Hepatitis C pathophysiology: Difference between revisions

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__NOTOC__
{{Hepatitis C}}
{{Hepatitis C}}
{{CMG}} '''Associate Editor(s)-In-Chief:''' [[User:YazanDaaboul|Yazan Daaboul]]; [[User:Sergekorjian|Serge Korjian]]; {{MehdiP}}
{{CMG}}; '''Associate Editor(s)-In-Chief:''' [[User:YazanDaaboul|Yazan Daaboul]], [[User:Sergekorjian|Serge Korjian]], {{MehdiP}}, {{JA}}
==Overview==
==Overview==
In isolated acute HCV infection, the host [[immune system]] leads to secretion of [[interferon-alpha]] and activation of [[natural killer cells]], followed by the activation of [[adaptive immune system]]. [[Chronic HCV]] is characterized by the impairment of these mechanisms. Eventually, chronic HCV infection leads to local [[inflammation]] and [[fibrogenesis]] causing hepatic injury and cirrhosis. [[Hepatocellular carcinoma]], a known complication of chronic HCV infection, arises in cases of [[cirrhosis]]; the role of oncogenic [[proteins]] of HCV in the pathogenesis of [[hepatocellular carcinoma]] is yet to be elucidated.
In isolated acute HCV infection, the host [[immune system]] stimulates the secretion of [[interferon alpha]] and the activation of [[natural killer cells]], which is followed by the activation of the [[adaptive immune system]]. Chronic HCV is characterized by the impairment of these mechanisms. Eventually, chronic HCV infection leads to local [[inflammation]] and [[fibrogenesis]], which cause hepatic injury and [[cirrhosis]]. [[Hepatocellular carcinoma]], a known complication of chronic HCV infection, arises in cases of [[cirrhosis]]; the role of oncogenic [[proteins]] of HCV in the pathogenesis of [[hepatocellular carcinoma]] has yet to be elucidated.
 
==Transmission==
==Transmission==
The transmission of HCV can be defined as percutaneous, sexual, healthcare-associated, or maternal-infant in nature.
===Percutaneous Transmission===
===Percutaneous Transmission===
*Blood and blood components transfusion
*Blood and blood components transfusion
:More than 90% of seronegative recipients who are transfused with blood from HCV-antibody positive donors will acquire infection.<ref name="pmid7815889">{{cite journal |vauthors=Vrielink H, van der Poel CL, Reesink HW, Zaaijer HL, Scholten E, Kremer LC, Cuypers HT, Lelie PN, van Oers MH |title=Look-back study of infectivity of anti-HCV ELISA-positive blood components |journal=Lancet |volume=345 |issue=8942 |pages=95–6 |year=1995 |pmid=7815889 |doi= |url=}}</ref>  
**More than 90% of seronegative recipients who are transfused with blood from HCV-antibody positive donors will acquire infection.<ref name="pmid7815889">{{cite journal |vauthors=Vrielink H, van der Poel CL, Reesink HW, Zaaijer HL, Scholten E, Kremer LC, Cuypers HT, Lelie PN, van Oers MH |title=Look-back study of infectivity of anti-HCV ELISA-positive blood components |journal=Lancet |volume=345 |issue=8942 |pages=95–6 |year=1995 |pmid=7815889 |doi= |url=}}</ref>  
*Contaminated shared needles among injecting drug users
*Contaminated shared needles among [[intravenous drug use (recreational)|intravenous drug users]]
:Since 1992, at least two thirds of new HCV infections in the United States have been associated with illicit drug use but now, it has been decreased significantly.<ref name="pmid9305666">{{cite journal |vauthors=Alter MJ |title=Epidemiology of hepatitis C |journal=Hepatology |volume=26 |issue=3 Suppl 1 |pages=62S–65S |year=1997 |pmid=9305666 |doi=10.1002/hep.510260711 |url=}}</ref>
**Before 1992, at least two-thirds of new HCV infections in the United States were associated with illicit drug use; the number has since decreased significantly.<ref name="pmid9305666">{{cite journal |vauthors=Alter MJ |title=Epidemiology of hepatitis C |journal=Hepatology |volume=26 |issue=3 Suppl 1 |pages=62S–65S |year=1997 |pmid=9305666 |doi=10.1002/hep.510260711 |url=}}</ref>
*Chronic hemodialysis
*Chronic hemodialysis
