Chimpanzee Reservoirs of Pandemic and Nonpandemic HIV-1". Science. 313 (5786): 523–6. doi:10.1126/science.1126531. PMID 16728595.
↑ Cohen J (2000). "Vaccine Theory of AIDS Origins Disputed at Royal Society". Science. 289 (5486): 1850&ndash, 1851. doi:10.1126/science.289.5486.1850. PMID 11012346.
↑ BBC News: 3D Structure of HIV Revealed
↑ The SIV Surface Spike Imaged by Electron Tomography: One Leg or Three? Subramaniam S PLoS Pathogens Vol. 2, No. 8, e91 doi:10.1371/journal.ppat.0020091
↑ Distribution and three-dimensional structure of AIDS virus envelope spikes Ping Zhu, Jun Liu, Julian Bess, Jr, Elena Chertova, Jeffrey D. Lifson, Henry Grisé, Gilad A. Ofek, Kenneth A. Taylor and Kenneth H. Roux, Nature 441, 847-852 (15 June 2006) | doi:10.1038/nature04817; Received 8 March 2006; Accepted 24 April 2006; Published online 24 May 2006
↑ Jeang, K. T. (1996) In: Human Retroviruses and AIDS: A Compilation and Analysis of Nucleic Acid and Amino Acid Sequences. Los Alamos National Laboratory (Ed.) pp. III-3–III-18
↑ Kim JB, Sharp PA. (2001) Positive transcription elongation factor B phosphorylates hSPT5 and RNA polymerase II carboxyl-terminal domain independently of cyclin-dependent kinase-activating kinase. J. Biol. Chem. 276, 12317-12323 PMID 11145967
↑ ^10.0 ^10.1 Xiao, H., Neuveut, C., Tiffany, H. L., Benkirane, M., Rich, E. A., Murphy, P. M. and Jeang, K. T. (2000) Selective CXCR4 antagonism by Tat: implications for in vivo expansion of coreceptor use by HIV-1. Proc. Natl. Acad. Sci. U.S.A. 97, 11466-11471 PMID 11027346
↑ Campbell GR, Pasquier E, Watkins J, Bourgarel-Rey V, Peyrot V, Esquieu D, Barbier P, de Mareuil J, Braguer D, Kaleebu P, Yirrell DL, Loret EP. (2004) The glutamine-rich region of the HIV-1 Tat protein is involved in T-cell apoptosis. J. Biol. Chem. 279, 48197-48204 PMID 15331610
↑ ^12.0 ^12.1 Strebel, K (2003) Virus-host interactions: role of HIV proteins Vif, Tat, and Rev. AIDS 17 Suppl 4, S25-S34 PMID 15080177
↑ Bukrinsky M, Adzhubei A. (1999) Viral protein R of HIV-1. Rev Med Virol 9, 39-49 PMID 10371671
↑ Muthumani K., et al (2006) The HIV-1 Vpr and glucocorticoid receptor complex: A gain of function interaction that prevents the nuclear localization of PARP-1. Nat Cell Biol. Feb;8(2):170-9.
↑ Learmont JC, Geczy AF, Mills J, Ashton LJ, Raynes-Greenow CH, Garsia RJ, Dyer WB, McIntyre L, Oelrichs RB, Rhodes DI, Deacon NJ, Sullivan JS. (1999) Immunologic and virologic status after 14 to 18 years of infection with an attenuated strain of HIV-1. A report from the Sydney Blood Bank Cohort. N Engl J Med 340, 1715-1722 PMID 10352163
↑ ^16.0 ^16.1 ^16.2 Coakley, E., Petropoulos, C. J. and Whitcomb, J. M. (2005). "Assessing chemokine co-receptor usage in HIV". Curr. Opin. Infect. Dis. 18 (1): 9–15. PMID 15647694.
↑ Knight, S. C., Macatonia, S. E. and Patterson, S. (1990). "HIV I infection of dendritic cells". Int. Rev. Immunol. 6 (2–3): 163–175. PMID 2152500.
↑ ^18.0 ^18.1 ^18.2 ^18.3 ^18.4 ^18.5 ^18.6 Chan D, Kim P (1998). "HIV entry and its inhibition". Cell. 93 (5): 681–4. PMID 9630213.
↑ ^19.0 ^19.1 ^19.2 ^19.3 ^19.4 ^19.5 Wyatt R, Sodroski J (1998). "The HIV-1 envelope glycoproteins: fusogens, antigens, and immunogens". Science. 280 (5371): 1884–8. doi:10.1126/science.280.5371.1884. PMID 9632381.
↑ ^20.0 ^20.1 Pope M, Haase A (2003). "Transmission, acute HIV-1 infection and the quest for strategies to prevent infection". Nat Med. 9 (7): 847–52. PMID 12835704.
↑ ^21.0 ^21.1 ^21.2 Zheng, Y. H., Lovsin, N. and Peterlin, B. M. (2005). "Newly identified host factors modulate HIV replication". Immunol. Lett. 97 (2): 225–234. PMID 15752562.
↑ Hiscott J, Kwon H, Genin P. (2001). "Hostile takeovers: viral appropriation of the NF-kappaB pathway". J Clin Invest. 107 (2): 143–151. PMID 11160127.
↑ Pollard, V. W. and Malim, M. H. (1998). "The HIV-1 Rev protein". Annu. Rev. Microbiol. 52: 491–532. PMID 9891806.
↑ Gelderblom, H. R (1997). "Fine structure of HIV and SIV" (PDF). In Los Alamos National Laboratory (ed.). HIV Sequence Compendium (PDF format)|format= requires |url= (help). Los Alamos, New Mexico: Los Alamos National Laboratory. pp. 31–44.
↑ ^25.0 ^25.1 ^25.2 ^25.3 Robertson DL, Hahn BH, Sharp PM. (1995). "Recombination in AIDS viruses". J Mol Evol. 40 (3): 249–259. PMID 7723052.
↑ Holzammer S, Holznagel E, Kaul A, Kurth R, Norley S (2001). "High virus loads in naturally and experimentally SIVagm-infected African green monkeys". Virology. 283 (2): 324–31. doi:10.1006/viro.2001.0870. PMID 11336557.
↑ Kurth, R. and Norley, S. (1996) Why don't the natural hosts of SIV develop simian AIDS?, J. NIH Res. 8, 33-37.
↑ Baier M, Dittmar MT, Cichutek K, Kurth R (1991). "Development of vivo of genetic variability of simian immunodeficiency virus". Proc. Natl. Acad. Sci. U.S.A. 88 (18): 8126–30. PMID 1896460.
↑ Daniel MD, King NW, Letvin NL, Hunt RD, Sehgal PK, Desrosiers RC (1984). "A new type D retrovirus isolated from macaques with an immunodeficiency syndrome". Science. 223 (4636): 602–5. doi:10.1126/science.6695172. PMID 6695172.
↑ Thomson, M. M., Perez-Alvarez, L. and Najera, R. (2002). "Molecular epidemiology of HIV-1 genetic forms and its significance for vaccine development and therapy". Lancet Infect. Dis. 2 (8): 461–471. PMID 12150845.
↑ Carr, J. K. (1998). "Reference Sequences Representing the Principal Genetic Diversity of HIV-1 in the Pandemic" (PDF). In Los Alamos National Laboratory (ed.). HIV Sequence Compendium (PDF format)|format= requires |url= (help). Los Alamos, New Mexico: Los Alamos National Laboratory. pp. 10–19. Unknown parameter |coauthors= ignored (help)
↑ Osmanov S, Pattou C, Walker N, Schwardlander B, Esparza J; WHO-UNAIDS Network for HIV Isolation and Characterization. (2002). "Estimated global distribution and regional spread of HIV-1 genetic subtypes in the year 2000". Acquir. Immune. Defic. Syndr. 29 (2): 184–190. PMID 11832690.
↑ Perrin L, Kaiser L, Yerly S. (2003). "Travel and the spread of HIV-1 genetic variants". Lancet Infect Dis. 3 (1): 22–27. PMID 12505029.

External links

Genome at sc.edu

[HIV-1] 1.0 ^1.1 "HIV monograph" (PDF).

[2] WainHobson, S., 1989. HIV genome variability in vivo. AIDS 3: supp 1; 139.

[Keele-3] Keele BF, van Heuverswyn F, Li YY; et al. (2006). "Chimpanzee Reservoirs of Pandemic and Nonpandemic HIV-1". Science. 313 (5786): 523–6. doi:10.1126/science.1126531. PMID 16728595.

[CohenOrigns-4] Cohen J (2000). "Vaccine Theory of AIDS Origins Disputed at Royal Society". Science. 289 (5486): 1850&ndash, 1851. doi:10.1126/science.289.5486.1850. PMID 11012346.

[5] BBC News: 3D Structure of HIV Revealed

[6] The SIV Surface Spike Imaged by Electron Tomography: One Leg or Three? Subramaniam S PLoS Pathogens Vol. 2, No. 8, e91 doi:10.1371/journal.ppat.0020091

[7] Distribution and three-dimensional structure of AIDS virus envelope spikes Ping Zhu, Jun Liu, Julian Bess, Jr, Elena Chertova, Jeffrey D. Lifson, Henry Grisé, Gilad A. Ofek, Kenneth A. Taylor and Kenneth H. Roux, Nature 441, 847-852 (15 June 2006) | doi:10.1038/nature04817; Received 8 March 2006; Accepted 24 April 2006; Published online 24 May 2006

[8] Jeang, K. T. (1996) In: Human Retroviruses and AIDS: A Compilation and Analysis of Nucleic Acid and Amino Acid Sequences. Los Alamos National Laboratory (Ed.) pp. III-3–III-18

[9] Kim JB, Sharp PA. (2001) Positive transcription elongation factor B phosphorylates hSPT5 and RNA polymerase II carboxyl-terminal domain independently of cyclin-dependent kinase-activating kinase. J. Biol. Chem. 276, 12317-12323 PMID 11145967

[Xiao-10] 10.0 ^10.1 Xiao, H., Neuveut, C., Tiffany, H. L., Benkirane, M., Rich, E. A., Murphy, P. M. and Jeang, K. T. (2000) Selective CXCR4 antagonism by Tat: implications for in vivo expansion of coreceptor use by HIV-1. Proc. Natl. Acad. Sci. U.S.A. 97, 11466-11471 PMID 11027346

[11] Campbell GR, Pasquier E, Watkins J, Bourgarel-Rey V, Peyrot V, Esquieu D, Barbier P, de Mareuil J, Braguer D, Kaleebu P, Yirrell DL, Loret EP. (2004) The glutamine-rich region of the HIV-1 Tat protein is involved in T-cell apoptosis. J. Biol. Chem. 279, 48197-48204 PMID 15331610

[Strebel-12] 12.0 ^12.1 Strebel, K (2003) Virus-host interactions: role of HIV proteins Vif, Tat, and Rev. AIDS 17 Suppl 4, S25-S34 PMID 15080177

[13] Bukrinsky M, Adzhubei A. (1999) Viral protein R of HIV-1. Rev Med Virol 9, 39-49 PMID 10371671

[14] Muthumani K., et al (2006) The HIV-1 Vpr and glucocorticoid receptor complex: A gain of function interaction that prevents the nuclear localization of PARP-1. Nat Cell Biol. Feb;8(2):170-9.

[15] Learmont JC, Geczy AF, Mills J, Ashton LJ, Raynes-Greenow CH, Garsia RJ, Dyer WB, McIntyre L, Oelrichs RB, Rhodes DI, Deacon NJ, Sullivan JS. (1999) Immunologic and virologic status after 14 to 18 years of infection with an attenuated strain of HIV-1. A report from the Sydney Blood Bank Cohort. N Engl J Med 340, 1715-1722 PMID 10352163

[Coakley-16] 16.0 ^16.1 ^16.2 Coakley, E., Petropoulos, C. J. and Whitcomb, J. M. (2005). "Assessing chemokine co-receptor usage in HIV". Curr. Opin. Infect. Dis. 18 (1): 9–15. PMID 15647694.

[Knight-17] Knight, S. C., Macatonia, S. E. and Patterson, S. (1990). "HIV I infection of dendritic cells". Int. Rev. Immunol. 6 (2–3): 163–175. PMID 2152500.

[Chan2-18] 18.0 ^18.1 ^18.2 ^18.3 ^18.4 ^18.5 ^18.6 Chan D, Kim P (1998). "HIV entry and its inhibition". Cell. 93 (5): 681–4. PMID 9630213.

[Wyatt-19] 19.0 ^19.1 ^19.2 ^19.3 ^19.4 ^19.5 Wyatt R, Sodroski J (1998). "The HIV-1 envelope glycoproteins: fusogens, antigens, and immunogens". Science. 280 (5371): 1884–8. doi:10.1126/science.280.5371.1884. PMID 9632381.

[Pope_2003-20] 20.0 ^20.1 Pope M, Haase A (2003). "Transmission, acute HIV-1 infection and the quest for strategies to prevent infection". Nat Med. 9 (7): 847–52. PMID 12835704.

[Zheng-21] 21.0 ^21.1 ^21.2 Zheng, Y. H., Lovsin, N. and Peterlin, B. M. (2005). "Newly identified host factors modulate HIV replication". Immunol. Lett. 97 (2): 225–234. PMID 15752562.

[Hiscott-22] Hiscott J, Kwon H, Genin P. (2001). "Hostile takeovers: viral appropriation of the NF-kappaB pathway". J Clin Invest. 107 (2): 143–151. PMID 11160127.

[Pollard-23] Pollard, V. W. and Malim, M. H. (1998). "The HIV-1 Rev protein". Annu. Rev. Microbiol. 52: 491–532. PMID 9891806.

[Gelderblom-24] Gelderblom, H. R (1997). "Fine structure of HIV and SIV" (PDF). In Los Alamos National Laboratory (ed.). HIV Sequence Compendium (PDF format)|format= requires |url= (help). Los Alamos, New Mexico: Los Alamos National Laboratory. pp. 31–44.

[RobertsonDL-25] 25.0 ^25.1 ^25.2 ^25.3 Robertson DL, Hahn BH, Sharp PM. (1995). "Recombination in AIDS viruses". J Mol Evol. 40 (3): 249–259. PMID 7723052.

[26] Holzammer S, Holznagel E, Kaul A, Kurth R, Norley S (2001). "High virus loads in naturally and experimentally SIVagm-infected African green monkeys". Virology. 283 (2): 324–31. doi:10.1006/viro.2001.0870. PMID 11336557.

[27] Kurth, R. and Norley, S. (1996) Why don't the natural hosts of SIV develop simian AIDS?, J. NIH Res. 8, 33-37.

[28] Baier M, Dittmar MT, Cichutek K, Kurth R (1991). "Development of vivo of genetic variability of simian immunodeficiency virus". Proc. Natl. Acad. Sci. U.S.A. 88 (18): 8126–30. PMID 1896460.

[29] Daniel MD, King NW, Letvin NL, Hunt RD, Sehgal PK, Desrosiers RC (1984). "A new type D retrovirus isolated from macaques with an immunodeficiency syndrome". Science. 223 (4636): 602–5. doi:10.1126/science.6695172. PMID 6695172.

[Thomson-30] Thomson, M. M., Perez-Alvarez, L. and Najera, R. (2002). "Molecular epidemiology of HIV-1 genetic forms and its significance for vaccine development and therapy". Lancet Infect. Dis. 2 (8): 461–471. PMID 12150845.

[Carr-31] Carr, J. K. (1998). "Reference Sequences Representing the Principal Genetic Diversity of HIV-1 in the Pandemic" (PDF). In Los Alamos National Laboratory (ed.). HIV Sequence Compendium (PDF format)|format= requires |url= (help). Los Alamos, New Mexico: Los Alamos National Laboratory. pp. 10–19. Unknown parameter |coauthors= ignored (help)

[Osmanov-32] Osmanov S, Pattou C, Walker N, Schwardlander B, Esparza J; WHO-UNAIDS Network for HIV Isolation and Characterization. (2002). "Estimated global distribution and regional spread of HIV-1 genetic subtypes in the year 2000". Acquir. Immune. Defic. Syndr. 29 (2): 184–190. PMID 11832690.

[Perrin-33] Perrin L, Kaiser L, Yerly S. (2003). "Travel and the spread of HIV-1 genetic variants". Lancet Infect Dis. 3 (1): 22–27. PMID 12505029.

