Hepatitis C virus
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Hepatitis C infection is caused by the hepatitis C virus.
Hepatitis C Virus
Mode of Transmission
HCV is primarily transmitted by blood. Exposure to blood is observed primarily in healthcare settings, such as in blood transfusions, surgical procedures, needle injuries, and hemodialysis. Also, the role of intravenous drug use has recently emerged as a great risk for viral transmission after the relatively successful control of nosocomial HCV transmission.
Humans are considered the only natural hosts for HCV. The full life cycle of the virus is poorly understood due to difficulty to culture in vitro. The expression of E1-E2, two important envelope glycoprotein complexes, on the surface of HCV allows the virus to interact with host-cell molecules (glycosaminoglycans) by acting as ligands for cellular receptors, such as tetraspanin CD81, scavenger receptor class B type I (SR-BI), and mannose binding lectins DC-SIGN and L-SIGN. This interaction is believed to have a crucial role in cell recognition and cellular tropism. The exact mechanism by which viral genome enters the host cell is poorly understood, but it is believed to be via receptor-mediated endocytosis. Then envelope glycoproteins utilize pH-dependent mechanisms to mediate fusion of the viral envelope using endosomal membrane. As soon as it is released into the cytoplasm, the viral nucleocapsid uncoats by unknown mechanisms.
Template HCV RNA allows viral replication to take place and protein synthesis is thus facilitated. Cap-independent protein translation takes place when ribosomal 40S subunit binds to internal ribosome entry site (IRES). IRES is a stem-loop structure that is located at the 5' untranslated region (UTR) of the virus and the initial 30-40 nucleotides of the viral core-encoding region. Nonetheless, full polyprotein translation also requires the use of 80S ribosomes and the viral 3' UTR, both of which presumably play a role in regulation of the translational process.
The following proteins are produced:
- Core (C) protein
- Envelope 1 (E1) glycoprotein
- Envelope 2 (E2) glycoprotein
C, E1, and E2 are separated from the remaining 7 non-structural proteins by the activity of p7, a small membrane polypeptide that belongs to viroporin family. The 3 proteins are released by the activity of signal peptidases mediated by the host cell.
Non-Structural (NS) Proteins:
- NS5A: Regulation of RNA polymerase activity and inhibition of antiviral activity of interferon
- p7: Separation of structural from non-structural proteins and possible formation of ion channel
Non-structural proteins NS3 to NS5B play an important role in the formation of a replication complex that includes an intracellular "membranous web", at least partially derived from host endoplasmic reticulum. The replication complex is responsible for synthesis template negative-strand RNA and consequent synthesis of its positive-strand counterpart. These RNA molecules are then enclosed in new virions.
Formation of Nucleocapsid and Envelope
New HCV nucleocapsid is formed by the action of core protein C along with viral genomic positive-strand RNA. The envelope of the newly formed nucleocapsid is later formed by budding action into the lumen of the endoplasmic reticulum. Nonetheless, envelope glycoproteins do not yet mature early on at this stage. When new virions are exported outside the host cell, via cellular secretory mechanisms, glycoproteins of the envelope finally mature.
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