:The frequency of anti-HCV in patients on hemodialysis ranges from less than 10% in the United States to 55% to 85% in Jordan, Saudi Arabia, and Iran.<ref name="pmid22310779">{{cite journal |vauthors=Jadoul M, Barril G |title=Hepatitis C in hemodialysis: epidemiology and prevention of hepatitis C virus transmission |journal=Contrib Nephrol |volume=176 |issue= |pages=35–41 |year=2012 |pmid=22310779 |doi=10.1159/000333761 |url=}}</ref>
**The frequency of anti-HCV in patients on hemodialysis ranges from less than 10% in the United States to 55% to 85% in Jordan, Saudi Arabia, and Iran.<ref name="pmid22310779">{{cite journal |vauthors=Jadoul M, Barril G |title=Hepatitis C in hemodialysis: epidemiology and prevention of hepatitis C virus transmission |journal=Contrib Nephrol |volume=176 |issue= |pages=35–41 |year=2012 |pmid=22310779 |doi=10.1159/000333761 |url=}}</ref>


===Sexual Transmission===
===Sexual Transmission===
*HCV RNA has been detected in semen and saliva.<ref name="pmid1331308">{{cite journal |vauthors=Liou TC, Chang TT, Young KC, Lin XZ, Lin CY, Wu HL |title=Detection of HCV RNA in saliva, urine, seminal fluid, and ascites |journal=J. Med. Virol. |volume=37 |issue=3 |pages=197–202 |year=1992 |pmid=1331308 |doi= |url=}}</ref> Persons with multiple sexual partners and commercial sex workers have a high HCV prevalence.<ref name="pmid1940879">{{cite journal |vauthors=van Doornum GJ, Hooykaas C, Cuypers MT, van der Linden MM, Coutinho RA |title=Prevalence of hepatitis C virus infections among heterosexuals with multiple partners |journal=J. Med. Virol. |volume=35 |issue=1 |pages=22–7 |year=1991 |pmid=1940879 |doi= |url=}}</ref>
*HCV RNA has been detected in semen and saliva.<ref name="pmid1331308">{{cite journal |vauthors=Liou TC, Chang TT, Young KC, Lin XZ, Lin CY, Wu HL |title=Detection of HCV RNA in saliva, urine, seminal fluid, and ascites |journal=J. Med. Virol. |volume=37 |issue=3 |pages=197–202 |year=1992 |pmid=1331308 |doi= |url=}}</ref> People with multiple sexual partners and commercial sex workers have a high HCV prevalence.<ref name="pmid1940879">{{cite journal |vauthors=van Doornum GJ, Hooykaas C, Cuypers MT, van der Linden MM, Coutinho RA |title=Prevalence of hepatitis C virus infections among heterosexuals with multiple partners |journal=J. Med. Virol. |volume=35 |issue=1 |pages=22–7 |year=1991 |pmid=1940879 |doi= |url=}}</ref>
 
===Health care Associated===
===Health care Associated===
*Nosocomial transmission has been shown in several different conditions e.g. needle stick, organ transplant and during surgery but, now because of infection control protocols it became rare except for breach in these protocols.<ref name="pmid17998149">{{cite journal |vauthors=Martínez-Bauer E, Forns X, Armelles M, Planas R, Solà R, Vergara M, Fàbregas S, Vega R, Salmerón J, Diago M, Sánchez-Tapias JM, Bruguera M |title=Hospital admission is a relevant source of hepatitis C virus acquisition in Spain |journal=J. Hepatol. |volume=48 |issue=1 |pages=20–7 |year=2008 |pmid=17998149 |doi=10.1016/j.jhep.2007.07.031 |url=}}</ref><ref name="pmid18023493">{{cite journal |vauthors=Alter MJ |title=Healthcare should not be a vehicle for transmission of hepatitis C virus |journal=J. Hepatol. |volume=48 |issue=1 |pages=2–4 |year=2008 |pmid=18023493 |doi=10.1016/j.jhep.2007.10.007 |url=}}</ref>
*Nosocomial transmission has been observed under several different conditions (e.g. needle stick, organ transplant, during surgery); now, however, because of infection control protocols, nosocomial transmission of HCV is rare except in cases of breach of protocols.<ref name="pmid17998149">{{cite journal |vauthors=Martínez-Bauer E, Forns X, Armelles M, Planas R, Solà R, Vergara M, Fàbregas S, Vega R, Salmerón J, Diago M, Sánchez-Tapias JM, Bruguera M |title=Hospital admission is a relevant source of hepatitis C virus acquisition in Spain |journal=J. Hepatol. |volume=48 |issue=1 |pages=20–7 |year=2008 |pmid=17998149 |doi=10.1016/j.jhep.2007.07.031 |url=}}</ref><ref name="pmid18023493">{{cite journal |vauthors=Alter MJ |title=Healthcare should not be a vehicle for transmission of hepatitis C virus |journal=J. Hepatol. |volume=48 |issue=1 |pages=2–4 |year=2008 |pmid=18023493 |doi=10.1016/j.jhep.2007.10.007 |url=}}</ref>
 