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@@ Line 1: / Line 1: @@
-{{Taxobox | color=violet
+<div style="-webkit-user-select: none;">
-| name = ''Human immunodeficiency virus''
+{|class="infobox" style="position: fixed; top: 65%; right: 10px; margin: 0 0 0 0; border: 0; float: right;
-| image = Aids virus.jpg
-| image_width = 100px
-| image_caption = Stylized rendering of a cross section<br /> of the human immunodeficiency virus
-| virus_group = vi
-| familia = ''[[Retroviridae]]''
-| genus = ''[[Lentivirus]]''
-| subdivision_ranks = Species
-| subdivision =
-* '''''Human immunodeficiency virus 1'''''
-* '''''Human immunodeficiency virus 2'''''
-}}
-{{DiseaseDisorder infobox |
- Name = International Statistical Classification of Diseases and Related Health Problems Codes |
- ICD10 = B20-B24 |
- ICD9 = {{ICD9|042}}-{{ICD9|044}} |
-}}
-'''To read more about AIDS''', click [[AIDS|'''here''']].
-'''To read about the difference between HIV & AIDS,''' click [[AIDS classification#Comparison between AIDS & HIV|'''here''']].
-{{CMG}}
-{{AIDS}}
-==Overview==
-'''Human immunodeficiency virus''' ('''HIV''') is a [[retrovirus]] that can lead to ''[[acquired immunodeficiency syndrome]]'' (AIDS), a condition in [[human]]s in which the [[immune system]] begins to fail, leading to life-threatening opportunistic infections. Previous names for the [[virus]] include '''human T-lymphotropic virus-III''' ('''HTLV-III'''), '''lymphadenopathy-associated virus''' ('''LAV'''), and '''AIDS-associated retrovirus''' ('''ARV''').<ref>{{cite web| author=Rick Sowadsky| year=1999 |url=http://thebody.org/Forums/AIDS/safesex/Archive/origins/Q8777.html |title=What is HTLV-III?| accessdate=2006-08-24}}</ref><ref name=Coffin>{{cite journal
-| author=Coffin, J., Haase, A., Levy, J. A., Montagnier, L., Oroszlan, S., Teich, N., Temin, H., Toyoshima, K., Varmus, H., Vogt, P. and Weiss, R. A. | title=What to call the AIDS virus? | journal=Nature | year=1986 | pages=10 | volume=321 | issue=6065 | pmid=3010128 |format=}}</ref>
-Infection with HIV occurs by the transfer of [[blood]], [[semen]], [[vaginal fluid]], [[pre-ejaculate]], or [[breast milk]]. Within these bodily fluids, HIV is present as both free virus particles and virus within infected immune cells. The four major routes of transmission are [[unprotected sex|unprotected sexual intercourse]], contaminated needles, breast milk, and transmission from an infected mother to her baby at [[childbirth|birth]]. Screening of blood products for HIV has largely eliminated transmission through blood transfusions or infected blood products in the developed world.
-HIV infection in humans is now [[pandemic]]. As of January 2006, the [[Joint United Nations Programme on HIV/AIDS]] (UNAIDS) and the [[World Health Organization]] (WHO) estimate that AIDS has killed more than 25 million people since it was first recognized on December 1, 1981, making it one of the most destructive [[AIDS pandemic|pandemics]] in recorded history.  It is estimated that about 0.6% of the world's population is infected with HIV.<ref name=UNAIDS2006>{{cite book
- | author =[[Joint United Nations Programme on HIV/AIDS]]
- | year = 2006
- | title = 2006 Report on the global AIDS epidemic
- | chapter = Overview of the global AIDS epidemic
- | chapterurl = http://data.unaids.org/pub/GlobalReport/2006/2006_GR_CH02_en.pdf
- | accessdate = 2006-06-08
- | format= [[PDF|PDF format]]
-}}</ref> In 2005 alone, AIDS claimed an estimated 2.4&ndash;3.3 million lives, of which more than 570,000 were children. A third of these deaths are occurring in sub-Saharan Africa, retarding economic growth and increasing poverty.<ref name=Greener>{{cite book
- | author =Greener, R.
- | year = 2002
- | title = State of The Art: AIDS and Economics
- | chapter = AIDS and macroeconomic impact
- | chapterurl = http://www.iaen.org/library/statepidemic/chapter7.pdf
- | editor = S, Forsyth (ed.)
- | edition =
- | pages = 49-55
- | publisher = IAEN
- | format= PDF
- | location =
-}}</ref> According to current estimates, HIV is set to infect 90 million people in Africa, resulting in a minimum estimate of 18 million orphans.<ref name=UNAIDS>{{cite web
- | author=[[Joint United Nations Programme on HIV/AIDS]]
- | publisher=
- | publishyear= 2005
- | url=http://www.unaids.org/Epi2005/doc/EPIupdate2005_pdf_en/epi-update2005_en.pdf
- | title=AIDS epidemic update, 2005
- | accessdate=2006-02-28|format=[[PDF|PDF format]]
-}}</ref> [[antiretroviral drug|Antiretroviral]] treatment reduces both the [[Mortality rate|mortality]] and the [[morbidity]] of HIV infection, but routine access to antiretroviral medication is not available in all countries.<ref name=Palella>{{cite journal
- | author=Palella, F. J. Jr, Delaney, K. M., Moorman, A. C., Loveless, M. O., Fuhrer, J., Satten, G. A., Aschman and D. J., Holmberg, S. D.
- | title=Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators
- | journal=N. Engl. J. Med
- | year=1998
- | pages=853-860
- | volume=338
- | issue=13
- | pmid=9516219
- | format=
-}}</ref>
-HIV primarily infects vital cells in the [[human]] [[immune system]] such as [[helper T cell]]s (specifically CD4<SUP>+</SUP> T cells), [[macrophages]] and [[dendritic cells]]. HIV infection leads to low levels of CD4<SUP>+</SUP> T cells through three main mechanisms: firstly, direct viral killing of infected cells; secondly, increased rates of [[apoptosis]] in infected cells; and thirdly, killing of infected CD4<SUP>+</SUP> T cells by [[CD8 cytotoxic lymphocyte]]s that recognize infected cells. When CD4<SUP>+</SUP> T cell numbers decline below a critical level, [[cell-mediated immunity]] is lost, and the body becomes progressively more susceptible to opportunistic infections. If untreated, eventually most HIV-infected individuals develop [[AIDS|AIDS (Acquired Immunodeficiency Syndrome)]] and die; however about one in ten remains healthy for many years, with no noticeable symptoms.<ref name=Buchbinder>{{cite journal
- | author=Buchbinder SP, Katz MH, Hessol NA, O'Malley PM, Holmberg SD.
- | title=Long-term HIV-1 infection without immunologic progression.
- | journal=AIDS
- | year=1994
- | pages=1123-1128
- | volume=8
- | issue=8
- | pmid=7986410
- | format=
-}}</ref> Treatment with anti-retrovirals, where available, increases the life expectancy of people infected with HIV. It is hoped that current and future treatments may allow HIV-infected individuals to achieve a life expectancy approaching that of the general public.
-==Origin and discovery==
-:''See [[AIDS origin]]''
-==Classification==
-HIV is a member of the genus [[Lentivirus]],<ref name=ICTV61.0.6>{{cite web
- | author=[[International Committee on Taxonomy of Viruses]]
- | publisher=[[National Institutes of Health]]
- | publishyear=2002
- | url=http://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/61060000.htm
- | title=61.0.6. Lentivirus
- | accessdate=2006-02-28
-}}</ref> part of the family of [[Retroviridae]].<ref name=ICTV61.>{{cite web
- | author=[[International Committee on Taxonomy of Viruses]]
- | publisher=[[National Institutes of Health]]
- | publishyear=2002
- | url=http://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/61000000.htm
- | title=61. Retroviridae
- | accessdate=2006-02-28
-}}</ref> Lentiviruses have many common morphologies and biological properties. Many species are infected by lentiviruses, which are characteristically responsible for long-duration illnesses with a long incubation period.<ref name=Levy>{{cite journal
- | author=Lévy, J. A.
- | title=HIV pathogenesis and long-term survival
- | journal=AIDS
- | year=1993
- | pages=1401-1410
- | volume=7
- | issue=11
- | pmid=8280406
- | format=
-}}</ref> Lentiviruses are transmitted as single-stranded, positive-[[Sense (molecular biology)|sense]], enveloped [[RNA virus]]es. Upon entry of the target cell, the viral RNA [[genome]] is converted to double-stranded [[DNA]] by a virally encoded [[reverse transcriptase]] that is present in the virus particle. This viral DNA is then integrated into the cellular DNA by a virally encoded [[integrase]] so that the genome can be [[Transcription (genetics)|transcribed]]. Once the virus has infected the cell, two pathways are possible: either the virus becomes [[Incubation period|latent]] and the infected cell continues to function, or the virus becomes active and replicates, and a large number of virus particles are liberated that can then infect other cells.
-Two species of HIV infect humans: HIV-1 and HIV-2.  HIV-1 is thought to have originated in southern Cameroon after jumping from wild chimpanzees (''Pan troglodytes troglodytes'') to humans during the twentieth century.<ref name=Gao>{{cite journal
- | author=Gao, F., Bailes, E., Robertson, D. L., Chen, Y., Rodenburg, C. M., Michael, S. F., Cummins, L. B., Arthur, L. O., Peeters, M., Shaw, G. M., Sharp, P. M., and Hahn, B. H.
- | title=Origin of HIV-1 in the Chimpanzee Pan troglodytes troglodytes
- | journal=Nature
- | year=1999
- | pages=436-441
- | volume=397
- | issue=6718
- | pmid=9989410
- | doi=10.1038/17130
- | format=
-}}</ref><ref name=Keele>{{cite journal
- | author=Keele, B. F., van Heuverswyn, F., Li, Y. Y., Bailes, E., Takehisa, J., Santiago, M. L., Bibollet-Ruche, F., Chen, Y., Wain, L. V., Liegois, F., Loul, S., Mpoudi Ngole, E., Bienvenue, Y., Delaporte, E., Brookfield, J. F. Y., Sharp, P. M., Shaw, G. M., Peeters, M., and Hahn, B. H.
- | title=Chimpanzee Reservoirs of Pandemic and Nonpandemic HIV-1
- | journal=Science | year=2006 | pages= | volume=Online [[2006-05-25]] | issue=
- | url= http://www.sciencemag.org/cgi/content/abstract/1126531
- | doi = 10.1126/science.1126531
- | format=
-}}</ref> HIV-1 is the virus that was initially discovered and termed LAV. It is more virulent and relatively easy transmitted and is the cause of the majority of HIV infections globally.  HIV-2 may have originated from the Sooty Mangabey (''Cercocebus atys''), an Old World monkey of Guinea-Bissau, Gabon, and Cameroon.<ref name=Reeves>{{cite journal
- | author=Reeves, J. D. and Doms, R. W
- | title=Human Immunodeficiency Virus Type 2
- | journal=J. Gen. Virol. | year=2002 | pages=1253-1265 | volume=83 | issue=Pt 6
- | pmid=12029140
-}}</ref> HIV-2 is less transmittable than HIV-1 and is largely confined to West Africa.<ref name=Reeves>{{cite journal
- | author=Reeves, J. D. and Doms, R. W
- | title=Human Immunodeficiency Virus Type 2
- | journal=J. Gen. Virol. | year=2002 | pages=1253-1265 | volume=83 | issue=Pt 6
- | pmid=12029140
-}}</ref>
-==Early history==
-:''See [[AIDS origin#History of known cases and spread|History of known cases and spread]] for early cases of HIV / AIDS''
-==Transmission==
-:''For more details on this topic, see [[AIDS#Transmission and prevention|AIDS transmission and prevention]]''
-{| class="prettytable" style="float:right; font-size:85%; margin-left:15px;"
-|- bgcolor="#efefef"
-! colspan=5 style="border-right:0px;";| Estimated per act risk for acquisition<br/>of HIV-1 by exposure route<ref name=MMWR>{{cite journal | author=Smith, D. K., Grohskopf, L. A., Black, R. J., Auerbach, J. D., Veronese, F., Struble, K. A., Cheever, L., Johnson, M., Paxton, L. A., Onorato, I. A. and Greenberg, A. E. | title=Antiretroviral Postexposure Prophylaxis After Sexual, Injection-Drug Use, or Other Nonoccupational Exposure to HIV in the United States | journal=MMWR | year=2005 | pages=1-20 | volume=54 | issue=RR02 | url=http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5402a1.htm#tab1}}</ref>
-|- bgcolor="#efefef"
-| align="center" style="width: 100px"|'''Exposure Route'''
-| align="center" style="width: 130px"|'''Estimated infections<br/>per 10,000 exposures<br/>to an infected source'''
 |-
-| Blood Transfusion
+| {{#ev:youtube|https://https://www.youtube.com/watch?v=5g1ijpBI6Dk|350}}
-| align="center" | 9,000<ref name=Donegan>{{cite journal
- | author=Donegan, E., Stuart, M., Niland, J. C., Sacks, H. S., Azen, S. P., Dietrich, S. L., Faucett, C., Fletcher, M. A., Kleinman, S. H., Operskalski, E. A., et al.
- | title=Infection with human immunodeficiency virus type 1 (HIV-1) among recipients of antibody-positive blood donations
- | journal=Ann. Intern. Med.
- | year=1990
- | pages=733-739
- | volume=113
- | issue=10
- | pmid=2240875
-}}</ref>
-|-
-| Childbirth
-| align="center" | 2,500<ref name=Coovadia>{{cite journal
- | author=Coovadia, H.
- | title=Antiretroviral agents&mdash;how best to protect infants from HIV and save their mothers from AIDS | journal=N. Engl. J. Med.
- | year=2004
- | pages=289-292
- | volume=351
- | issue=3
- | pmid=15247337
- | format=
-}}</ref>
 |-
-| Needle-sharing injection drug use
-| align="center" | 67<ref name=Kaplan>{{cite journal | author=Kaplan, E. H. and Heimer, R. | title=HIV incidence among New Haven needle exchange participants: updated estimates from syringe tracking and testing data | journal=J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. | year=1995 | pages=175-176 | volume=10 | issue=2
- | pmid=7552482 }}</ref>
-|-
-| Receptive anal intercourse<sup>*</sup>
-| align="center" | 50<ref name=ESG>{{cite journal | author=European Study Group on Heterosexual Transmission of HIV | title=Comparison of female to male and male to female transmission of HIV in 563 stable couples | journal=BMJ. | year=1992 | pages=809-813 | volume=304 | issue=6830 | pmid=1392708 |format=}}</ref><ref name=Varghese>{{cite journal | author=Varghese, B., Maher, J. E., Peterman, T. A., Branson, B. M. and Steketee, R. W. | title=Reducing the risk of sexual HIV transmission: quantifying the per-act risk for HIV on the basis of choice of partner, sex act, and condom use | journal=Sex. Transm. Dis. | year=2002 | pages=38-43 | volume=29 | issue=1 | pmid=11773877 |format=}}</ref>
-|-
-| Percutaneous needle stick
-| align="center" | 30<ref name=Bell>{{
- cite journal | author=Bell, D. M. | title=Occupational risk of human immunodeficiency virus infection in healthcare workers: an overview. | journal=Am. J. Med. | year=1997 | pages=9-15 | volume=102 | issue=5B | pmid=9845490
-}}</ref>
-|-
-| Receptive penile-vaginal intercourse<sup>*</sup>
-| align="center" | 10<ref name=ESG /><ref name=Varghese /><ref name=Leynaert>{{
- cite journal | author=Leynaert, B., Downs, A. M. and de Vincenzi, I. | title=Heterosexual transmission of human immunodeficiency virus: variability of infectivity throughout the course of infection. European Study Group on Heterosexual Transmission of HIV | journal=Am. J. Epidemiol. | year=1998 | pages=88-96 | volume=148 | issue=1 | pmid=9663408
-}}</ref>
-|-
-| Insertive anal intercourse<sup>*</sup>
-| align="center" | 6.5<ref name=ESG /><ref name=Varghese />
-|-
-| Insertive penile-vaginal [[sexual intercourse|intercourse]]<sup>*</sup>
-| align="center" | 5<ref name=ESG /><ref name=Varghese />
-|-
-| Receptive [[fellatio]]<sup>*</sup>
-| align="center" | 1<ref name=Varghese />
-|-
-| Insertive fellatio<sup>*</sup>
-| align="center" | 0.5<ref name=Varghese />
-|- bgcolor="#efefef"
-! colspan=5 style="border-right:0px;";| <sup>*</sup> assuming no condom use </br>
 |}
-Since the beginning of the [[pandemic]], three main transmission routes for HIV have been identified:
+__NOTOC__
-*'''Sexual route.''' The majority of HIV infections are acquired through unprotected sexual relations. Sexual transmission can occur when infected sexual secretions of one partner come into contact with the genital, oral, or rectal [[mucous membranes]] of another.
+{{AIDS}}
-*'''Blood or blood product route.''' This transmission route can account for infections in intravenous drug users, [[hemophiliac]]s and recipients of [[blood transfusion]]s (though most transfusions are checked for HIV in the developed world) and blood products. It is also of concern for persons receiving medical care in regions where there is prevalent substandard hygiene in the use of injection equipment, such as the reuse of needles in Third World countries. HIV can also be spread through the sharing of needles. Health care workers such as nurses, laboratory workers, and doctors, have also been infected, although this occurs more rarely. People who give and receive tattoos, piercings, and scarification procedures can also be at risk of infection.
+{{CMG}}; {{AE}} {{Ammu}}, {{AL}}
-*'''Mother-to-child transmission''' (MTCT). The transmission of the virus from the mother to the child can occur ''in utero'' during pregnancy and ''intrapartum'' at childbirth. In the absence of treatment, the transmission rate between the mother and child is around 25%.<ref name=Coovadia /> However, where combination [[antiretroviral]] drug treatment and [[Cesarian section]] are available, this risk can be reduced to as low as 1%.<ref name=Coovadia /> Breast feeding also presents a risk of infection for the baby.
+==Overview==
+AIDS is caused by the human immunodeficiency virus (HIV). HIV is a [[retrovirus]] classified into the family of ''[[Retroviridae]]'' and the sub family ''[[orthoretroviridae]]''.<ref name=HIV>{{cite web | title =HIV monograph| url = http://monographs.iarc.fr/ENG/Monographs/vol100B/mono100B-10.pdf }}</ref>.  Two main subspecies of HIV exist: HIV-1, and HIV-2. HIV-1 is composed of two copies of single-stranded [[RNA]] enclosed by a conical [[capsid]] comprising the viral protein p24. The [[genome]] consists of several major [[genes]] that code for structural and functional [[protein]]s. These include the ''gag'', ''pol'', ''env'', ''tat'', and ''nef'' [[gene]]s. The [[genome]] and [[proteins]] of [[HIV]] have been the subject of extensive research since the discovery of the [[virus]] in 1983. It is a well known fact that no two HIV [[genome]]s are the same, not even from the same person, causing some to speculate that HIV is a "[[Quasispecies model|quasispecies]]" of a [[virus]].<ref>WainHobson, S., 1989. HIV genome variability in vivo. AIDS 3: supp 1; 139.</ref>  A major requirement for all [[retroviruses]] is [[reverse transcriptase]] that transcribes the [[viral RNA]] into [[double-stranded DNA]] and [[integrase]] that integrates this newly formed [[DNA]] into the host [[genome]].
-HIV-2 is transmitted much less frequently by the MTCT and sexual route than HIV-1.
+==Taxonomy==
+* HIV 1 and HIV 2 are classified into the family of ''[[Retroviridae]]'' and sub family ''orthoretroviridae''.<ref name=HIV>{{cite web | title =HIV monograph| url = http://monographs.iarc.fr/ENG/Monographs/vol100B/mono100B-10.pdf }}</ref>
+* Retrovirus are enveloped [[RNA]] viruses which requires a [[DNA]] intermediate to replicate.
+* HIV 1 and HIV 2 belongs to the genus [[Lentivirus]] (Lentus which in latin means slow)
+* The [[retrovirus]] rely on [[enzyme]] [[reverse transcriptase]] to transcribe their genome from [[RNA]] to [[DNA]].
+* [[Integrase]] incorporates the [[DNA]] into the host [[DNA]] and becomes a part of cellular [[DNA]] replicating with it.
-HIV has been found at low concentrations in the [[saliva]], [[tears]] and [[urine]] of infected individuals, but there are no recorded cases of infection by these secretions and the potential risk of transmission is negligible.<ref name="pmid2963151">{{cite journal
+==Origin==
-|author=Lifson AR
+* Both HIV-1 and HIV-2 are of primate origin. The origin of HIV-1 is the Central Common Chimpanzee (''Pan troglodytes troglodytes'') found in southern Cameroon.<ref name=Keele>{{
-|title=Do alternate modes for transmission of human immunodeficiency virus exist? A review
-|journal=JAMA
-|volume=259
-|issue=9
-|pages=1353–6
-|year=1988
-|pmid=2963151
-|doi=
-}}</ref> The use of physical barriers such as the latex [[condom]] is widely advocated to reduce the sexual transmission of HIV. [[Spermicide]], when used alone or with vaginal contraceptives like a [[diaphragm (contraceptive)|diaphragm]], actually increases the male to female transmission rate due to inflammation of the vagina; it should not be considered a barrier to infection.<ref name="spermicide">{{cite web |url=http://www.fda.gov/oashi/aids/condom.html#should |title=Should spermicides be used with condoms? |accessdate=2006-10-23 |work=Condom Brochure, FDA OSHI HIV STDs }}</ref>
-Trials, in which [[Circumcision|uncircumcised]] men were randomly assigned to be medically circumcised in sterile conditions and given counseling and other men were not circumcised, have been conducted in South Africa,<ref name=Williams>{{
   cite journal
-  | author=Williams BG, Lloyd-Smith JO, Gouws E, Hankins C, Getz WM, Hargrove J, de Zoysa I, Dye C, Auvert B.
+  | author=Keele BF, van Heuverswyn F, Li YY, et al | title=Chimpanzee Reservoirs of Pandemic and Nonpandemic HIV-1
- | title=The Potential Impact of Male Circumcision on HIV in Sub-Saharan Africa.
+  | journal=Science | year=2006 |volume=313 |issue=5786 |pages=523–6
-  | journal=PLoS Med | year=2006 | pages=e262 | volume=3 | issue=7
+ | url= http://www.sciencemag.org/cgi/content/abstract/1126531
-  | pmid=16822094
+  | pmid=16728595 | doi=10.1126/science.1126531
-}}</ref> Kenya<ref>{{cite journal |author=Bailey RC, Moses S, Parker CB, ''et al'' |title=Male circumcision for HIV prevention in young men in Kisumu, Kenya: a randomised controlled trial |journal=Lancet |volume=369 |issue=9562 |pages=643–56 |year=2007 |pmid=17321310 |doi=10.1016/S0140-6736(07)60312-2}}</ref> and Uganda<ref>{{cite journal
+}}</ref>
- | quotes =
+* It is believed that HIV-2 originated from the Sooty Mangabey (''Cercocebus atys''), an Old World monkey of Guinea Bissau, Gabon, and Cameroon.
- | author = Gray RH et al
+* Most experts believe that HIV probably transferred to humans as a result of direct contact with primates, for instance during hunting or butchery.<ref name=CohenOrigns>{{
- | date = 24 February, 2007
- | year = 2007
- | month = February
- | title = Male circumcision for HIV prevention in men in Rakai, Uganda: a randomised trial.
- | journal = Lancet
- | volume = 369
- | issue = 9562
- | pages = 657-66
- | issn =
- | pmid = 17321311
- | doi = 10.1016/S0140-6736(07)60313-4
- | id =
- | url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=abstractplus&db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=17321311
- | language = English
- | format =
- | accessdate = 2007-04-17
- | laysummary =
- | laysource =
- | laydate =
- | quote =
- }}</ref> showing reductions in HIV transmission for heterosexual sex of 60%, 53%, and 51% respectively. As a result, a panel of experts convened by WHO and the UNAIDS Secretariat has "recommended that male circumcision now be recognized as an additional important intervention to reduce the risk of heterosexually acquired HIV infection in men."<ref name=WHOUNAIDScircum>{{
- cite web
- | author=WHO | publisher=WHO.int | year=2007
- | url=http://www.who.int/hiv/mediacentre/news68/en/index.html
- | title=WHO and UNAIDS announce recommendations from expert consultation on male circumcision for HIV prevention
- | accessdate=2007-07-13
-}}</ref> Research is clarifying whether there is a historical relationship between rates of male circumcision and rates of HIV in differing social and cultural contexts. Previously, Siegfried ''et al.'' suggested that it was possible that the correlation between circumcision and HIV in observational studies may be due to [[Confounding variable|confounding factors]], and remarked that the randomised controlled trials would therefore provide "essential evidence" about the effects of circumcision.<ref name=Siegfred>
-{{cite journal
-| author=Siegfried, N., Muller, M., Deeks, J., Volmink, J., Egger, M., Low, N., Walker, S. and Williamson, P. | title=HIV and male circumcision--a systematic review with assessment of the quality of studies | journal=Lancet Infect. Dis. | year=2005 | pages=165-173 | volume=5 | issue=3 | pmid=15766651
+ cite journal
+ | author=Cohen J
+ | title=Vaccine Theory of AIDS Origins Disputed at Royal Society
+ | journal=Science | year=2000 | pages=1850&ndash;1851 | volume= 289| issue=5486 |
+ pmid=11012346 | doi=10.1126/science.289.5486.1850
 }}</ref>
-There is little data on circumcision's effect on HIV risk with homosexual men and it is still being studied. A study of foreign and American men by scientists at the University of Washington, Seattle concluded: "Uncircumcised homosexual men in Seattle had a two fold increased risk of HIV infection... If the relative risk that we observed in Seattle were also present in other populations, the population attributable risk of uncircumcised status for HIV in homosexual men would be 40%, i.e., 40% of homosexual transmission of HIV could be potentially preventable with universal circumcision."[http://gateway.nlm.nih.gov/MeetingAbstracts/102199521.html] A study of Australian men headed by David Templeton, MD, from the University of New South Wales found "no relationship at all between circumcision and HIV seroconversion in" homosexual men. Templeton theorizes that this may be because most HIV occurs "following receptive rather than insertive intercourse," as he finds data on circumcision's effect on heterosexual men "compelling".[http://www.medscape.com/viewarticle/560823] South African medical experts are concerned that the repeated use of unsterilized blades in the [[Circumcision#Cultures and religions|ritual]] (not medical) circumcision of adolescent boys may be spreading HIV.<ref name=Kaisercircum>{{
- cite web
+==Structure==
- | author=Various | publisher=Kaisernetwork.org | year=2005
+[[Image:HIV Viron.png|thumb|left|200px|Figure 1. Diagram of HIV - By US National Institute of Health]]
- | url=http://www.kaisernetwork.org/daily_reports/rep_index.cfm?DR_ID=31199
- | title=Repeated Use of Unsterilized Blades in Ritual Circumcision Might Contribute to HIV Spread in S. Africa, Doctors Say
- | accessdate=2006-03-28
-}}</ref>
+* HIV is different in structure from other [[retrovirus]]es. It is around 120 [[nanometer|nm]] in diameter (120 billionths of a meter; around 60 times smaller than a red blood cell) and roughly spherical.
+* HIV-1 is composed of two copies of single-stranded [[RNA]] enclosed by a conical [[capsid]] comprising the viral protein [[#p24, p6, p7, p21|p24]], typical of [[lentivirus]]es (Figure 1). The RNA component is 9749 nucleotides long. This is in turn surrounded by a [[cell membrane|plasma membrane]] of host-cell origin. The single-strand [[RNA]] is tightly bound to the [[nucleocapsid proteins]], [[#p24, p6, p7, p21|p7]] and [[enzymes]] that are indispensable for the development of the [[virion]], such as [[reverse transcriptase]] and [[integrase]]. The nucleocapsid (p7 and p6) associates with the genomic [[RNA]] (one molecule per hexamer) and protects the [[RNA]] from digestion by [[nuclease]]s. A matrix composed of an association of the viral protein p17 surrounds the [[capsid]], ensuring the integrity of the [[virion particle]]. Also enclosed within the virion particle are [[#Vif|Vif]], [[#Vpr|Vpr]], [[#Nef|Nef]], p7 and viral [[#protease|protease]] (Figure 1). The envelope is formed when the capsid buds from the host cell, taking some of the host-cell membrane with it. The envelope includes the glycoproteins [[#gp120|gp120]] and [[#gp41|gp41]].
+* Recently, an Anglo-German team compiled a 3D structure of HIV by combining multiple images. It is hoped that this new information would contribute to scientific understanding of the virus, and help in the creation of a cure. Oxford University's Professor Stephen D. Fuller said the 3D map would assist in understanding how the virus grows. <ref>BBC News: [http://news.bbc.co.uk/1/hi/health/4642940.stm 3D Structure of HIV Revealed]</ref>   The validity of this work remains a matter of debate <ref>The SIV Surface Spike Imaged by Electron Tomography: One Leg or Three?  Subramaniam S PLoS Pathogens Vol. 2, No. 8, e91 doi:10.1371/journal.ppat.0020091</ref>, with a conflicting model produced by another team led by Florida State University Professor [[Kenneth Roux]] in the US <ref>Distribution and three-dimensional structure of AIDS virus envelope spikes Ping Zhu, Jun Liu, Julian Bess, Jr, Elena Chertova, Jeffrey D. Lifson, Henry Grisé, Gilad A. Ofek, Kenneth A. Taylor  and Kenneth H. Roux, Nature 441, 847-852 (15 June 2006) | doi:10.1038/nature04817; Received 8 March 2006; Accepted 24 April 2006; Published online 24 May 2006</ref>.
-==Structure and genome==
+==Genome organization==
-{{main|HIV structure and genome}}
+* HIV has several major [[gene]]s coding for structural proteins that are found in all [[retroviruses]], and several nonstructural ("accessory") genes that are unique to HIV. The ''gag'' gene provides the basic physical infrastructure of the [[virus]], and ''pol'' provides the basic mechanism by which retroviruses reproduce, while the others help HIV to enter the host [[cell]] and enhance its reproduction. Though they may be altered by mutation, all of these genes except ''tev'' exist in all known variants of HIV; see [[HIV#Genetic variability|Genetic variability of HIV]].
-{| align=right
+:* ''gag'' (Group-specific Antigen): codes for [[#p24|p24]], the viral capsid; [[#p6 and p7|p6 and p7]], the nucleocapsid proteins; and [[#p17|p17]], a matrix protein.
-| [[Image:HIV Viron.png|left|thumb|300px|Diagram of HIV]]
-|-
-| [[Image:ElecMicro of HIV Retrovirus serum isolate Samp-HM47.jpg‎|left|thumb|200px|[[Electron microscope|Electron]] [[micrograph]] of HIV]]
-|}
-HIV is different in structure from other retroviruses. It is about 120&nbsp;nm in diameter (120&nbsp;billionths of a meter; around 60&nbsp;times smaller than a red blood cell) and roughly spherical.<ref name=McGovern>{{
+:* ''pol'': Codes for viral [[enzyme]]s, the most important of which are [[#reverse transcriptase|reverse transcriptase]], [[#integrase|integrase]], and [[#protease|protease]] which cleaves the proteins derived from ''gag'' and ''pol'' into functional proteins.
- cite journal | author=McGovern SL, Caselli E, Grigorieff N, Shoichet BK | title=A common mechanism underlying promiscuous inhibitors from virtual and high-throughput screening | journal=J Med Chem | year=2002 | pages=1712-22 | volume=45 | issue=8
+:* ''env'' (for "envelope"): Codes for the precursor to [[#gp120|gp120]] and [[#gp41|gp41]], proteins embedded in the viral envelope which enable the virus to attach to and fuse with target cells.
- | pmid=11931626
-}}</ref>
+:* ''tat'', ''rev'', ''nef'', ''vif'', ''vpr'', ''vpu'': Each of these genes codes for a single protein with the same names; see [[#Tat|Tat]], [[#Rev|Rev]], [[#Nef|Nef]], [[#Vif|Vif]], [[#Vpr|Vpr]], [[#Vpu|Vpu]].
-It is composed of two copies of positive single-stranded [[RNA]] that codes for the virus's nine [[gene]]s enclosed by a conical [[capsid]] composed of 2,000 copies of the viral protein [[HIV structure and genome|p24]].<ref name=compendia>{{
-cite book
- | author = Various
- | year = 2005
- | title = HIV Sequence Compendium 2005
- | url = http://www.hiv.lanl.gov/content/hiv-db/COMPENDIUM/2005/0.pdf
- | accessdate = 2006-03-06
- | format= [[PDF|PDF format]]
-}}</ref> The single-stranded RNA is tightly bound to nucleocapsid proteins, p7 and enzymes needed for the development of the virion such as [[reverse transcriptase]], [[aspartyl protease|proteases]], [[ribonuclease]] and [[integrase]]. A matrix composed of the viral protein p17 surrounds the capsid ensuring the integrity of the virion particle.<ref name=compendia/> This is, in turn, surrounded by the viral envelope which is composed of two layers of fatty molecules called [[phospholipid]]s taken from the membrane of a human cell when a newly formed virus particle buds from the cell. Embedded in the viral envelope are proteins from the host cell and about 70 copies of a complex HIV protein that protrudes through the surface of the virus particle.<ref name=compendia/> This protein, known as Env, consists of a cap made of three molecules called [[gp120|glycoprotein (gp) 120]], and a stem consisting of three [[gp41]] molecules that anchor the structure into the viral envelope.<ref name=Chan>{{
+:* ''tev'': This gene is only present in a few HIV-1 isolates. It is a fusion of parts of the ''tat'', ''env'', and ''rev'' genes, and codes for a protein with some of the properties of [[#Tat|Tat]], but little or none of the properties of [[#Rev|Rev]].
-cite journal
+==Protein function==
-| author=Chan, DC., Fass, D., Berger, JM., Kim, PS. | title=Core Structure of gp41 from the HIV Envelope Glycoprotein | journal=Cell | year=1997 | pages=263–273 | volume=89 | pmid=9108481 |format=pdf |url=http://www.its.caltech.edu/~chanlab/PDFs/Chan_Cell_1997.pdf
+===Gag===
+* These proteins are encoded by the ''gag'' [[gene]], and provide structural elements of the [[virus]].
-}}</ref> This glycoprotein complex enables the virus to attach to and fuse with target cells to initiate the infectious cycle.<ref name=Chan>{{
+====p24====
+* p24 makes up the viral [[capsid]].
-cite journal
+* When a [[Western blot]] test is used to detect HIV [[infection]], p24 is one of the three major proteins tested for, along with [[#gp120|gp120]]/gp160 and [[#gp41|gp41]].
-| author=Chan, DC., Fass, D., Berger, JM., Kim, PS. | title=Core Structure of gp41 from the HIV Envelope Glycoprotein | journal=Cell | year=1997 | pages=263–273 | volume=89 | pmid=9108481 |format=pdf |url=http://www.its.caltech.edu/~chanlab/PDFs/Chan_Cell_1997.pdf
+====p6, p7, and p17====
+* p6 and p7 provide the [[nucleocapsid]].
-}}</ref>
+* p17 provides a protective [[matrix]].
-Both these surface proteins, especially gp120, have been considered as targets of future treatments or vaccines against HIV.<ref name=nih1998>{{
+===Pol===
+====Reverse transcriptase====
-cite news
+{{main|Reverse transcriptase}}
-| author=National Institute of Health | title=Crystal Structure of Key HIV Protein Reveals New Prevention, Treatment Targets | date=June 17, 1998 |url=http://www3.niaid.nih.gov/news/newsreleases/1998/hivprotein.htm | accessdate = 2006-09-14
+* Common to all [[retroviruses]], this enzyme transcribes the viral [[RNA]] into double-stranded [[DNA]].
+====Integrase====
-}}</ref>
+{{main|Integrase}}
+* This enzyme integrates the [[DNA]] produced by reverse transcriptase into the host's [[genome]].
-Of the nine genes that are encoded within the RNA genome, three of these genes, ''gag'', ''pol'', and ''env'', contain information needed to make the structural proteins for new virus particles.<ref name=compendia/> For example, ''env'' codes for a protein called gp160 that is broken down by a viral enzyme to form gp120 and gp41. The six remaining genes, ''tat'', ''rev'', ''nef'', ''vif'', ''vpr'', and ''vpu'' (or ''vpx'' in the case of HIV-2), are regulatory genes for proteins that control the ability of HIV to infect cells, produce new copies of virus (replicate), or cause disease.<ref name=compendia/> The protein encoded by ''nef'', for instance, appears necessary for the virus to replicate efficiently, and the ''vpu''-encoded protein influences the release of new virus particles from infected cells.<ref name=compendia/> The ends of each strand of HIV RNA contain an RNA sequence called the long terminal repeat (LTR). Regions in the LTR act as switches to control production of new viruses and can be triggered by proteins from either HIV or the host cell.<ref name=compendia/>