===Maternal Infant Transmission ===
===Maternal Infant Transmission ===
*Perinatal transmission frequency range from 0% to 4% in larger studies.<ref name="pmid8107740">{{cite journal |vauthors=Ohto H, Terazawa S, Sasaki N, Sasaki N, Hino K, Ishiwata C, Kako M, Ujiie N, Endo C, Matsui A |title=Transmission of hepatitis C virus from mothers to infants. The Vertical Transmission of Hepatitis C Virus Collaborative Study Group |journal=N. Engl. J. Med. |volume=330 |issue=11 |pages=744–50 |year=1994 |pmid=8107740 |doi=10.1056/NEJM199403173301103 |url=}}</ref><ref name="pmid7530793">{{cite journal |vauthors=Zanetti AR, Tanzi E, Paccagnini S, Principi N, Pizzocolo G, Caccamo ML, D'Amico E, Cambiè G, Vecchi L |title=Mother-to-infant transmission of hepatitis C virus. Lombardy Study Group on Vertical HCV Transmission |journal=Lancet |volume=345 |issue=8945 |pages=289–91 |year=1995 |pmid=7530793 |doi= |url=}}</ref>
*Perinatal transmission frequency ranges from 0% to 4% in larger studies.<ref name="pmid8107740">{{cite journal |vauthors=Ohto H, Terazawa S, Sasaki N, Sasaki N, Hino K, Ishiwata C, Kako M, Ujiie N, Endo C, Matsui A |title=Transmission of hepatitis C virus from mothers to infants. The Vertical Transmission of Hepatitis C Virus Collaborative Study Group |journal=N. Engl. J. Med. |volume=330 |issue=11 |pages=744–50 |year=1994 |pmid=8107740 |doi=10.1056/NEJM199403173301103 |url=}}</ref><ref name="pmid7530793">{{cite journal |vauthors=Zanetti AR, Tanzi E, Paccagnini S, Principi N, Pizzocolo G, Caccamo ML, D'Amico E, Cambiè G, Vecchi L |title=Mother-to-infant transmission of hepatitis C virus. Lombardy Study Group on Vertical HCV Transmission |journal=Lancet |volume=345 |issue=8945 |pages=289–91 |year=1995 |pmid=7530793 |doi= |url=}}</ref>


==HCV Clearance and Persistence==
==HCV Clearance and Persistence==
Acute viral infection and HCV replication triggers the activation of host immune responses, first by secretion of type I [[interferon-alpha]] ([[IFN-alpha]]) and activation of natural killer (NK) cells. Nonetheless, secretion of endogenous IFN does not seem to effectively inhibit HCV [[replication]].<ref name="pmid11714747">{{cite journal| author=Thimme R, Oldach D, Chang KM, Steiger C, Ray SC, Chisari FV| title=Determinants of viral clearance and persistence during acute hepatitis C virus infection. | journal=J Exp Med | year= 2001 | volume= 194 | issue= 10 | pages= 1395-406 | pmid=11714747 | doi= | pmc=PMC2193681 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11714747  }} </ref><ref name="pmid12441397">{{cite journal| author=Thimme R, Bukh J, Spangenberg HC, Wieland S, Pemberton J, Steiger C et al.| title=Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease. | journal=Proc Natl Acad Sci U S A | year= 2002 | volume= 99 | issue= 24 | pages= 15661-8 | pmid=12441397 | doi=10.1073/pnas.202608299 | pmc=PMC137773 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12441397  }} </ref><ref name="pmid12441396">{{cite journal| author=Su AI, Pezacki JP, Wodicka L, Brideau AD, Supekova L, Thimme R et al.| title=Genomic analysis of the host response to hepatitis C virus infection. | journal=Proc Natl Acad Sci U S A | year= 2002 | volume= 99 | issue= 24 | pages= 15669-74 | pmid=12441396 | doi=10.1073/pnas.202608199 | pmc=PMC137774 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12441396  }} </ref>