+====Protease====
+* A [[protease]] is any enzyme that cuts proteins into segments. HIV's ''gag'' and ''pol'' genes do not produce their proteins in their final form, but as larger combination proteins; the specific protease used by HIV cleaves these into separate functional units. [[Antiretroviral drug#Protease inhibitors (PIs)|Protease inhibitor]] drugs block this step.
+===Env===
+* The ''env'' gene does not actually code for gp120 and gp41, but for a precursor to both, gp160. During HIV reproduction, the host cell's own enzymes cleave gp160 into gp120 and gp41. See [[HIV#Replication cycle of HIV|Replication cycle of HIV]].
+====gp120====
+{{main|gp120}}
+* Exposed on the surface of the [[viral envelope]], the [[glycoprotein]] gp120 binds to the [[CD4]] [[receptor (biochemistry)|receptor]] on any target cell that has such a receptor, particularly the [[helper T-cell]]. See [[HIV#HIV tropism|HIV tropism]] and [[HIV#Replication cycle of HIV|Replication cycle of HIV]].
+* Since [[CD4]] receptor binding is the most obvious step in HIV infection, gp120 was among the first targets of [[HIV vaccine]] research. These efforts have been hampered by its chemical properties, which make it difficult for antibodies to bind to gp120; also, it can easily be shed from the [[virus]] due to its loose binding with gp41.
+====gp41====
+* The [[glycoprotein]] gp41 is non-[[covalent bond|covalently]] bound to gp120, and provides the second step by which [[viral entry|HIV enters]] the [[cell]]. It is originally buried within the viral envelope, but when gp120 binds to a [[CD4]] receptor, gp120 changes its [[chemical conformation|conformation]] causing gp41 to become exposed, where it can assist in fusion with the host [[cell]].
+* [[Fusion inhibitor]] drugs such as [[enfuvirtide]] block the fusion process by binding to gp41.
+===Transactivators===
+====Tat====
+* Stands for "Trans-Activator of Transcription". Tat consists of between 86 and 101 amino acids depending on the subtype.<ref>Jeang, K. T. (1996) In: Human Retroviruses and AIDS: [http://hiv.lanl.gov/content/hiv-db/COMPENDIUM/1996/PART-III/1.pdf A Compilation and Analysis of Nucleic Acid and Amino Acid Sequences.] Los Alamos National Laboratory (Ed.) pp. III-3–III-18</ref>  Tat helps HIV reproduce by compensating for a defect in its genome: the HIV [[RNA]] initially has a hairpin-structured portion which prevents full transcription occurring. However, a small number of [[RNA]] transcripts will be made, which allow the Tat protein to be produced. Tat then binds to and phosphorylates cellular factors, eliminating the effect of the hairpin [[RNA]] structure and allowing transcription of the HIV [[DNA]].<ref>Kim JB, Sharp PA. (2001) [http://www.jbc.org/cgi/content/full/276/15/12317 Positive transcription elongation factor B phosphorylates hSPT5 and RNA polymerase II carboxyl-terminal domain independently of cyclin-dependent kinase-activating kinase]. ''J. Biol. Chem.'' '''276''', 12317-12323  PMID 11145967</ref>  This itself increases the rate of transcription, providing a [[positive feedback]] cycle. This in turn allows HIV to have an explosive response once a threshold amount of Tat is produced, a useful tool for defeating the body's [[response]].  Tat also appears to play a more direct role in the HIV disease process. The protein is released by infected cells in culture, and is found in the blood of HIV-1 infected patients.<ref name="Xiao">Xiao, H., Neuveut, C., Tiffany, H. L., Benkirane, M., Rich, E. A., Murphy, P. M. and Jeang, K. T. (2000) [http://www.ncbi.nlm.nih.gov/entrez/utils/lofref.fcgi?PrId=3494&uid=11027346&db=pubmed&url=http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=11027346 Selective CXCR4 antagonism by Tat: implications for in vivo expansion of coreceptor use by HIV-1]. ''Proc. Natl. Acad. Sci. U.S.A.'' '''97''', 11466-11471 PMID 11027346</ref>  It can be absorbed by [[cells]] that are not infected with HIV, and can act directly as a [[toxin]] producing cell death via [[apoptosis]] in uninfected "bystander" [[T cell]]s, assisting in progression toward [[AIDS]].<ref>Campbell GR, Pasquier E, Watkins J, Bourgarel-Rey V, Peyrot V, Esquieu D, Barbier P, de Mareuil J, Braguer D, Kaleebu P, Yirrell DL, Loret EP. (2004) [http://www.ncbi.nlm.nih.gov/entrez/utils/lofref.fcgi?PrId=3051&uid=15331610&db=pubmed&url=http://www.jbc.org/cgi/pmidlookup?view=long&pmid=15331610 The glutamine-rich region of the HIV-1 Tat protein is involved in T-cell apoptosis]. ''J. Biol. Chem.'' '''279''', 48197-48204 PMID 15331610</ref>  By interacting with the [[CXCR4]] receptor, Tat also appears to encourage the reproduction of less virulent M-tropic strains of HIV early in the course of infection, allowing the more rapidly pathogenic T-tropic strains to emerge later.<ref name="Xiao"> </ref>
+====Rev====
+{| style="float:right"
+|[[Image:Rev-mediated HIV mRNA transport.png|thumb|left|300px|'''Rev-mediated HIV mRNA transport.''' Rev (red) binds the Rev response element (RRE, blue) to mediate export of unspliced and singly spliced mRNA from the nucleus to the cytoplasm. - De I, Vossman, CC BY 2.5, https://commons.wikimedia.org/w/index.php?curid=2401724]]
+|}
+* Stands for "Regulator of Virion". This protein allows fragments of HIV [[mRNA]] that contain a Rev Response Unit (RRE) to be exported from the nucleus to the [[cytoplasm]]. In the absence of the ''rev'' gene, [[RNA]] splicing machinery in the nucleus quickly splices the [[RNA]] so that only the smaller, regulatory proteins can be produced; in the presence of ''rev'', [[RNA]] is exported from the nucleus before it can be spliced, so that the structural proteins and [[RNA]] [[genome]] can be produced. Again, this mechanism allows a positive feedback loop to allow [[HIV]] to overwhelm the host's defenses, and provides time-dependent regulation of replication (a common process in viral infections)<ref name="Strebel">Strebel, K (2003) Virus-host interactions: role of HIV proteins Vif, Tat, and Rev. ''AIDS'' '''17 Suppl 4''', S25-S34 PMID 15080177</ref>
+====Vpr====
+* Stands for "Viral Protein R". Vpr, a 96 amino acid 14-kDa protein, plays an important role in regulating nuclear import of the HIV-1 pre-integration complex, and is required for virus replication in non-dividing [[cell]]s such as [[macrophages]]. Vpr also induces [[cell cycle]] arrest and [[apoptosis]] in proliferating cells, which can result in [[immune dysfunction]].<ref>Bukrinsky M, Adzhubei A. (1999) Viral protein R of HIV-1. ''Rev Med Virol'' '''9''', 39-49 PMID 10371671</ref><ref>Muthumani K., et al (2006) The HIV-1 Vpr and glucocorticoid receptor complex: A gain of function interaction that prevents the nuclear localization of PARP-1. Nat Cell Biol. Feb;8(2):170-9.</ref>
+* Vpr is also immunosuppressive due to its ability to sequester a proinflammatory transcriptional activator in the [[cytoplasm]]. HIV-2 contains both a Vpr [[protein]] and a related (by sequence homology) Vpx protein (Viral Protein X). Two functions of Vpr in HIV-1 are split between Vpr and Vpx in HIV-2, with the HIV-2 Vpr protein inducing [[cell cycle]] arrest and the Vpx protein required for nuclear import.
+===Other regulatory proteins===
+====Nef====
+* Stands for "Negative Regulatory Factor". The expression of Nef early in the viral [[life cycle]] ensures T cell activation and the establishment of a persistent state of infection, two basic attributes of HIV [[infection]]. Nef also promotes the survival of infected cells by downmodulating the expression of several surface molecules important in [[host]] [[immune]] function. These include [[major histocompatibility complex]]-I (MHC I) and MHC II present on [[antigen presenting cell]]s (APCs) and target cells, [[CD4]] and [[CD28]] present on CD4+ T cells. One group of patients in Sydney were infected with a nef-deleted virus and took much longer than expected to progress to AIDS.<ref>Learmont JC, Geczy AF, Mills J, Ashton LJ, Raynes-Greenow CH, Garsia RJ, Dyer WB, McIntyre L, Oelrichs RB, Rhodes DI, Deacon NJ, Sullivan JS. (1999) [http://content.nejm.org/cgi/content/abstract/340/22/1715 Immunologic and virologic status after 14 to 18 years of infection with an attenuated strain of HIV-1]. A report from the Sydney Blood Bank Cohort. ''N Engl J Med'' '''340''', 1715-1722 PMID 10352163</ref>
+* A ''nef''-deleted virus vaccine has not been trialed in humans and has failed in nonhuman animals.HIV-1 Nef-induced FasL induction and bystander killing requires p38 MAPK activation.
+====Vif====
+* Stands for "[[Viral infectivity factor]]". Vif is a 23-[[kilodalton]] protein that is essential for viral replication.<ref name="Strebel"> </ref> Vif inhibits the cellular protein, [[APOBEC3G]], from entering the virion during budding from a host cell by targeting it for proteasomal degredation. Vif hijacks the cellular Cullin5 E3 ubiquitin ligase in order to target APOBEC3G for degradation. In the absence of Vif, APOBEC3G  causes hypermutation of the viral genome, rendering it dead-on-arrival at the next host cell. APOBEC3G is thus a host defence to retroviral infection which HIV-1 has overcome by the acquisition of Vif.
+====Vpu====
+* Stands for "Viral Protein U". Vpu is involved in viral budding, enhancing [[virion]] release from the [[cell]].
 ==Tropism==
-The term [[viral tropism]] refers to which cell types HIV infects. HIV can infect a variety of immune cells such as [[Helper T cell|CD4<SUP>+</SUP> T cells]], [[macrophage]]s, and [[microglial cell]]s. HIV-1 entry to macrophages and CD4<SUP>+</SUP> T cells is mediated through interaction of the virion envelope glycoproteins (gp120) with the CD4 molecule on the target cells and also with [[chemokine]] coreceptors.<ref name=Chan/>
+* '''HIV tropism''' refers to the [[cell type]] that the [[human immunodeficiency virus]] (HIV) infects and replicates in. HIV [[tropism]] of a patient's [[virus]] is measured by the [[Trofile assay]].
+* HIV can infect a variety of [[cell (biology)|cell]]s such as [[Helper T cell|CD4+ helper T-cells]] and [[macrophage]]s that express the [[CD4]] molecule on their surface. HIV-1 entry to [[macrophages]] and T helper [[cells]] is mediated not only through interaction of the [[virion]] envelope glycoproteins ([[gp120]]) with the CD4 molecule on the target cells but also with its [[chemokine]] coreceptors.
-Macrophage (M-tropic) strains of HIV-1, or non-[[syncitia]]-inducing strains (NSI) use the ''β''-chemokine receptor [[CCR5]] for entry and are thus able to replicate in macrophages and CD4<SUP>+</SUP> T cells.<ref name=Coakley>{{
+* [[Macrophage]] (M-tropic) strains of HIV-1, or non-syncitia-inducing strains (NSI) use the beta-chemokine [[receptor]] [[CCR5]] for entry and are thus able to replicate in [[macrophages]] and [[CD4+]] [[T-cell]]s <ref name=Coakley>
+{{cite journal
-cite journal
+| author=Coakley, E., Petropoulos, C. J. and Whitcomb, J. M. | title=Assessing chemokine co-receptor usage in HIV | journal=Curr. Opin. Infect. Dis. | year=2005 | pages=9-15 | volume=18 | issue=1 | id={{PMID|15647694}}
-| author=Coakley, E., Petropoulos, C. J. and Whitcomb, J. M. | title=Assessing ch vbgemokine co-receptor usage in HIV | journal=Curr. Opin. Infect. Dis. | year=2005 | pages=9-15 | volume=18 | issue=1 | pmid=15647694 |format=
+}}</ref>. The normal [[ligand]]s for this receptor, [[RANTES]], macrophage inflammatory protein (MIP)-1-beta and MIP-1-alpha, are able to suppress HIV-1 infection ''in vitro''. This CCR5 coreceptor is used by almost all primary HIV-1 isolates regardless of viral genetic subtype.
-}}</ref> This CCR5 coreceptor is used by almost all primary HIV-1 isolates regardless of viral genetic subtype. Indeed, macrophages play a key role in several critical aspects of HIV infection. They appear to be the first cells infected by HIV and perhaps the source of HIV production when CD4<SUP>+</SUP> cells become depleted in the patient. Macrophages and microglial cells are the cells infected by HIV in the [[central nervous system]]. In tonsils and adenoids of HIV-infected patients, macrophages fuse into multinucleated giant cells that produce huge amounts of virus.
+* T-tropic isolates, or [[syncitia]]-inducing (SI) strains replicate in primary CD4+ T-cells as well as in [[macrophages]] and use the alpha-chemokine receptor, [[CXCR4]], for entry <ref name=Coakley>
+{{cite journal
-T-tropic isolates, or [[syncitia]]-inducing (SI) strains replicate in primary CD4<SUP>+</SUP> T cells as well as in macrophages and use the ''α''-chemokine receptor, [[CXCR4]], for entry.<ref name=Coakley /><ref name=Deng>
+| author=Coakley, E., Petropoulos, C. J. and Whitcomb, J. M. | title=Assessing chemokine co-receptor usage in HIV | journal=Curr. Opin. Infect. Dis. | year=2005 | pages=9-15 | volume=18 | issue=1 | id={{PMID|15647694}}
+}}</ref>. The alpha-chemokine, [[Stromal cell-derived factor-1|SDF-1]], a ligand for [[CXCR4]], suppresses replication of T-tropic HIV-1 isolates. It does this by down regulating the expression of [[CXCR4]] on the surface of these [[cell]]s.
-{{cite journal
+* Viruses that use only the [[CCR5]] receptor are termed R5, those that only use [[CXCR4]] are termed X4, and those that use both, X4R5. However, the use of coreceptor alone does not explain viral [[tropism]], as not all '''R5 viruses''' are able to use CCR5 on [[macrophages]] for a productive [[infection]] <ref name=Coakley>
-| author=Deng H, Liu R, Ellmeier W, Choe S, Unutmaz D, Burkhart M, Di Marzio P, Marmon S, Sutton RE, Hill CM, Davis CB, Peiper SC, Schall TJ, Littman DR, Landau NR. | title=Identification of a major co-receptor for primary isolates of HIV-1. | journal=Nature | year=1996 | pages=661-666 | volume=381 | issue=6584 | pmid=8649511 | doi=10.1038/381661a0
+{{cite journal
+| author=Coakley, E., Petropoulos, C. J. and Whitcomb, J. M. | title=Assessing chemokine co-receptor usage in HIV | journal=Curr. Opin. Infect. Dis. | year=2005 | pages=9-15 | volume=18 | issue=1 | id={{PMID|15647694}}
-}}</ref><ref name=Feng>
+}}</ref>.
+* HIV can also infect a subtype of [[dendritic cells]] <ref name=Knight>
 {{cite journal
-| author=Feng Y, Broder CC, Kennedy PE, Berger EA. | title=HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. | journal=Science | year=1996 | pages=872-877 | volume=272 | issue=5263 | pmid=8629022 | doi=10.1126/science.272.5263.872
+| author=Knight, S. C., Macatonia, S. E. and Patterson, S. | title=HIV I infection of dendritic cells | journal=Int. Rev. Immunol. | year=1990 | pages=163-175 | volume=6 | issue=2-3 | id={{PMID|2152500}}
+}}</ref>, MDC-1, which probably constitute a major reservoir that maintains infection when T helper cell numbers have declined to extremely low levels.
-}}</ref> Dual-tropic HIV-1 strains are thought to be transitional strains of the HIV-1 virus and thus are able to use both CCR5 and CXCR4 as co-receptors for viral entry.
-The ''α''-chemokine, SDF-1, a ligand for CXCR4, suppresses replication of T-tropic HIV-1 isolates. It does this by down-regulating the expression of CXCR4 on the surface of these cells. HIV that use only the CCR5 receptor are termed [[HIV tropism|R5]], those that only use CXCR4 are termed [[HIV tropism|X4]], and those that use both, X4R5. However, the use of coreceptor alone does not explain viral tropism, as not all R5 viruses are able to use CCR5 on macrophages for a productive infection<ref name=Coakley /> and HIV can also infect a subtype of [[myeloid dendritic cells]],<ref name=Knight>
-{{cite journal
-| author=Knight, S. C., Macatonia, S. E. and Patterson, S. | title=HIV I infection of dendritic cells | journal=Int. Rev. Immunol. | year=1990 | pages=163-175 | volume=6 | issue=2-3 | pmid=2152500
-}}</ref> which probably constitute a reservoir that maintains infection when CD4<SUP>+</SUP> T cell numbers have declined to extremely low levels.
-Some people are resistant to certain strains of HIV.<ref name=Tang>{{
- cite journal
- | author=Tang, J. and Kaslow, R. A.
- | title=The impact of host genetics on HIV infection and disease progression in the era of highly active antiretroviral therapy
- | journal=AIDS | year=2003 | pages=S51-S60 | volume=17 | issue=Suppl 4
- | pmid=15080180
-}}</ref> One example of how this occurs is people with the [[CCR5-Δ32]] mutation; these people are resistant to infection with R5 virus as the mutation stops HIV from binding to this coreceptor, reducing its ability to infect target cells.
-Sexual intercourse is the major mode of HIV transmission. Both X4 and R5 HIV are present in the [[seminal fluid]] which is passed from partner to partner. The virions can then infect numerous cellular targets and disseminate into the whole organism. However, a selection process leads to a predominant transmission of the R5 virus through this pathway.<ref name=Zhu1993>
-{{cite journal
-| author=Zhu T, Mo H, Wang N, Nam DS, Cao Y, Koup RA, Ho DD. | title=Genotypic and phenotypic characterization of HIV-1 patients with primary infection | journal=Science | year=1993 | pages=1179–1181 | volume=261 | issue=5125 | pmid=8356453 | doi=10.1126/science.8356453
-}}</ref><ref name=Wout>
-{{cite journal
-| author=van’t Wout AB, Kootstra NA, Mulder-Kampinga GA, Albrecht-van Lent N, Scherpbier HJ, Veenstra J, Boer K, Coutinho RA, Miedema F, Schuitemaker H. | title=Macrophage-tropic variants initiate human immunodeficiency virus type 1 infection after sexual, parenteral, and vertical transmission | journal=J Clin Invest | year=1994 | pages=2060–2067 | volume=94 | issue=5 | pmid=7962552
-}}</ref><ref name=Zhu1996>
-{{cite journal
-| author=Zhu T, Wang N, Carr A, Nam DS, Moor-Jankowski R, Cooper DA, Ho DD. | title=Genetic characterization of human immunodeficiency virus type 1 in blood and genital secretions: evidence for viral compartmentalization and selection during sexual transmission | journal=J Virol | year=1996 | pages=3098-3107 | volume=70 | issue=5 | pmid=8627789
-}}</ref> How this selective process works is still under investigation, but one model is that [[spermatozoa]] may selectively carry R5 HIV as they possess both CCR3 and CCR5 but not CXCR4 on their surface<ref name=Muciaccia>
-{{cite journal
-| author=Muciaccia B, Padula F, Vicini E, Gandini L, Lenzi A, Stefanini M. | title=Beta-chemokine receptors 5 and 3 are expressed on the head region of human spermatozoon | journal=FASEB J | year=2005 | pages=2048-2050 | volume=19 | issue=14 | pmid=16174786
-}}</ref> and that genital [[epithelial cell]]s preferentially sequester X4 virus.<ref name=Berlier>
-{{cite journal
-| author=Berlier W, Bourlet T, Lawrence P, Hamzeh H, Lambert C, Genin C, Verrier B, Dieu-Nosjean MC, Pozzetto B, Delezay O. | title=Selective sequestration of X4 isolates by human genital epithelial cells: Implication for virus tropism selection process during sexual transmission of HIV | journal=J Med Virol. | year=2005 | pages=465-474 | volume=77 | issue=4 | pmid=16254974
-}}</ref> In patients infected with subtype B HIV-1, there is often a co-receptor switch in late-stage disease and T-tropic variants appear that can infect a variety of T cells through CXCR4.<ref name=Clevestig>
-{{cite journal
-| author=Clevestig P, Maljkovic I, Casper C, Carlenor E, Lindgren S, Naver L, Bohlin AB, Fenyo EM, Leitner T, Ehrnst A. | title=The X4 phenotype of HIV type 1 evolves from R5 in two children of mothers, carrying X4, and is not linked to transmission | journal=AIDS Res Hum Retroviruses | year=2005 | pages=371-378 | volume=5 | issue=21 | pmid=15929699
-}}</ref> These variants then replicate more aggressively with heightened virulence that causes rapid T cell depletion, immune system collapse, and opportunistic infections that mark the advent of AIDS.<ref name=Moore>
-{{cite journal
-| author=Moore JP.| title=Coreceptors: implications for HIV pathogenesis and therapy | journal=Science | year=1997 | pages=51-52 | volume=276 | issue=5309 | pmid=9122710 | doi=10.1126/science.276.5309.51
-}}</ref> Thus, during the course of infection, viral adaptation to the use of CXCR4 instead of CCR5 may be a key step in the progression to AIDS. A number of studies with subtype B-infected individuals have determined that between 40 and 50% of AIDS patients can harbour viruses of the SI, and presumably the X4, phenotype.<ref name=Karlsson>
-{{cite journal
-| author=Karlsson A, Parsmyr K, Aperia K, Sandstrom E, Fenyo EM, Albert J.| title=MT-2 cell tropism of human immunodeficiency virus type 1 isolates as a marker for response to treatment and development of drug resistance | journal=J Infect Dis. | year=1994 | pages=1367-1375 | volume=170 | issue=6 | pmid=7995974
-}}</ref><ref name=Koot>
-{{cite journal
-| author=Koot M, van 't Wout AB, Kootstra NA, de Goede RE, Tersmette M, Schuitemaker H.| title=Relation between changes in cellular load, evolution of viral phenotype, and the clonal composition of virus populations in the course of human immunodeficiency virus type 1 infection | journal=J Infect Dis. | year=1996 | pages=349-354 | volume=173 | issue=2 | pmid=8568295
-}}</ref>
 ==Replication cycle==
-[[Image:Hiventrytocell.jpg|left|thumb|Schematic representation of the key structural features of HIV-1 entry into T cells.  The two bottom images show alternate models for entry into cells.]]
+[[File:HIV Life Cycle.jpg|thumb|600px|none|Image obtained from AIDSinfo.org http://aidsinfo.nih.gov/education-materials/fact-sheets/19/73/the-hiv-life-cycle]]
-[[Image:Hiv gross.png|right|thumbnail|The HIV replication cycle]]
+<br>
+'''Steps in the HIV Replication Cycle'''
+# Fusion of the HIV cell to the host cell surface.
+# HIV RNA, reverse transcriptase, integrase, and other viral proteins enter the host cell.
+# Viral DNA is formed by reverse transcription.
+# Viral DNA is transported across the nucleus and integrates into the host DNA.
+# New viral RNA is used as genomic RNA and to make viral proteins.
+# New viral RNA and proteins move to cell surface and a new, immature, HIV virus forms.
+# The virus matures by protease releasing individual HIV proteins.
+{|
+|[[Image:Hiventrytocell.jpg|left|thumb|350px|Schematic representation of the key structural features of HIV-1 entry into T cells.  The two bottom images show alternate models for entry into cells. - By Rachid Sougrat, Alberto Bartesaghi, Jeffrey D. Lifson, Adam E. Bennett, Julian W. Bess, Daniel J. Zabransky, Sriram Subramaniam - Sougrat R, Bartesaghi A, Lifson JD, et al (May 2007). "Electron tomography of the contact between T cells and SIV/HIV-1: implications for viral entry". PLoS Pathog. 3 (5): e63. PMID 17480119. doi:10.1371/journal.ppat.0030063Direct link to image: http://www.plospathogens.org/article/showImageLarge.action?uri=info%3Adoi%2F10.1371%2Fjournal.ppat.0030063.g008, CC BY 2.5, https://commons.wikimedia.org/w/index.php?curid=4198856]]
+|[[Image:Hiv gross.png|left|thumbnail|250px|The HIV replication cycle - By Translated by Raul654 - Originally from GFDL image Image:Hiv gross german.png, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=32862]]
+|}
 ===Entry to the cell===
+* HIV enters [[macrophages]] and CD4<SUP>+</SUP> T cells by the [[adsorption]] of [[glycoproteins]] on its surface to receptors on the target [[cell]] followed by fusion of the viral [[envelope]] with the [[cell membrane]] and the release of the HIV [[capsid]] into the [[cell]].<ref name=Chan2>{{cite journal |author=Chan D, Kim P |title=HIV entry and its inhibition |journal=Cell |volume=93 |issue=5 |pages=681-4 |year=1998 |pmid=9630213}}</ref><ref name=Wyatt>{{cite journal |author=Wyatt R, Sodroski J |title=The HIV-1 envelope glycoproteins: fusogens, antigens, and immunogens |journal=Science |volume=280 |issue=5371 |pages=1884-8 |year=1998 | doi=10.1126/science.280.5371.1884 |pmid=9632381}}</ref>
-HIV enters macrophages and CD4<SUP>+</SUP> T cells by the [[adsorption]] of [[glycoproteins]] on its surface to receptors on the target cell followed by fusion of the viral envelope with the cell membrane and the release of the HIV capsid into the cell.<ref name=Chan2>{{cite journal |author=Chan D, Kim P |title=HIV entry and its inhibition |journal=Cell |volume=93 |issue=5 |pages=681-4 |year=1998 |pmid=9630213}}</ref><ref name=Wyatt>{{cite journal |author=Wyatt R, Sodroski J |title=The HIV-1 envelope glycoproteins: fusogens, antigens, and immunogens |journal=Science |volume=280 |issue=5371 |pages=1884-8 |year=1998 | doi=10.1126/science.280.5371.1884 |pmid=9632381}}</ref>
+* Entry to the [[cell]] begins through interaction of the trimeric [[envelope]] complex (gp160 spike, discussed above) and both [[CD4]] and a chemokine receptor (generally either [[CCR5]] or [[CXCR4]], but others are known to interact) on the [[cell]] surface.<ref name=Chan2/><ref name=Wyatt/> The [[gp160]] spike contains binding domains for both [[CD4]] and [[chemokine]] receptors.<ref name=Chan2/><ref name=Wyatt/> The first step in fusion involves the high-affinity attachment of the [[CD4]] binding domains of [[gp120]] to [[CD4]]. Once [[gp120]] is bound with the [[CD4]] protein, the envelope complex undergoes a structural change, exposing the [[chemokine]] binding domains of [[gp120]] and allowing them to interact with the target chemokine [[receptor]].<ref name=Chan2/><ref name=Wyatt/> This allows for a more stable two-pronged attachment, which allows the N-terminal fusion peptide gp41 to penetrate the cell membrane.<ref name=Chan2/><ref name=Wyatt/> Repeat sequences in [[gp41]], HR1 and HR2 then interact, causing the collapse of the extracellular portion of [[gp41]] into a hairpin. This loop structure brings the virus and [[cell membranes]] close together, allowing fusion of the membranes and subsequent entry of the [[viral capsid]].<ref name=Chan2/><ref name=Wyatt/>
+* Once HIV has bound to the target cell, the HIV [[RNA]] and various [[enzymes]], including [[reverse transcriptase]], [[integrase]], [[ribonuclease]] and [[protease]], are injected into the cell.<ref name=Chan2/>
-Entry to the cell begins through interaction of the trimeric envelope complex (gp160 spike, discussed above) and both [[CD4]] and a chemokine receptor (generally either CCR5 or CXCR4, but others are known to interact) on the cell surface.<ref name=Chan2/><ref name=Wyatt/> The gp160 spike contains binding domains for both CD4 and chemokine receptors.<ref name=Chan2/><ref name=Wyatt/> The first step in fusion involves the high-affinity attachment of the CD4 binding domains of [[gp120]] to CD4. Once gp120 is bound with the CD4 protein, the envelope complex undergoes a structural change, exposing the chemokine binding domains of gp120 and allowing them to interact with the target chemokine receptor.<ref name=Chan2/><ref name=Wyatt/> This allows for a more stable two-pronged attachment, which allows the N-terminal fusion peptide gp41 to penetrate the cell membrane.<ref name=Chan2/><ref name=Wyatt/> Repeat sequences in gp41, HR1 and HR2 then interact, causing the collapse of the extracellular portion of gp41 into a hairpin. This loop structure brings the virus and cell membranes close together, allowing fusion of the membranes and subsequent entry of the viral capsid.<ref name=Chan2/><ref name=Wyatt/>
+* HIV can infect [[dendritic cells]] (DCs) by this CD4-CCR5 route, but another route using mannose-specific C-type lectin receptors such as [[DC-SIGN]] can also be used.<ref name=Pope_2003>{{cite journal |author=Pope M, Haase A |title=Transmission, acute HIV-1 infection and the quest for strategies to prevent infection |journal=Nat Med |volume=9 |issue=7 |pages=847-52 |year=2003 |pmid=12835704}}</ref> DCs are one of the first cells encountered by the virus during sexual transmission. They are currently thought to play an important role by transmitting HIV to T cells once the virus has been captured in the [[mucosa]] by DCs.<ref name=Pope_2003 />
-Once HIV has bound to the target cell, the HIV [[RNA]] and various [[enzymes]], including reverse transcriptase, integrase, ribonuclease and protease, are injected into the cell.<ref name=Chan2/>
-HIV can infect [[dendritic cells]] (DCs) by this CD4-CCR5 route, but another route using mannose-specific C-type lectin receptors such as [[DC-SIGN]] can also be used.<ref name=Pope_2003>{{cite journal |author=Pope M, Haase A |title=Transmission, acute HIV-1 infection and the quest for strategies to prevent infection |journal=Nat Med |volume=9 |issue=7 |pages=847-52 |year=2003 |pmid=12835704}}</ref> DCs are one of the first cells encountered by the virus during sexual transmission. They are currently thought to play an important role by transmitting HIV to T cells once the virus has been captured in the [[mucosa]] by DCs.<ref name=Pope_2003 />
 ===Replication and transcription===
-Once the viral capsid enters the cell, an [[enzyme]] called ''[[reverse transcriptase]]'' liberates the single-stranded (+)[[RNA]] from the attached viral proteins and copies it into a complementary [[DNA]].<ref name=Zheng>
+* Once the viral capsid enters the cell, an [[enzyme]] called ''[[reverse transcriptase]]'' liberates the single-stranded (+)[[RNA]] from the attached viral proteins and copies it into a complementary [[DNA]].<ref name=Zheng>
 {{cite journal
 | author=Zheng, Y. H., Lovsin, N. and Peterlin, B. M. | title=Newly identified host factors modulate HIV replication | journal=Immunol. Lett. | year=2005 | pages=225-234 | volume=97 | issue=2 | pmid=15752562
+}}</ref> This process of reverse transcription is extremely error-prone and it is during this step that mutations may occur. Such mutations may cause [[Resistance to antiviral drugs|drug resistance]]. The [[reverse transcriptase]] then makes a complementary [[DNA]] strand to form a double-stranded viral DNA intermediate (vDNA). This vDNA is then transported into the [[cell nucleus]]. The integration of the viral DNA into the host cell's [[genome]] is carried out by another viral enzyme called ''[[integrase]]''.<ref name=Zheng/>
-}}</ref> This process of reverse transcription is extremely error-prone and it is during this step that mutations may occur. Such mutations may cause [[Resistance to antiviral drugs|drug resistance]]. The reverse transcriptase then makes a complementary DNA strand to form a double-stranded viral DNA intermediate (vDNA). This vDNA is then transported into the [[cell nucleus]]. The integration of the viral DNA into the host cell's [[genome]] is carried out by another viral enzyme called ''[[integrase]]''.<ref name=Zheng/>
+* This integrated viral DNA may then lie dormant, in the latent stage of HIV infection.<ref name=Zheng/> To actively produce the virus, certain cellular [[transcription factors]] need to be present, the most important of which is [[NF-kB|NF-''κ''B]] (NF kappa B), which is upregulated when T cells become activated.<ref name=Hiscott>
-This integrated viral DNA may then lie dormant, in the latent stage of HIV infection.<ref name=Zheng/> To actively produce the virus, certain cellular [[transcription factors]] need to be present, the most important of which is [[NF-kB|NF-''κ''B]] (NF kappa B), which is upregulated when T cells become activated.<ref name=Hiscott>
 {{cite journal
 | author=Hiscott J, Kwon H, Genin P. | title=Hostile takeovers: viral appropriation of the NF-kappaB pathway | journal=J Clin Invest. | year=2001 | pages=143-151 | volume=107 | issue=2 | pmid=11160127
 }}</ref> This means that those cells most likely to be killed by HIV are those currently fighting infection.
+* In this replication process, the integrated [[provirus]] is copied to [[mRNA]] which is then [[Splicing (genetics)|spliced]] into smaller pieces. These small pieces produce the regulatory proteins [[HIV structure and genome#Tat|Tat]] (which encourages new virus production) and [[HIV structure and genome#Rev|Rev]]. As Rev accumulates it gradually starts to inhibit [[mRNA]] splicing.<ref name=Pollard>
-[[Image:Rev-mediated HIV mRNA transport.png|thumb|250px|'''Rev-mediated HIV mRNA transport.''' Rev (red) binds the Rev response element (RRE, blue) to mediate export of unspliced and singly spliced mRNA from the nucleus to the cytoplasm.]]
-In this replication process, the integrated [[provirus]] is copied to [[mRNA]] which is then [[Splicing (genetics)|spliced]] into smaller pieces. These small pieces produce the regulatory proteins [[HIV structure and genome#Tat|Tat]] (which encourages new virus production) and [[HIV structure and genome#Rev|Rev]]. As Rev accumulates it gradually starts to inhibit [[mRNA]] splicing.<ref name=Pollard>
 {{cite journal
 | author=Pollard, V. W. and Malim, M. H. | title=The HIV-1 Rev protein | journal=Annu. Rev. Microbiol. | year=1998 | pages=491-532 | volume=52 | issue= | pmid=9891806
 }}</ref> At this stage, the structural proteins Gag and Env are produced from the full-length mRNA. The full-length RNA is actually the virus genome; it binds to the Gag protein and is packaged into new virus particles.
+* HIV-1 and HIV-2 appear to package their [[RNA]] differently; HIV-1 will bind to any appropriate RNA whereas HIV-2 will preferentially bind to the mRNA which was used to create the [[Gag]] protein itself. This may mean that HIV-1 is better able to mutate (HIV-1 infection progresses to AIDS faster than HIV-2 infection and is responsible for the majority of global infections).
-HIV-1 and HIV-2 appear to package their RNA differently; HIV-1 will bind to any appropriate RNA whereas HIV-2 will preferentially bind to the mRNA which was used to create the Gag protein itself. This may mean that HIV-1 is better able to mutate (HIV-1 infection progresses to AIDS faster than HIV-2 infection and is responsible for the majority of global infections).
 ===Assembly and release===
-The final step of the viral cycle, assembly of new HIV-1 virons, begins at the plasma membrane of the host cell. The Env polyprotein (gp160) goes through the [[endoplasmic reticulum]] and is transported to the [[Golgi apparatus|Golgi]] complex where it is cleaved by [[HIV-1 protease|protease]] and processed into the two HIV envelope glycoproteins gp41 and gp120. These are transported to the [[plasma membrane]] of the host cell where gp41 anchors the gp120 to the membrane of the infected cell.
+* The final step of the viral cycle, assembly of new HIV-1 virons, begins at the plasma membrane of the host cell. The Env polyprotein (gp160) goes through the [[endoplasmic reticulum]] and is transported to the [[Golgi apparatus|Golgi]] complex where it is cleaved by [[HIV-1 protease|protease]] and processed into the two HIV envelope [[glycoproteins]] gp41 and gp120. These are transported to the [[plasma membrane]] of the [[host]] cell where gp41 anchors the [[gp120]] to the membrane of the infected [[cell]].
+* The Gag (p55) and Gag-Pol (p160) polyproteins also associate with the inner surface of the plasma membrane along with the HIV genomic [[RNA]] as the forming virion begins to bud from the host [[cell]].