Acute viral infection and HCV replication triggers the activation of host immune responses, first by secretion of type I [[interferon alpha]] (IFN-alpha) and activation of [[natural killer cells|natural killer (NK) cells]]. Nonetheless, secretion of endogenous IFN does not seem to effectively inhibit HCV [[replication]].<ref name="pmid11714747">{{cite journal| author=Thimme R, Oldach D, Chang KM, Steiger C, Ray SC, Chisari FV| title=Determinants of viral clearance and persistence during acute hepatitis C virus infection. | journal=J Exp Med | year= 2001 | volume= 194 | issue= 10 | pages= 1395-406 | pmid=11714747 | doi= | pmc=PMC2193681 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11714747  }} </ref><ref name="pmid12441397">{{cite journal| author=Thimme R, Bukh J, Spangenberg HC, Wieland S, Pemberton J, Steiger C et al.| title=Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease. | journal=Proc Natl Acad Sci U S A | year= 2002 | volume= 99 | issue= 24 | pages= 15661-8 | pmid=12441397 | doi=10.1073/pnas.202608299 | pmc=PMC137773 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12441397  }} </ref><ref name="pmid12441396">{{cite journal| author=Su AI, Pezacki JP, Wodicka L, Brideau AD, Supekova L, Thimme R et al.| title=Genomic analysis of the host response to hepatitis C virus infection. | journal=Proc Natl Acad Sci U S A | year= 2002 | volume= 99 | issue= 24 | pages= 15669-74 | pmid=12441396 | doi=10.1073/pnas.202608199 | pmc=PMC137774 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12441396  }} </ref>


HCV proteins play a crucial role in inhibiting IFN-alpha effectors, such as [[IFN regulatory factor-3]] ([[IRF-3]]), double stranded RNA-dependent [[protein kinase]] (PKR), and [[Jak-Stat]] pathway.<ref name="pmid12209136">{{cite journal| author=Katze MG, He Y, Gale M| title=Viruses and interferon: a fight for supremacy. | journal=Nat Rev Immunol | year= 2002 | volume= 2 | issue= 9 | pages= 675-87 | pmid=12209136 | doi=10.1038/nri888 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12209136  }} </ref><ref name="pmid12702807">{{cite journal| author=Foy E, Li K, Wang C, Sumpter R, Ikeda M, Lemon SM et al.| title=Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. | journal=Science | year= 2003 | volume= 300 | issue= 5622 | pages= 1145-8 | pmid=12702807 | doi=10.1126/science.1082604 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12702807  }} </ref><ref name="pmid12730885">{{cite journal| author=Blindenbacher A, Duong FH, Hunziker L, Stutvoet ST, Wang X, Terracciano L et al.| title=Expression of hepatitis c virus proteins inhibits interferon alpha signaling in the liver of transgenic mice. | journal=Gastroenterology | year= 2003 | volume= 124 | issue= 5 | pages= 1465-75 | pmid=12730885 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12730885  }} </ref> More importantly, chronic carriage of HCV is associated with impaired activation of [[NK cells]] despite [[IFN-alpha]] secretion. It is believed that cross-linking of CD81 and envelope protein E2 of the virus is a key mechanism by which [[NK cells]] are inactivated and [[INF-gamma]] by these cells is failed to be produced.<ref name="pmid15036326">{{cite journal| author=Pawlotsky JM| title=Pathophysiology of hepatitis C virus infection and related liver disease. | journal=Trends Microbiol | year= 2004 | volume= 12 | issue= 2 | pages= 96-102 | pmid=15036326 | doi=10.1016/j.tim.2003.12.005 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15036326  }} </ref>  
HCV proteins play a crucial role in inhibiting [[IFN-α|IFN-alpha]] effectors, such as IFN regulatory factor-3 (IRF-3), double stranded RNA-dependent [[protein kinase]] (PKR), and the [[JAK-STAT signaling pathway]].<ref name="pmid12209136">{{cite journal| author=Katze MG, He Y, Gale M| title=Viruses and interferon: a fight for supremacy. | journal=Nat Rev Immunol | year= 2002 | volume= 2 | issue= 9 | pages= 675-87 | pmid=12209136 | doi=10.1038/nri888 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12209136  }} </ref><ref name="pmid12702807">{{cite journal| author=Foy E, Li K, Wang C, Sumpter R, Ikeda M, Lemon SM et al.