-The Gag (p55) and Gag-Pol (p160) polyproteins also associate with the inner surface of the plasma membrane along with the HIV genomic RNA as the forming virion begins to bud from the host cell.
+* Maturation either occurs in the forming bud or in the immature [[virion]] after it buds from the host cell. During maturation, HIV [[proteases]] cleave the [[polyproteins]] into individual functional HIV [[protein]]s and [[enzyme]]s. The various structural components then assemble to produce a mature HIV [[virion]].<ref name=Gelderblom>{{cite book
+| last = Gelderblom | first = H. R | year = 1997 | title = '''HIV Sequence Compendium''' | chapter = Fine structure of HIV and SIV | chapterurl = http://hiv.lanl.gov/content/hiv-db/COMPENDIUM/1997/partIII/Gelderblom.pdf | editor = Los Alamos National Laboratory (ed.) | edition = | pages = 31-44 | publisher = [[Los Alamos National Laboratory]] | location = [[Los Alamos, New Mexico]] | format = [[PDF|PDF format]]}}</ref> This cleavage step can be inhibited by protease inhibitors. The mature [[virus]] is then able to infect another [[cell]].
-Maturation either occurs in the forming bud or in the immature virion after it buds from the host cell. During maturation, HIV proteases cleave the polyproteins into individual functional HIV proteins and enzymes. The various structural components then assemble to produce a mature HIV virion.<ref name=Gelderblom>{{cite book
-| last = Gelderblom | first = H. R | year = 1997 | title = '''HIV Sequence Compendium''' | chapter = Fine structure of HIV and SIV | chapterurl = http://hiv.lanl.gov/content/hiv-db/COMPENDIUM/1997/partIII/Gelderblom.pdf | editor = Los Alamos National Laboratory (ed.) | edition = | pages = 31-44 | publisher = [[Los Alamos National Laboratory]] | location = [[Los Alamos, New Mexico]] | format = [[PDF|PDF format]]}}</ref> This cleavage step can be inhibited by protease inhibitors. The mature virus is then able to infect another cell.
 ==Genetic variability==
-{| align=right
+* HIV differs from many viruses in that it has very high genetic variability. This diversity is a result of its fast [[HIV#Life cycle of HIV|replication cycle]], with the generation of 10<sup>9</sup> to 10<sup>10</sup> virions every day, coupled with a high mutation rate of approximately 3 x 10<sup>-5</sup> per nucleotide base per cycle of replication and [[Genetic recombination|recombinogenic]] properties of reverse transcriptase.<ref name=RobertsonDL>
-| [[Image:HIV-SIV-phylogenetic-tree.png|thumb|200px|The [[phylogenetic tree]] of the SIV and HIV (click on image for a detailed description).]]
-|-
-| [[Image:subtype.png|thumb|200px|Map showing HIV-1 subtype prevalence. The bigger the pie chart, the more infections are present.]]
-|}
-HIV differs from many viruses in that it has very high genetic variability. This diversity is a result of its fast [[HIV#Life cycle of HIV|replication cycle]], with the generation of 10<sup>9</sup> to 10<sup>10</sup> virions every day, coupled with a high mutation rate of approximately 3 x 10<sup>-5</sup> per nucleotide base per cycle of replication and [[Genetic recombination|recombinogenic]] properties of reverse transcriptase.<ref name=RobertsonDL>
 {{cite journal
-| author=Robertson DL, Hahn BH, Sharp PM. | title=Recombination in AIDS viruses | journal=J Mol Evol. | year=1995 | pages=249-259 | volume=40 | issue=3 | pmid=7723052
+| author=Robertson DL, Hahn BH, Sharp PM. | title=Recombination in AIDS viruses | journal=J Mol Evol. | year=1995 | pages=249-259 | volume=40 | issue=3 | pmid=7723052}}</ref>
+* This complex scenario leads to the generation of many variants of HIV in a single infected patient in the course of one day.<ref name=RobertsonDL/> This variability is compounded when a single [[cell]] is simultaneously infected by two or more different strains of HIV. When simultaneous infection occurs, the genome of progeny [[virions]] may be composed of [[RNA]] strands from two different strains. This hybrid [[virion]] then infects a new cell where it undergoes replication. As this happens, the [[reverse transcriptase]], by jumping back and forth between the two different [[RNA]] templates, will generate a newly synthesized retroviral [[DNA]] sequence that is a recombinant between the two parental genomes.<ref name=RobertsonDL/> This recombination is most obvious when it occurs between subtypes.<ref name=RobertsonDL/>
-}}</ref> This complex scenario leads to the generation of many variants of HIV in a single infected patient in the course of one day.<ref name=RobertsonDL/> This variability is compounded when a single cell is simultaneously infected by two or more different strains of HIV. When simultaneous infection occurs, the genome of progeny virions may be composed of RNA strands from two different strains. This hybrid virion then infects a new cell where it undergoes replication. As this happens, the reverse transcriptase, by jumping back and forth between the two different RNA templates, will generate a newly synthesized retroviral DNA sequence that is a recombinant between the two parental genomes.<ref name=RobertsonDL/> This recombination is most obvious when it occurs between subtypes.<ref name=RobertsonDL/>
+* The closely related [[simian immunodeficiency virus]] (SIV) exhibits a somewhat different behavior: in its natural hosts, African green monkeys and sooty mangabeys, the retrovirus is present in high levels in the [[blood]], but evokes only a mild immune response,<ref>{{cite journal |author=Holzammer S, Holznagel E, Kaul A, Kurth R, Norley S |title=High virus loads in naturally and experimentally SIVagm-infected African green monkeys |journal=Virology |volume=283 |issue=2 |pages=324–31 |year=2001 |pmid=11336557 |doi=10.1006/viro.2001.0870}}</ref> does not cause the development of simian AIDS,<ref>Kurth, R. and Norley, S. (1996) Why don't the natural hosts of SIV develop simian AIDS?, ''J. NIH Res.'' '''8''', 33-37.</ref> and does not undergo the extensive mutation and recombination typical of HIV.<ref>{{cite journal |author=Baier M, Dittmar MT, Cichutek K, Kurth R |title=Development of vivo of genetic variability of simian immunodeficiency virus |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=88 |issue=18 |pages=8126–30 |year=1991 |pmid=1896460 |doi=}}</ref> By contrast, infection of heterologous hosts (rhesus or cynomologus macaques) with SIV results in the generation of genetic diversity that is on the same order as HIV in infected humans; these heterologous hosts also develop simian AIDS.<ref>{{cite journal |author=Daniel MD, King NW, Letvin NL, Hunt RD, Sehgal PK, Desrosiers RC |title=A new type D retrovirus isolated from macaques with an immunodeficiency syndrome |journal=Science |volume=223 |issue=4636 |pages=602–5 |year=1984 |pmid=6695172 |doi=10.1126/science.6695172}}</ref> The relationship, if any, between genetic diversification, [[immune]] response, and disease progression is unknown.
+* Three groups of HIV-1 have been identified on the basis of differences in ''env'': M, N, and O.<ref name=Thomson>
-The closely related [[simian immunodeficiency virus]] (SIV) exhibits a somewhat different behavior: in its natural hosts, African green monkeys and sooty mangabeys, the retrovirus is present in high levels in the blood, but evokes only a mild immune response,<ref>{{cite journal |author=Holzammer S, Holznagel E, Kaul A, Kurth R, Norley S |title=High virus loads in naturally and experimentally SIVagm-infected African green monkeys |journal=Virology |volume=283 |issue=2 |pages=324–31 |year=2001 |pmid=11336557 |doi=10.1006/viro.2001.0870}}</ref> does not cause the development of simian AIDS,<ref>Kurth, R. and Norley, S. (1996) Why don't the natural hosts of SIV develop simian AIDS?, ''J. NIH Res.'' '''8''', 33-37.</ref> and does not undergo the extensive mutation and recombination typical of HIV.<ref>{{cite journal |author=Baier M, Dittmar MT, Cichutek K, Kurth R |title=Development of vivo of genetic variability of simian immunodeficiency virus |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=88 |issue=18 |pages=8126–30 |year=1991 |pmid=1896460 |doi=}}</ref> By contrast, infection of heterologous hosts (rhesus or cynomologus macaques) with SIV results in the generation of genetic diversity that is on the same order as HIV in infected humans; these heterologous hosts also develop simian AIDS.<ref>{{cite journal |author=Daniel MD, King NW, Letvin NL, Hunt RD, Sehgal PK, Desrosiers RC |title=A new type D retrovirus isolated from macaques with an immunodeficiency syndrome |journal=Science |volume=223 |issue=4636 |pages=602–5 |year=1984 |pmid=6695172 |doi=10.1126/science.6695172}}</ref> The relationship, if any, between genetic diversification, immune response, and disease progression is unknown.
-Three groups of HIV-1 have been identified on the basis of differences in ''env'': M, N, and O.<ref name=Thomson>
 {{cite journal
 | author=Thomson, M. M., Perez-Alvarez, L. and Najera, R. | title=Molecular epidemiology of HIV-1 genetic forms and its significance for vaccine development and therapy | journal=Lancet Infect. Dis. | year=2002 | pages=461-471 | volume=2 | issue=8 | pmid=12150845
 }}</ref> Group M is the most prevalent and is subdivided into eight subtypes (or [[clade]]s), based on the whole genome, which are geographically distinct.<ref name=Carr>{{cite book
 | last = Carr | first = J. K. | coauthors = Foley, B. T., Leitner, T., Salminen, M., Korber, B. and McCutchan, F. | year = 1998 | title = '''HIV Sequence Compendium''' | chapter = Reference Sequences Representing the Principal Genetic Diversity of HIV-1 in the Pandemic | chapterurl = http://hiv.lanl.gov/content/hiv-db/COMPENDIUM/1998/III/Carr.pdf | editor = Los Alamos National Laboratory (ed.) | edition = | pages = 10-19 | publisher = [[Los Alamos National Laboratory]] | location = [[Los Alamos, New Mexico]] | format=[[PDF|PDF format]]}}</ref> The most prevalent are subtypes B (found mainly in North America and Europe), A and D (found mainly in Africa), and C (found mainly in Africa and Asia); these subtypes form branches in the phylogenetic tree representing the lineage of the M group of HIV-1. Coinfection with distinct subtypes gives rise to circulating recombinant forms (CRFs). In 2000, the last year in which an analysis of global subtype prevalence was made, 47.2% of infections worldwide were of subtype C, 26.7% were of subtype A/CRF02_AG, 12.3% were of subtype B, 5.3% were of subtype D, 3.2% were of CRF_AE, and the remaining 5.3% were composed of other subtypes and CRFs.<ref name=Osmanov>
 {{cite journal
 | author=Osmanov S, Pattou C, Walker N, Schwardlander B, Esparza J; WHO-UNAIDS Network for HIV Isolation and Characterization. | title=Estimated global distribution and regional spread of HIV-1 genetic subtypes in the year 2000 | journal=Acquir. Immune. Defic. Syndr. | year=2002 | pages=184-190 | volume=29 | issue=2 | pmid=11832690
 }}</ref> Most HIV-1 research is focused on subtype B; few laboratories focus on the other subtypes.<ref name=Perrin>
 {{cite journal
 | author=Perrin L, Kaiser L, Yerly S. | title=Travel and the spread of HIV-1 genetic variants | journal=Lancet Infect Dis. | year=2003 | pages=22-27 | volume=3 | issue=1 | pmid=12505029
 }}</ref>
+* The genetic sequence of HIV-2 is only partially homologous to HIV-1 and more closely resembles that of SIV than HIV-1.
-The genetic sequence of HIV-2 is only partially homologous to HIV-1 and more closely resembles that of SIV than HIV-1.
+{| style="float:center"
+| [[Image:HIV-SIV-phylogenetic-tree.png|thumb|left|300px|The [[phylogenetic tree]] of the SIV and HIV (click on image for a detailed description). - By Kuiken, C., Foley, B., Hahn, B., Marx, P., McCutchan, F., Mellors, J. W., Mullins, J., Wolinsky, S. & Korber, B. (1999). A compilation and analysis of nucleic acid and amino acid sequences. In Human Retroviruses and AIDS. Los Alamos, New Mexico: Theoretical Biology and Biophysics Group, Los Alamos National Laboratory. - Theoretical Biology and Biophysics Group, Los Alamos National Laboratory.http://www.hiv.lanl.gov/content/sequence/HIV/COMPENDIUM/99compendium.htmlhttp://www.hiv.lanl.gov/content/sequence/HIV/COMPENDIUM/1999/1/intro.pdf, Public Domain, https://commons.wikimedia.org/w/index.php?curid=3915158]]
-==The clinical course of infection==
+| [[Image:subtype.png|thumb|left|500px|Map showing HIV-1 subtype prevalence. The bigger the pie chart, the more infections are present. - By The original uploader was Grcampbell at English WikipediaLater version(s) were uploaded by Renegadeviking, Emmojo666 at en.wikipedia.(Original text: en.User:Grcampbell) - Based on Osmanov S, Pattou C, Walker N, Schwardlander B, Esparza J; WHO-UNAIDS Network for HIV Isolation and Characterization. (2002) Estimated global distribution and regional spread of HIV-1 genetic subtypes in the year 2000. J Acquir Immune Defic Syndr. 29(2):184-90., CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=3745709]]
-:''For more details on this topic, see [[AIDS#Diagnosis|AIDS Diagnosis]], [[AIDS#Symptoms and Complications|AIDS Symptoms and Complications]] and [[WHO Disease Staging System for HIV Infection and Disease]]''
-[[Image:Hiv-timecourse.png|400px|thumb|right|A generalized graph of the relationship between HIV copies (viral load) and CD4 counts over the average course of untreated HIV infection; any particular individual's disease course may vary considerably.
-{{legend-line|blue solid 2px|CD4<sup>+</sup> T cell count (cells per µL)}}
-{{legend-line|red solid 2px|HIV RNA copies per&nbsp;mL of plasma}}
-]]
-Infection with HIV-1 is associated with a progressive decrease of the CD4<SUP>+</SUP> T cell count and an increase in [[viral load]]. The stage of infection can be determined by measuring the patient's CD4<SUP>+</SUP> T cell count, and the level of HIV in the blood.
-The initial infection with HIV generally occurs after transfer of body fluids from an infected person to an uninfected one. The first stage of infection, the primary, or acute infection, is a period of rapid viral replication that immediately follows the individual's exposure to HIV leading to an abundance of virus in the peripheral blood with levels of HIV commonly approaching several million viruses per&nbsp;mL.<ref name=Piatak> {{cite journal | author=Piatak, M., Jr, Saag, M. S., Yang, L. C., Clark, S. J., Kappes, J. C., Luk, K. C., Hahn, B. H., Shaw, G. M. and Lifson, J.D. | title=High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR | journal=Science | year=1993 | pages=1749-1754 | volume=259 | issue=5102 | pmid=8096089 | doi=10.1126/science.8096089}}</ref> This response is accompanied by a marked drop in the numbers of circulating CD4<sup>+</sup> T cells. This acute viremia is associated in virtually all patients with the activation of [[cytotoxic T cell|CD8<sup>+</sup> T cells]], which kill HIV-infected cells, and subsequently with antibody production, or [[seroconversion]]. The CD8<sup>+</sup> T cell response is thought to be important in controlling virus levels, which peak and then decline, as the CD4<sup>+</sup> T cell counts rebound to around 800 cells per&nbsp;mL (the normal value is 1200 cells per&nbsp;mL ). A good CD8<sup>+</sup> T cell response has been linked to slower disease progression and a better prognosis, though it does not eliminate the virus.<ref name=Pantaleo1998>
-{{cite journal
-| author=Pantaleo G, Demarest JF, Schacker T, Vaccarezza M, Cohen OJ, Daucher M, Graziosi C, Schnittman SS, Quinn TC, Shaw GM, Perrin L, Tambussi G, Lazzarin A, Sekaly RP, Soudeyns H, Corey L, Fauci AS. | title=The qualitative nature of the primary immune response to HIV infection is a prognosticator of disease progression independent of the initial level of plasma viremia | journal=Proc Natl Acad Sci U S A. | year=1997 | pages=254-258 | volume=94 | issue=1 | pmid=8990195
-}}</ref> During this period (usually 2-4 weeks post-exposure) most individuals (80 to 90%) develop an influenza or mononucleosis-like illness called [[acute HIV infection]], the most common symptoms of which may include [[fever]], [[lymphadenopathy]], [[pharyngitis]], [[rash]], [[myalgia]], [[malaise]], mouth and esophagal sores, and may also include, but less commonly, [[headache]], [[nausea]] and [[vomiting]], enlarged liver/spleen, [[weight loss]], [[Candidiasis|thrush]], and neurological symptoms. Infected individuals may experience all, some, or none of these symptoms. The duration of symptoms varies, averaging 28 days and usually lasting at least a week.<ref name=Kahn>
-{{cite journal
-| author=Kahn, J. O. and Walker, B. D. | title=Acute Human Immunodeficiency Virus type 1 infection | journal=N. Engl. J. Med. | year=1998 | pages=33-39 | volume=331 | issue=1 | pmid=9647878
-}}</ref> Because of the nonspecific nature of these symptoms, they are often not recognized as signs of HIV infection. Even if patients go to their doctors or a hospital, they will often be misdiagnosed as having one of the more common infectious diseases with the same symptoms. Consequently, these primary symptoms are not used to diagnose HIV infection as they do not develop in all cases and because many are caused by other more common diseases. However, recognizing the syndrome can be important because the patient is much more infectious during this period.
-<ref name="pmid11187417">{{cite journal |author=Daar ES, Little S, Pitt J, ''et al'' |title=Diagnosis of primary HIV-1 infection. Los Angeles County Primary HIV Infection Recruitment Network |journal=Ann. Intern. Med. |volume=134 |issue=1 |pages=25–9 |year=2001 |pmid=11187417 |doi=}}</ref>
-{|  class="wikitable sortable"
-|+ History and physical findings for primary HIV infection<ref name="pmid11187417">{{cite journal |author=Daar ES, Little S, Pitt J, ''et al'' |title=Diagnosis of primary HIV-1 infection. Los Angeles County Primary HIV Infection Recruitment Network |journal=Ann. Intern. Med. |volume=134 |issue=1 |pages=25–9 |year=2001 |pmid=11187417 |doi=}}</ref>
-! !! [[sensitivity (tests)|sensitivity]]!! [[specificity (tests)|specificity]]
-|-
-| Fever || 88% || 50%
-|-
-| Malaise || 73%|| 58%
-|-
-| Myalgia || 60%|| 74%
-|-
-| Rash || 58%|| 79%
-|-
-| Headache|| 55%|| 56%
-|-
-| Night sweats || 50%|| 68%
-|-
-| Sore throat || 43%|| 51%
-|-
-| Lymphadenopathy|| 38%|| 71%
-|-
-| Arthralgia || 28%|| 87%
-|-
-| Nasal congestion|| 18%|| 62%
 |}
-A strong immune defense reduces the number of viral particles in the blood stream, marking the start of the infection's [[incubation period|clinical latency]] stage. Clinical latency can vary between two weeks and 20 years. During this early phase of infection, HIV is active within [[Lymphatic system|lymphoid organs]], where large amounts of virus become trapped in the follicular [[dendritic cell]]s (FDC) network.<ref name=burton>
-{{cite journal
-| author=Burton GF, Keele BF, Estes JD, Thacker TC, Gartner S. | title=Follicular dendritic cell contributions to HIV pathogenesis | journal=Semin Immunol. | year=2002 | pages=275-284 | volume=14 | issue=4 | pmid=12163303
-}}</ref> The surrounding tissues that are rich in CD4<SUP>+</SUP> T cells may also become infected, and viral particles accumulate both in infected cells and as free virus. Individuals who are in this phase are still infectious. During this time, [[Helper T cell|CD4<SUP>+</SUP> CD45RO<SUP>+</SUP> T cells]] carry most of the proviral load.<ref name=clapham>
-{{cite journal
-| author=Clapham PR, McKnight A. | title=HIV-1 receptors and cell tropism | journal=Br Med Bull. | year=2001 | pages=43-59 | volume=58 | issue=4 | pmid=11714623
-}}</ref>
-When CD4<sup>+</sup> T cell numbers decline below a critical level, cell-mediated immunity is lost, and infections with a variety of opportunistic microbes appear. The first symptoms often include moderate and unexplained weight loss, recurring respiratory tract infections (such as [[sinusitis]], [[bronchitis]], [[otitis media]], [[pharyngitis]]), [[prostatitis]], skin rashes, and oral ulcerations. Common opportunistic infections and tumors, most of which are normally controlled by robust CD4<sup>+</sup> T cell-mediated immunity then start to affect the patient. Typically, resistance is lost early on to oral Candida species and to ''Mycobacterium tuberculosis'', which leads to an increased susceptibility to [[oral candidiasis]] (thrush) and [[tuberculosis]]. Later, reactivation of latent [[Herpesviridae|herpes viruses]] may cause worsening recurrences of [[herpes simplex]] eruptions, [[shingles]], [[Epstein-Barr virus]]-induced B-cell lymphomas, or [[Kaposi's sarcoma]], a [[tumor]] of [[endothelial cell]]s that occurs when HIV proteins such as Tat interact with [[Kaposi's sarcoma-associated herpesvirus|Human Herpesvirus-8]]. Pneumonia caused by the fungus ''[[Pneumocystis jirovecii]]'' is common and often fatal. In the final stages of AIDS, infection with [[cytomegalovirus]] (another herpes virus) or [[Mycobacterium avium complex]] is more prominent. Not all patients with AIDS get all these infections or tumors, and there are other tumors and infections that are less prominent but still significant.
-==HIV test==
-{{main|HIV test}}
-Many HIV-positive people are unaware that they are infected with the virus.<ref name=Kumaranayake>
-{{cite journal
-| author=Kumaranayake, L. and Watts, C. | title=
-Resource allocation and priority setting of HIV/AIDS interventions: addressing the generalized epidemic in sub-Saharan Africa | journal=J. Int. Dev. | year=2001 | pages=451-466 | volume=13 | issue=4 | doi = 10.1002/jid.797
-}}</ref> For example, less than 1% of the sexually active urban population in Africa have been tested and this proportion is even lower in rural populations.<ref name=Kumaranayake /> Furthermore, only 0.5% of pregnant women attending urban health facilities are counselled, tested or receive their test results.<ref name=Kumaranayake/> Again, this proportion is even lower in rural health facilities.<ref name=Kumaranayake/> Since donors may therefore be unaware of their infection, donor blood and blood products used in medicine and medical research are routinely screened for HIV.
-HIV-1 testing consists of initial screening with an [[enzyme-linked immunosorbent assay]] (ELISA) to detect antibodies to HIV-1. Specimens with a nonreactive result from the initial ELISA are considered HIV-negative unless new exposure to an infected partner or partner of unknown HIV status has occurred. Specimens with a reactive ELISA result are retested in duplicate.<ref name=CDC2001>
-{{cite journal
-| author=Centers for Disease Control and Prevention. | title=Revised guidelines for HIV counseling, testing, and referral | journal=MMWR Recomm Rep. | year=2001 | pages=1-57 | volume=50 | issue=RR-19 | pmid=11718472
-}}</ref> If the result of either duplicate test is reactive, the specimen is reported as repeatedly reactive and undergoes confirmatory testing with a more specific supplemental test (e.g., [[Western blot]] or, less commonly, an [[immunofluorescence assay]] (IFA)). Only specimens that are repeatedly reactive by ELISA and positive by IFA or reactive by Western blot are considered HIV-positive and indicative of HIV infection. Specimens that are repeatedly ELISA-reactive occasionally provide an indeterminate Western blot result, which may be either an incomplete antibody response to HIV in an infected person, or nonspecific reactions in an uninfected person.<ref name=celum>
-{{cite journal
-| author=Celum CL, Coombs RW, Lafferty W, Inui TS, Louie PH, Gates CA, McCreedy BJ, Egan R, Grove T, Alexander S, et al. | title=Indeterminate human immunodeficiency virus type 1 western blots: seroconversion risk, specificity of supplemental tests, and an algorithm for evaluation | journal=J Infect Dis. | year=1991 | pages=656-664 | volume=164 | issue=4 | pmid=1894929
-}}</ref> Although IFA can be used to confirm infection in these ambiguous cases, this assay is not widely used. Generally, a second specimen should be collected more than a month later and retested for persons with indeterminate Western blot results. Although much less commonly available, nucleic acid testing (e.g., viral RNA or proviral DNA amplification method) can also help diagnosis in certain situations.<ref name=CDC2001 /> In addition, a few tested specimens might provide inconclusive results because of a low quantity specimen. In these situations, a second specimen is collected and tested for HIV infection.
-==Treatment==
-<!-- Note that HIV and AIDS are two different pages, so the link to the AIDS treatment section is not simply redirecting here. -->
-:''See also [[AIDS#Treatment|AIDS Treatment]] and [[Antiretroviral drug]].''
-[[Image:Abacavir (Ziagen) 300mg.jpg|right|thumb|100px|''[[Abacavir]]'' - a nucleoside analog reverse transcriptase inhibitors (NARTIs or NRTIs)]]
-[[Image:Abacavir structure.svg|right|thumb|100px|The chemical structure of Abacavir]]
-There is currently no [[HIV vaccine|vaccine]] or cure for HIV or AIDS. The only known method of prevention is avoiding exposure to the virus. However, an antiretroviral treatment, known as [[post-exposure prophylaxis]], is believed to reduce the risk of infection if begun directly after exposure.<ref name=Fan>{{cite book
-| author = | year = 2005 | title = '''AIDS : science and society''' | chapter = | chapterurl = | editor = Fan, H., Conner, R. F. and Villarreal, L. P. eds | edition = 4th edition | pages = | publisher = Jones and Bartlett Publishers | location = [[Boston, Massachusetts|Boston, MA]] | id = ISBN 0-7637-0086-X}}</ref> Current treatment for HIV infection consists of [[highly active antiretroviral therapy]], or HAART.<ref name=DhhsHivTreatment>{{
- cite web
- | author=[[Department of Health and Human Services]] | publisher=
- | year=January, 2005
- | url=http://www.hab.hrsa.gov/tools/HIVpocketguide05/PktGARTtables.htm
- | title=A Pocket Guide to Adult HIV/AIDS Treatment January 2005 edition
- | accessdate=2006-01-17
-}}</ref> This has been highly beneficial to many HIV-infected individuals since its introduction in 1996, when the protease inhibitor-based HAART initially became available.<ref name=Pallelal>{{
- cite journal
- | author=Palella, F. J., Delaney, K. M., Moorman, A. C., Loveless, M. O., Fuhrer, J., Satten, G. A., Aschman, D. J. and Holmberg, S. D. | title=Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection | journal=N. Engl. J. Med. | year=1998 | pages=853-860 | volume=338 | issue=13 | pmid=9516219
-}}</ref> Current HAART options are combinations (or "cocktails") consisting of at least three drugs belonging to at least two types, or "classes," of [[anti-retroviral]] agents. Typically, these classes are two [[nucleoside analogue reverse transcriptase inhibitor]]s (NARTIs or NRTIs) plus either a [[protease inhibitor (pharmacology)|protease inhibitor]] or a [[non-nucleoside reverse transcriptase inhibitor]] (NNRTI). Because AIDS progression in children is more rapid and less predictable than in adults, particularly in young infants, more aggressive treatment is recommended for children than adults.<ref name=2005dhhsHivChildren>{{
- cite web
- | author=[[Department of Health and Human Services]] Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children
- | publisher= | year=[[November 3]], [[2005]]
- | url=http://www.aidsinfo.nih.gov/ContentFiles/PediatricGuidelines_PDA.pdf
- | title=Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
- | format= PDF
- | accessdate=2006-01-17
-}}</ref> In developed countries where HAART is available, doctors assess their patients thoroughly: measuring the [[viral load]], how fast CD4 declines, and patient readiness. They then decide when to recommend starting treatment.<ref name=2005DhhsHivTreatment>{{
- cite web
- | author=[[Department of Health and Human Services]] Panel on Clinical Practices for Treatment of HIV Infection
- | publisher= | year=[[October 6]], [[2005]]
- | url=http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf
- | title=Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents
- | format= PDF
- | accessdate=2006-01-17
-}}</ref>
-HAART allows the stabilisation of the patient’s symptoms and viremia, but it neither cures the patient, nor alleviates the symptoms; high levels of HIV-1, often HAART resistant, return once treatment is stopped.<ref name=martinez>{{
- cite journal
- | author=Martinez-Picado, J., DePasquale, M. P., Kartsonis, N., Hanna, G. J., Wong, J., Finzi, D., Rosenberg, E., Gunthard, H. F., Sutton, L., Savara, A., Petropoulos, C. J., Hellmann, N., Walker, B. D., Richman, D. D., Siliciano, R. and D'Aquila, R. T. | title=Antiretroviral resistance during successful therapy of human immunodeficiency virus type 1 infection | journal=Proc. Natl. Acad. Sci. U. S. A. | year=2000 | pages=10948-10953 | volume=97 | issue=20 | pmid=11005867
-}}</ref><ref name=Dybul>{{
- cite journal
- | author=Dybul, M., Fauci, A. S., Bartlett, J. G., Kaplan, J. E., Pau, A. K.; Panel on Clinical Practices for Treatment of HIV.
- | title=Guidelines for using antiretroviral agents among HIV-infected adults and adolescents
- | journal=Ann. Intern. Med. | year=2002 | pages=381-433 | volume=137 | issue=5 Pt 2
- | pmid=12617573
-}}</ref> Moreover, it would take more than a lifetime for HIV infection to be cleared using HAART.<ref name=blankson>{{
- cite journal
- | author=Blankson, J. N., Persaud, D., Siliciano, R. F. | title=The challenge of viral reservoirs in HIV-1 infection | journal=Annu. Rev. Med. | year=2002 | pages=557-593 | volume=53 | issue= | pmid=11818490
-}}</ref> Despite this, many HIV-infected individuals have experienced remarkable improvements in their general health and quality of life, which has led to a large reduction in HIV-associated [[morbidity]] and mortality in the developed world.<ref name=Pallelal>{{
- cite journal
- | author=Palella, F. J., Delaney, K. M., Moorman, A. C., Loveless, M. O., Fuhrer, J., Satten, G. A., Aschman, D. J. and Holmberg, S. D. | title=Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection | journal=N. Engl. J. Med. | year=1998 | pages=853-860 | volume=338 | issue=13 | pmid=9516219
-}}</ref><ref name=Wood>{{
- cite journal
- | author=Wood, E., Hogg, R. S., Yip, B., Harrigan, P. R., O'Shaughnessy, M. V. and Montaner, J. S.
- | title=Is there a baseline CD4 cell count that precludes a survival response to modern antiretroviral therapy?
- | journal=AIDS | year=2003 | pages=711-720 | volume=17 | issue=5
- | pmid=12646794
-}}</ref><ref name=Chene>{{
- cite journal
- | author=Chene, G., Sterne, J. A., May, M., Costagliola, D., Ledergerber, B., Phillips, A. N., Dabis, F., Lundgren, J., D'Arminio Monforte, A., de Wolf, F., Hogg, R., Reiss, P., Justice, A., Leport, C., Staszewski, S., Gill, J., Fatkenheuer, G., Egger, M. E. and the Antiretroviral Therapy Cohort Collaboration.
- | title=Prognostic importance of initial response in HIV-1 infected patients starting potent antiretroviral therapy: analysis of prospective studies
- | journal=Lancet | year=2003 | pages=679-686 | volume=362 | issue=9385
- | pmid=12957089
-}}</ref> A computer based study in 2006 projected that following the 2004 United States treatment guidelines gave an average life expectancy of an HIV infected individual to be 32.1 years from the time of infection if treatment was started when the CD4 count was 350/µL.<ref name=schack>{{
- cite journal
- | author=Schackman BR, Gebo KA, Walensky RP, Losina E, Muccio T, Sax PE, Weinstein MC, Seage GR 3rd, Moore RD, Freedberg KA.
- | title=The lifetime cost of current HIV care in the United States
- | journal=Med Care | year=2006 | pages=990-997 | volume=44 | issue=11
- | pmid=17063130
-}}</ref> This study was limited as it did not take into account possible future treatments and the projection has not been confirmed within a clinical cohort setting. In the absence of HAART, progression from HIV infection to AIDS has been observed to occur at a [[median]] of between nine to ten years and the median survival time after developing AIDS is only 9.2 months.<ref name=Morgan2>{{
- cite journal
- | author=Morgan, D., Mahe, C., Mayanja, B., Okongo, J. M., Lubega, R. and Whitworth, J. A.
- | title=HIV-1 infection in rural Africa: is there a difference in median time to AIDS and survival compared with that in industrialized countries?
- | journal=AIDS | year=2002 | pages=597-632 | volume=16 | issue=4 | pmid=11873003
-}}</ref> However, HAART sometimes achieves far less than optimal results, in some circumstances being effective in less than fifty percent of patients. This is due to a variety of reasons such as medication intolerance/side effects, prior ineffective antiretroviral therapy and infection with a drug-resistant strain of HIV. However, non-adherence and non-persistence with antiretroviral therapy is the major reason most individuals fail to benefit from HAART.<ref name=becker>{{
- cite journal
- | author=Becker SL, Dezii CM, Burtcel B, Kawabata H, Hodder S. | title=Young HIV-infected adults are at greater risk for medication nonadherence | journal=MedGenMed. | year=2002 | pages=21 | volume=4| issue=3 | pmid=12466764
-}}</ref> The reasons for non-adherence and non-persistence with HAART are varied and overlapping. Major psychosocial issues, such as poor access to medical care, inadequate social supports, psychiatric disease and drug abuse contribute to non-adherence. The complexity of these HAART regimens, whether due to pill number, dosing frequency, meal restrictions or other issues along with side effects that create intentional non-adherence also contribute to this problem.<ref name=Nieuwkerk>{{
- cite journal
- | author=Nieuwkerk, P., Sprangers, M., Burger, D., Hoetelmans, R. M., Hugen, P. W., Danner, S. A., van Der Ende, M. E., Schneider, M. M., Schrey, G., Meenhorst, P. L., Sprenger, H. G., Kauffmann, R. H., Jambroes, M., Chesney, M. A., de Wolf, F., Lange, J. M. and the ATHENA Project. | title=Limited Patient Adherence to Highly Active Antiretroviral Therapy for HIV-1 Infection in an Observational Cohort Study | journal=Arch. Intern. Med. | year=2001 | pages=1962-1968 | volume=161 | issue=16 | pmid=11525698
-}}</ref><ref name=Kleeberger>{{
- cite journal
- | author=Kleeberger, C., Phair, J., Strathdee, S., Detels, R., Kingsley, L. and Jacobson, L. P. | title=Determinants of Heterogeneous Adherence to HIV-Antiretroviral Therapies in the Multicenter AIDS Cohort Study| journal=J. Acquir. Immune Defic. Syndr. | year=2001 | pages=82-92 | volume=26 | issue=1 | pmid=11176272
-}}</ref><ref name=heath>{{
- cite journal
- | author=Heath, K. V., Singer, J., O'Shaughnessy, M. V., Montaner, J. S. and Hogg, R. S. | title=Intentional Nonadherence Due to Adverse Symptoms Associated With Antiretroviral Therapy | journal=J. Acquir. Immune Defic. Syndr. | year=2002 | pages=211-217 | volume=31 | issue=2 | pmid=12394800
-}}</ref> The side effects include [[lipodystrophy]], [[dyslipidaemia]], [[insulin resistance]], an increase in [[cardiovascular]] risks and [[birth defect]]s.<ref name=Montessori>{{
- cite journal |
- author=Montessori, V., Press, N., Harris, M., Akagi, L., Montaner, J. S. |