| title=Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. | journal=Science | year= 2003 | volume= 300 | issue= 5622 | pages= 1145-8 | pmid=12702807 | doi=10.1126/science.1082604 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12702807  }} </ref><ref name="pmid12730885">{{cite journal| author=Blindenbacher A, Duong FH, Hunziker L, Stutvoet ST, Wang X, Terracciano L et al.| title=Expression of hepatitis c virus proteins inhibits interferon alpha signaling in the liver of transgenic mice. | journal=Gastroenterology | year= 2003 | volume= 124 | issue= 5 | pages= 1465-75 | pmid=12730885 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12730885  }} </ref> More importantly, chronic carriage of HCV is associated with impaired activation of [[NK cells]] despite IFN-alpha secretion. It is believed that the cross-linking of CD81 and the envelope protein E2 of the virus is a key mechanism by which [[NK cells]] are inactivated and INF-gamma is not produced by these cells.<ref name="pmid15036326">{{cite journal| author=Pawlotsky JM| title=Pathophysiology of hepatitis C virus infection and related liver disease. | journal=Trends Microbiol | year= 2004 | volume= 12 | issue= 2 | pages= 96-102 | pmid=15036326 | doi=10.1016/j.tim.2003.12.005 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15036326  }} </ref>  


It is confirmed that activation of [[IFN-gamma]] is a pre-requisite for the appropriate clearance of HCV. When activation occurs appropriately, [[antibodies]] start to form 7-31 weeks later.<ref name="pmid7519785">{{cite journal| author=Farci P, Alter HJ, Wong DC, Miller RH, Govindarajan S, Engle R et al.| title=Prevention of hepatitis C virus infection in chimpanzees after antibody-mediated in vitro neutralization. | journal=Proc Natl Acad Sci U S A | year= 1994 | volume= 91 | issue= 16 | pages= 7792-6 | pmid=7519785 | doi= | pmc=PMC44488 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7519785  }} </ref><ref name="pmid8806581">{{cite journal| author=Shimizu YK, Igarashi H, Kiyohara T, Cabezon T, Farci P, Purcell RH et al.| title=A hyperimmune serum against a synthetic peptide corresponding to the hypervariable region 1 of hepatitis C virus can prevent viral infection in cell cultures. | journal=Virology | year= 1996 | volume= 223 | issue= 2 | pages= 409-12 | pmid=8806581 | doi=10.1006/viro.1996.0497 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8806581  }} </ref><ref name="pmid12615904">{{cite journal| author=Bartosch B, Dubuisson J, Cosset FL| title=Infectious hepatitis C virus pseudo-particles containing functional E1-E2 envelope protein complexes. | journal=J Exp Med | year= 2003 | volume= 197 | issue= 5 | pages= 633-42 | pmid=12615904 | doi= | pmc=PMC2193821 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12615904  }} </ref><ref name="pmid9649423">{{cite journal| author=Puntoriero G, Meola A, Lahm A, Zucchelli S, Ercole BB, Tafi R et al.| title=Towards a solution for hepatitis C virus hypervariability: mimotopes of the hypervariable region 1 can induce antibodies cross-reacting with a large number of viral variants. | journal=EMBO J | year= 1998 | volume= 17 | issue= 13 | pages= 3521-33 | pmid=9649423 | doi=10.1093/emboj/17.13.3521 | pmc=PMC1170689 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9649423  }} </ref> While most epitopes for antibodies have not been discovered yet, [[hypervariable region 1]] ([[HVR1]]) of the E2 envelope glycoprotein was found to be a target by [[anti-HVR1]] antibodies. Antibodies play a role in clearing the virus from the host. It is currently unknown whether "escape" mechanisms are present in HCV that favor persistent HCV infection despite an adequate antibody response.<ref name="pmid7519785">{{cite journal| author=Farci P, Alter HJ, Wong DC, Miller RH, Govindarajan S, Engle R et al.| title=Prevention of hepatitis C virus infection in chimpanzees after antibody-mediated in vitro neutralization. | journal=Proc Natl Acad Sci U S A | year= 1994 | volume= 91 | issue= 16 | pages= 7792-6 | pmid=7519785 | doi= | pmc=PMC44488 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7519785  }} </ref><ref name="pmid8806581">{{cite journal| author=Shimizu YK, Igarashi H, Kiyohara T, Cabezon T, Farci P, Purcell RH et al.