- title=Adverse effects of antiretroviral therapy for HIV infection. |
- journal=CMAJ | year=2004 | pages=229-238 | volume=170 | issue=2 | pmid=14734438
-}}</ref><ref name=Saitoh>{{
- cite journal
- | author=Saitoh, A., Hull, A. D., Franklin, P. and Spector, S. A.
- | title=Myelomeningocele in an infant with intrauterine exposure to efavirenz
- | journal=J. Perinatol. | year=2005 | pages=555-556 | volume=25 | issue=8
- | pmid=16047034
-}}</ref>
-The timing for starting HIV treatment is still debated. There is no question that treatment should be started before the patient's CD4 count falls below 200, and most national guidelines say to start treatment once the CD4 count falls below 350; but there is some evidence from cohort studies that treatment should be started before the CD4 count falls below 350.<ref name="Wang2004">{{
- cite journal
- | author=Wang C, Vlahov D, Galai N, ''et al.''
- | title=Mortality in HIV-seropositive versus seronegative persons in the era of highly active antiretroviral therapy.
- | journal=J. Infect. Dis. | year=2004 | volume=190 | pages=1046&ndash;54
- | pmid=15319852
-}}</ref><ref name="Wood">{{
- cite journal
- | author=Wood E, HoggRS, Harrigan PR, Montaner JS.
- | title=When to initial antiretroviral therapy in HIV-1-infected adults: a review for clinicians and patients
- | journal=Lancet Infect. Dis.
- | year=2005
- | volume=5
- | pages=407&ndash;14
-}}</ref> There is also evidence to say that treatment should be started before CD4 percentage falls below 15%.<ref name="">{{
- cite journal
- | author=Moore, D.M.; Hogg, R.S.; Yip, B.; ''et al.''
- | title=CD4 percentage is an independent predictor of survival in patients starting antiretroviral therapy with absolute CD4 cell counts between 200 and 350 cells/μL
- | journal=HIV Med
- | year=2006
- | volume=7
- | pages=383&ndash;8
- | pmid=16903983
-}}</ref> In those countries where CD4 counts are not available, patients with WHO stage III or IV disease<ref name="WHO">{{
- cite web
- | author=World Health Organisation
- | title=WHO case definitions of HIV for surveillance and revised clinical staging and immunological classification
- | year=2006
- | url=http://www.who.int/hiv/pub/guidelines/WHO%20HIV%20Staging.pdf
- | accessdate=2006-12-27
-}}</ref> should be offered treatment.
-Anti-retroviral drugs are expensive, and the majority of the world's infected individuals do not have access to medications and treatments for HIV and AIDS.<ref name=Ferrantelli>{{
- cite journal
- | author=Ferrantelli F, Cafaro A, Ensoli B. | title=Nonstructural HIV proteins as targets for prophylactic or therapeutic vaccines | journal=Curr Opin Biotechnol. | year=2004 | pages=543-556 | volume=15 | issue=6
- | pmid=15560981
-}}</ref> Research to improve current treatments includes decreasing side effects of current drugs, further simplifying drug regimens to improve adherence, and determining the best sequence of regimens to manage drug resistance. Unfortunately, only a vaccine is thought to be able to halt the pandemic. This is because a vaccine would cost less, thus being affordable for developing countries, and would not require daily treatment.<ref name=Ferrantelli/> However, after over 20 years of research, HIV-1 remains a difficult target for a vaccine.<ref name=Ferrantelli/> In February 2007, The National Institute of Allergy and Infectious Diseases published a report that gave details of a region on HIV's surface that is a potential target for a vaccine.<ref name="HIV weak spot">{{
- cite web
- | author=BBC News
- | title=Scientists expose HIV weak spot
- | year=2007
- | url=http://news.bbc.co.uk/2/hi/health/6357287.stm
- | accessdate=2007-04-20
-}}</ref>
-Researchers at the Heinrich Pette Institute of Experimental Virology and Immunology at Hamburg have engineered an enzyme called Cre recombinase which is able to remove HIV from an infected cell.<ref name="Cre recombinase">{{
- cite web
- | author=Paternity Testing Labs
- | title=German scientists “cure” HIV-infected human lymphocytes
- | year=2007
- | url=http://www.paternitytestinglabs.com/german-scientists-cure-hiv-infected-human-lymphocytes/
- | accessdate=2007-10-25
-}}</ref>  Similarly, scientists at the Max Planck Institute for Molecular Cell Biology and Genetics in Dresden have engineered an enzyme called Tre recombinase which is able to remove HIV from an infected cell.<ref name="Tre recombinase">{{
- cite web
- | author=Terra Daily
- | title=Another Potential Cure For HIV Discovered
- | year=2007
- | url=http://www.terradaily.com/reports/Another_Potential_Cure_For_HIV_Discovered_999.html
- | accessdate=2007-06-29
-}}</ref>  These enzymes promise a treatment in which a patient's stem cells are extracted, cured, and reinjected to promulgate the enzyme into the body.  The carried enzyme then finds and removes the virus.
-==Epidemiology==
-{{main|AIDS pandemic}}
-[[Image:HIV Epidemx3.png|250px|thumb|right|Prevalence of HIV among adults per country at the end of 2005
-{{legend|#800000|15&ndash;50%}}
-{{legend|#FF0000|5&ndash;15%}}
-{{legend|#E08040|1&ndash;5%}}
-{{legend|#e0c000|0.5&ndash;1.0%}}
-{{legend|#e0e080|0.1&ndash;0.5%}}
-{{legend|#00e080|<0.1%}}
-{{legend|#c0c0c0|no data}}
-]]
-UNAIDS and the WHO estimate that AIDS has killed more than 25&nbsp;million people since it was first recognized in 1981, making it one of the most destructive pandemics in recorded history. Despite recent improved access to antiretroviral treatment and care in many regions of the world, the AIDS pandemic claimed an estimated 2.8&nbsp;million (between 2.4 and 3.3&nbsp;million) lives in 2005 of which more than half a&nbsp;million (570,000) were children.<ref name=UNAIDS2006 />
-Globally, between 33.4 and 46&nbsp;million people currently live with HIV.<ref name=UNAIDS2006 /> In 2005, between 3.4 and 6.2&nbsp;million people were newly infected and between 2.4 and 3.3&nbsp;million people with AIDS died, an increase from 2004 and the highest number since 1981.
-[[AIDS pandemic#Sub-Saharan Africa|Sub-Saharan Africa]] remains by far the worst-affected region, with an estimated 21.6 to 27.4&nbsp;million people currently living with HIV. Two&nbsp;million &#91;1.5–3.0&nbsp;million&#93; of them are children younger than 15 years of age. More than 64% of all people living with HIV are in sub-Saharan Africa, as are more than three quarters of all women living with HIV. In 2005, there were 12.0&nbsp;million &#91;10.6&ndash;13.6&nbsp;million&#93; AIDS orphans living in sub-Saharan Africa 2005.<ref name=UNAIDS2006 /> [[AIDS pandemic#South and South-East Asia|South & South East Asia]] are second-worst affected with 15% of the total. AIDS accounts for the deaths of 500,000 children in this region. South Africa has the largest number of HIV patients in the world followed by Nigeria.<ref>{{cite news |first=Donald |last=McNeil, Jr. |authorlink= |coauthors= |title= U.N. Agency to Say It Overstated Extent of H.I.V. Cases by Millions |url=http://query.nytimes.com/gst/fullpage.html?res=9C01EEDF103BF933A15752C1A9619C8B63&n |work= |publisher=''The New York Times'' |date=November 20, 2007 |accessdate=2008-01-16 }}</ref> India has an estimated 2.5 &nbsp;million infections (0.23% of population), making India the country with the third largest population of HIV patients. In the 35 African nations with the highest prevalence, average [[life expectancy]] is 48.3 years&mdash;6.5 years less than it would be without the disease.<ref name=UNAIDS2001>{{
- cite web
- | author=UNAIDS | publisher= | year=2001
- | url=http://data.unaids.org/Publications/External-Documents/GAS26-rt3_en.pdf
- | title=Special Session of the General Assembly on HIV/AIDS Round table 3 Socio-economic impact of the epidemic and the strengthening of national capacities to combat HIV/AIDS
- | accessdate=2006-06-15
- | format= [[PDF|PDF format]]
-}}</ref>
-The latest evaluation report of the World Bank's Operations Evaluation Department assesses the development effectiveness of the World Bank's country-level HIV/AIDS assistance defined as policy dialogue, analytic work, and lending with the explicit objective of reducing the scope or impact of the AIDS epidemic.<ref name=Worldbank>{{
- cite web
- | author=[[World Bank Group|World Bank]] | publisher= | year=2005
- | url=http://www.worldbank.org/oed/aids/main_report.html
- | title=Evaluating the World Bank's Assistance for Fighting the HIV/AIDS Epidemic
- | accessdate=2006-01-17
-}}</ref> This is the first comprehensive evaluation of the World Bank's HIV/AIDS support to countries, from the beginning of the epidemic through mid-2004. Because the Bank aims to assist in implementation of national government programmes, their experience provides important insights on how national AIDS programmes can be made more effective.
-The development of [[HAART]] as effective therapy for HIV infection and AIDS has substantially reduced the death rate from this disease in those areas where these drugs are widely available. This has created the misperception that the disease has vanished. In fact, as the life expectancy of persons with AIDS has increased in countries where HAART is widely used, the number of persons living with AIDS has increased substantially. In the United States, the number of persons with AIDS increased from about 35,000 in 1988 to over 220,000 in 1996.<ref name=CDC1996>{{
- cite journal |
- author=[[Centers for Disease Control and Prevention]] |
- title=U.S. HIV and AIDS cases reported through December 1996 |
- journal=HIV/AIDS Surveillance Report | year=1996 | pages=1-40 | volume=8 | issue=2 | url=http://www.cdc.gov/hiv/stats/hivsur82.pdf | format= [[PDF|PDF format]]
-}}</ref>
-In Africa, the number of MTCT and the prevalence of AIDS is beginning to reverse decades of steady progress in child survival. Countries such as Uganda are attempting to curb the MTCT epidemic by offering VCT (voluntary counselling and testing), PMTCT (prevention of mother-to-child transmission) and ANC (ante-natal care) services, which include the distribution of antiretroviral therapy.
-==AIDS denialism==
-{{main|AIDS reappraisal}}
-A small minority of scientists and activists question the connection between HIV and AIDS,<ref name=Duesberg>{{cite journal
- | author=Duesberg, P. H.
- | title=HIV is not the cause of AIDS
- | journal=Science | year=1988 | pages=514, 517 | volume=241 | issue=4865
- | pmid=3399880 | doi=10.1126/science.3399880
-}}</ref> the existence of HIV itself,<ref name=Papadopulos>{{
-cite journal
- | author=Papadopulos-Eleopulos, E., Turner, V. F., Papadimitriou, J., Page, B., Causer, D., Alfonso, H., Mhlongo, S., Miller, T., Maniotis, A. and Fiala, C.
- | title=A critique of the Montagnier evidence for the HIV/AIDS hypothesis
- | journal=Med Hypotheses | year=2004 | pages=597&ndash;601 | volume=63 | issue=4
- | pmid=15325002
-}}</ref> or the validity of current testing and treatment methods. These claims have been examined and widely rejected by the scientific community,<ref name=consensus>For evidence of the [[scientific consensus]] that HIV is the cause of AIDS, see (for example):
-*{{cite journal |author= |title=The Durban Declaration |journal=Nature |volume=406 |issue=6791 |pages=15-6 |year=2000 |pmid=10894520 |doi=10.1038/35017662}} - full text [http://www.nature.com/nature/journal/v406/n6791/full/406015a0.html here].
-*{{cite journal
- | author=Cohen, J.
- | title=The Controversy over HIV and AIDS
- | journal=Science | year=1994 | pages=1642&ndash;1649 | volume=266 | issue=5191
- | url=http://www.sciencemag.org/feature/data/cohen/266-5191-1642a.pdf}}
-*{{cite web
-| author=Various
-| publisher=[[National Institute of Allergy and Infectious Diseases]] | year=
-| url=http://www3.niaid.nih.gov/news/focuson/hiv/resources/
-| title=Focus on the HIV-AIDS Connection: Resource links
-| accessdate = 2006-09-07
-}}
-*{{cite journal |author=O'Brien SJ, Goedert JJ |title=HIV causes AIDS: Koch's postulates fulfilled |journal=Curr. Opin. Immunol. |volume=8 |issue=5 |pages=613-8 |year=1996 |pmid=8902385 |doi=}}
-*{{cite journal |author=Galéa P, Chermann JC |title=HIV as the cause of AIDS and associated diseases |journal=Genetica |volume=104 |issue=2 |pages=133-42 |year=1998 |pmid=10220906 |doi=}}</ref> although they have had a political impact, particularly in South Africa, where governmental acceptance of AIDS denialism has been blamed for an ineffective response to that country's AIDS epidemic.<ref>{{cite journal |author=Watson J |title=Scientists, activists sue South Africa's AIDS 'denialists' |journal=Nat. Med. |volume=12 |issue=1 |pages=6 |year=2006 |pmid=16397537 |doi=10.1038/nm0106-6a}}</ref><ref>{{cite journal |author=Baleta A |title=S Africa's AIDS activists accuse government of murder |journal=Lancet |volume=361 |issue=9363 |pages=1105 |year=2003 |pmid=12672319 |doi=10.1016/S0140-6736(03)12909-1}}</ref><ref>{{cite journal |author=Cohen J |title=South Africa's new enemy |journal=Science |volume=288 |issue=5474 |pages=2168-70 |year=2000 |pmid=10896606 |doi=10.1126/science.288.5474.2168}}</ref>
-==Related Chapters==
-* [[AIDS]]
-* [[HIV disease]]
 ==References==
@@ Line 874: / Line 190: @@
 ==External links==
-*[http://www.unaids.org UNAIDS - Joint United Nations Programme on HIV/AIDS webpage]
+*[http://pathmicro.med.sc.edu/lecture/hiv9.htm Genome at sc.edu]
-**[http://www.unaids.org/en/HIV_data/2006GlobalReport/default.asp 2006 Report on the Global AIDS Epidemic] by [[UNAIDS]]
-*[http://www.plusnews.org/ PlusNews, The United Nations HIV and AIDS news service]
-*[http://aidshistory.nih.gov/ History of AIDS research at the NIH]
-*[http://www.doctorswithoutborders.org/news/hiv-aids/index.cfm Medecins Sans Frontieres/Doctors Without Borders HIV/AIDS Pages]
-*[http://aidsinfo.nih.gov AIDSinfo - HIV/AIDS Information] - Comprehensive resource for HIV/AIDS treatment and clinical trial information from the U. S. Department of Health and Human Services
-*[http://hivinsite.org/InSite HIV InSite] - University of California San Francisco
-*[http://www.aids.org AIDS.ORG: Educating - Raising HIV Awareness - Building Community]
-*[http://www.aidsportal.org AIDSPortal - Latest policy, research, guidelines and case studies]
-* [http://www.AIDS.gov AIDS.gov] Portal for all Federal domestic HIV/AIDS information and resources
-;News media
-*[http://www.pbs.org/wgbh/pages/frontline/aids/ "The Age of Aids"] [[March 30]], [[2006]] ''Frontline''
-*[http://www.newscientist.com/channel/health/hiv Everything you wanted to know about HIV and AIDS] — Provided by ''[[New Scientist]]''.
-*[http://www.time.com/time/magazine/article/0,9171,1223367,00.html "The Graying of AIDS" - Older Americans living with HIV face unique challenges] - ''TIME'' magazine, 08/14/06
-*[http://www.topix.net/forum/city/diamond-springs-ca/TA59HSBVGG8042DNC "Elite" HIV patients mystify doctors] - Aug 16, 2006 | Reuters on Topix.net
-;Online textbooks
-*[http://www.HIVMedicine.com HIV Medicine 2006], medical textbook, 14th edition, 825 pages (free download)
-*[http://www.mcld.co.uk/hiv/ "The Molecules of HIV" information resource]
-;Advocacy
-*[http://www.bethegeneration.org Be the Generation - Information on HIV Vaccine Clinical Research in 20 American Cities]
-*[http://www.knowhivaids.org Media Campaign: HIV leads to AIDS]
-*[http://fightaidsathome.scripps.edu/ FightAIDS@Home]
-*[http://www.hiv-aids-help-desk.com/hiv-aids-counseling.html HIV-AIDS-Counseling-Online.com]
-;Articles
-*[http://www.structure.org/content/article/fulltext?uid=PIIS0969212605003898 The Mechanism of HIV-1 Core Assembly: Insights from Three-Dimensional Reconstructions of Authentic Virions]
-*[http://www.phrusa.org/campaigns/aids/release080103.html Unsafe Health Care and the HIV/AIDS Pandemic] 2003
-*[http://www.fedde.eu/HIV_DC The role of dendritic cells in HIV pathogenesis]
-*[http://www.hiv.lanl.gov The HIV databases, Los Alamos National Laboratory]
-;Multimedia/video
-*[http://digilander.libero.it/camdic/HIVIndex.html HIV DERMATOLOGY]
-*[http://health.howstuffworks.com/aids.htm How Aids Works] (with animation)
-*[http://www.sumanasinc.com/webcontent/anisamples/microbiology/hiv.html Watch an animated tutorial on the life cycle of HIV]
-*[http://video.google.com/videoplay?docid=-5961064535480432230&q=hiv+treatment&pr=goog-sl/ Video of Treatment Update 2006 from the Conference on Retrovirus']
-;Other sites
-*[http://aids.about.com HIV/AIDS at About.com provides a comprehensive collection of HIV and AIDS information, articles, statistics, and forums.]
-*[http://www.POZ.com POZ provides information and networking opportunities for the HIV community.]
-*[http://www.AIDSmeds.com AIDSmeds is a place to find complete and easy-to-read information on treating HIV & AIDS.]
-*[http://www.aegis.org AEGiS.org: AIDS Education Global Information System- Patient/clinician information & Historical news and treatment database]
-*[http://www.acria.org AIDS Community Research Initiative of America] - Community-based research and education for people living with HIV
-*[http://www.data360.org/graph_group.aspx?Graph_Group_Id=253 Data about people living with HIV/AIDS in the world (regional totals and percentage of adults with AIDS that are women)- from Data360]
-* [http://www.hivandsrh.org Resources for HIV/AIDS and Sexual and Reproductive Health Integration] Johns Hopkins Bloomberg School of Public Health, Center for Communication Programs
 [[Category:HIV/AIDS]]
@@ Line 927: / Line 196: @@
 [[Category:Sexually transmitted diseases]]
 [[Category:Immunodeficiency]]
-[[Category:Acronyms]]
-{{WH}}
-{{WS}}