| title=A hyperimmune serum against a synthetic peptide corresponding to the hypervariable region 1 of hepatitis C virus can prevent viral infection in cell cultures. | journal=Virology | year= 1996 | volume= 223 | issue= 2 | pages= 409-12 | pmid=8806581 | doi=10.1006/viro.1996.0497 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8806581  }} </ref><ref name="pmid12615904">{{cite journal| author=Bartosch B, Dubuisson J, Cosset FL| title=Infectious hepatitis C virus pseudo-particles containing functional E1-E2 envelope protein complexes. | journal=J Exp Med | year= 2003 | volume= 197 | issue= 5 | pages= 633-42 | pmid=12615904 | doi= | pmc=PMC2193821 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12615904  }} </ref><ref name="pmid9649423">{{cite journal| author=Puntoriero G, Meola A, Lahm A, Zucchelli S, Ercole BB, Tafi R et al.| title=Towards a solution for hepatitis C virus hypervariability: mimotopes of the hypervariable region 1 can induce antibodies cross-reacting with a large number of viral variants. | journal=EMBO J | year= 1998 | volume= 17 | issue= 13 | pages= 3521-33 | pmid=9649423 | doi=10.1093/emboj/17.13.3521 | pmc=PMC1170689 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9649423  }} </ref>
The activation of [[IFN-gamma]] is a prerequisite for the appropriate clearance of HCV. When activation occurs normally, [[antibodies]] start to form 7-31 weeks later.<ref name="pmid7519785">{{cite journal| author=Farci P, Alter HJ, Wong DC, Miller RH, Govindarajan S, Engle R et al.| title=Prevention of hepatitis C virus infection in chimpanzees after antibody-mediated in vitro neutralization. | journal=Proc Natl Acad Sci U S A | year= 1994 | volume= 91 | issue= 16 | pages= 7792-6 | pmid=7519785 | doi= | pmc=PMC44488 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7519785  }} </ref><ref name="pmid8806581">{{cite journal| author=Shimizu YK, Igarashi H, Kiyohara T, Cabezon T, Farci P, Purcell RH et al.| title=A hyperimmune serum against a synthetic peptide corresponding to the hypervariable region 1 of hepatitis C virus can prevent viral infection in cell cultures. | journal=Virology | year= 1996 | volume= 223 | issue= 2 | pages= 409-12 | pmid=8806581 | doi=10.1006/viro.1996.0497 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8806581  }} </ref><ref name="pmid12615904">{{cite journal| author=Bartosch B, Dubuisson J, Cosset FL| title=Infectious hepatitis C virus pseudo-particles containing functional E1-E2 envelope protein complexes. | journal=J Exp Med | year= 2003 | volume= 197 | issue= 5 | pages= 633-42 | pmid=12615904 | doi= | pmc=PMC2193821 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12615904  }} </ref><ref name="pmid9649423">{{cite journal| author=Puntoriero G, Meola A, Lahm A, Zucchelli S, Ercole BB, Tafi R et al.| title=Towards a solution for hepatitis C virus hypervariability: mimotopes of the hypervariable region 1 can induce antibodies cross-reacting with a large number of viral variants. | journal=EMBO J | year= 1998 | volume= 17 | issue= 13 | pages= 3521-33 | pmid=9649423 | doi=10.1093/emboj/17.13.3521 | pmc=PMC1170689 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9649423  }} </ref> While most epitopes for antibodies have not been discovered yet, hypervariable region 1 (HVR1) of the E2 envelope glycoprotein was found to be a target for anti-HVR1 antibodies. Antibodies play a role in clearing the virus from the host. It is currently unknown whether "escape" mechanisms are present in HCV that favor persistent HCV infection despite an adequate antibody response.<ref name="pmid7519785">{{cite journal| author=Farci P, Alter HJ, Wong DC, Miller RH, Govindarajan S, Engle R et al.| title=Prevention of hepatitis C virus infection in chimpanzees after antibody-mediated in vitro neutralization. | journal=Proc Natl Acad Sci U S A | year= 1994 | volume= 91 | issue= 16 | pages= 7792-6 | pmid=7519785 | doi= | pmc=PMC44488 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7519785  }} </ref><ref name="pmid8806581">{{cite journal| author=Shimizu YK, Igarashi H, Kiyohara T, Cabezon T, Farci P, Purcell RH et al.| title=A hyperimmune serum against a synthetic peptide corresponding to the hypervariable region 1 of hepatitis C virus can prevent viral infection in cell cultures. | journal=Virology | year= 1996 | volume= 223 | issue= 2 | pages= 409-12 | pmid=8806581 | doi=10.1006/viro.1996.0497 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8806581  }} </ref><ref name="pmid12615904">{{cite journal| author=Bartosch B, Dubuisson J, Cosset FL| title=Infectious hepatitis C virus pseudo-particles containing functional E1-E2 envelope protein complexes. | journal=J Exp Med | year= 2003 | volume= 197 | issue= 5 | pages= 633-42 | pmid=12615904 | doi= | pmc=PMC2193821 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12615904  }} </ref><ref name="pmid9649423">{{cite journal| author=Puntoriero G, Meola A, Lahm A, Zucchelli S, Ercole BB, Tafi R et al.| title=Towards a solution for hepatitis C virus hypervariability: mimotopes of the hypervariable region 1 can induce antibodies cross-reacting with a large number of viral variants. | journal=EMBO J | year= 1998 | volume= 17 | issue= 13 | pages= 3521-33 | pmid=9649423 | doi=10.1093/emboj/17.13.3521 | pmc=PMC1170689 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9649423  }} </ref>


Similarly, activation of CD4+ and CD8+ [[T-cell response]] is required for viral clearance. This cellular response allows long-term immunity against HCV.<ref name="pmid12829979">{{cite journal| author=Bertoletti A, Ferrari C| title=Kinetics of the immune response during HBV and HCV infection. | journal=Hepatology | year= 2003 | volume= 38 | issue= 1 | pages= 4-13 | pmid=12829979 | doi=10.1053/jhep.2003.50310 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12829979  }} </ref> Studies also proved that delayed or inadequate activation of T-cell response is associated with persistence of infection. It is not known why T-cell response may fail in response to acute infection, but it is hypothesized that persistence might be related to viral inhibition of T-cell maturation, defective [[dendritic cells]], and/or failure of interleukin (IL) 12 activation.<ref name="pmid12829979">{{cite journal| author=Bertoletti A, Ferrari C| title=Kinetics of the immune response during HBV and HCV infection. | journal=Hepatology | year= 2003 | volume= 38 | issue= 1 | pages= 4-13 | pmid=12829979 | doi=10.1053/jhep.2003.50310 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12829979  }} </ref><ref name="pmid11159892">{{cite journal| author=Bain C, Fatmi A, Zoulim F, Zarski JP, Trépo C, Inchauspé G| title=Impaired allostimulatory function of dendritic cells in chronic hepatitis C infection. | journal=Gastroenterology | year= 2001 | volume= 120 | issue= 2 | pages= 512-24 | pmid=11159892 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11159892  }} </ref><ref name="pmid12218168">{{cite journal| author=Wedemeyer H, He XS, Nascimbeni M, Davis AR, Greenberg HB, Hoofnagle JH et al.| title=Impaired effector function of hepatitis C virus-specific CD8+ T cells in chronic hepatitis C virus infection. | journal=J Immunol | year= 2002 | volume= 169 | issue= 6 | pages= 3447-58 | pmid=12218168 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12218168  }} </ref><ref name="pmid10790425">{{cite journal| author=Lechner F, Wong DK, Dunbar PR, Chapman R, Chung RT, Dohrenwend P et al.| title=Analysis of successful immune responses in persons infected with hepatitis C virus. | journal=J Exp Med | year= 2000 | volume= 191 | issue= 9 | pages= 1499-512 | pmid=10790425 | doi= | pmc=PMC2213430 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10790425  }} </ref><ref name="pmid11927944">{{cite journal| author=Appay V, Dunbar PR, Callan M, Klenerman P, Gillespie GM, Papagno L et al.| title=Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. | journal=Nat Med | year= 2002 | volume= 8 | issue= 4 | pages= 379-85 | pmid=11927944 | doi=10.1038/nm0402-379 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11927944  }} </ref><ref name="pmid11086025">{{cite journal| author=Kittlesen DJ, Chianese-Bullock KA, Yao ZQ, Braciale TJ, Hahn YS| title=Interaction between complement receptor gC1qR and hepatitis C virus core protein inhibits T-lymphocyte proliferation. | journal=J Clin Invest | year= 2000 | volume= 106 | issue= 10 | pages= 1239-49 | pmid=11086025 | doi=10.1172/JCI10323 | pmc=PMC381434 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11086025  }} </ref>
Similarly, the activation of the [[CD4+]] and [[CD8+ T cells|CD8+]] T-cell response is required for viral clearance. This cellular response allows for the development of long-term immunity against HCV.<ref name="pmid12829979">{{cite journal| author=Bertoletti A, Ferrari C| title=Kinetics of the immune response during HBV and HCV infection. | journal=Hepatology | year= 2003 | volume= 38 | issue= 1 | pages= 4-13 | pmid=12829979 | doi=10.1053/jhep.2003.50310 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12829979  }} </ref> Studies also proved that delayed or inadequate activation of [[T cell|T-cell]] response is associated with persistence of infection. It is not known why [[T cell|T-cell]] response may fail in response to acute infection, but it is hypothesized that persistence might be related to viral inhibition of T-cell maturation, defective [[dendritic cells]], and/or failure of [[interleukin 12|interleukin (IL) 12]] activation.<ref name="pmid12829979">{{cite journal| author=Bertoletti A, Ferrari C| title=Kinetics of the immune response during HBV and HCV infection. | journal=Hepatology | year= 2003 | volume= 38 | issue= 1 | pages= 4-13 | pmid=12829979 | doi=10.1053/jhep.2003.50310 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12829979  }} </ref><ref name="pmid11159892">{{cite journal| author=Bain C, Fatmi A, Zoulim F, Zarski JP, Trépo C, Inchauspé G| title=Impaired allostimulatory function of dendritic cells in chronic hepatitis C infection. | journal=Gastroenterology | year= 2001 | volume= 120 | issue= 2 | pages= 512-24 | pmid=11159892 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11159892  }} </ref><ref name="pmid12218168">{{cite journal| author=Wedemeyer H, He XS, Nascimbeni M, Davis AR, Greenberg HB, Hoofnagle JH et al.| title=Impaired effector function of hepatitis C virus-specific CD8+ T cells in chronic hepatitis C virus infection. | journal=J Immunol | year= 2002 | volume= 169 | issue= 6 | pages= 3447-58 | pmid=12218168 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12218168  }} </ref><ref name="pmid10790425">{{cite journal| author=Lechner F, Wong DK, Dunbar PR, Chapman R, Chung RT, Dohrenwend P et al.| title=Analysis of successful immune responses in persons infected with hepatitis C virus. | journal=J Exp Med | year= 2000 | volume= 191 | issue= 9 | pages= 1499-512 | pmid=10790425 | doi= | pmc=PMC2213430 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10790425  }} </ref><ref name="pmid11927944">{{cite journal| author=Appay V, Dunbar PR, Callan M, Klenerman P, Gillespie GM, Papagno L et al.| title=Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. | journal=Nat Med | year= 2002 | volume= 8 | issue= 4 | pages= 379-85 | pmid=11927944 | doi=10.1038/nm0402-379 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11927944  }} </ref><ref name="pmid11086025">{{cite journal| author=Kittlesen DJ, Chianese-Bullock KA, Yao ZQ, Braciale TJ, Hahn YS| title=Interaction between complement receptor gC1qR and hepatitis C virus core protein inhibits T-lymphocyte proliferation. | journal=J Clin Invest | year= 2000 | volume= 106 | issue= 10 | pages= 1239-49 | pmid=11086025 | doi=10.1172/JCI10323 | pmc=PMC381434 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11086025  }} </ref>


==Liver Injury and Cirrhosis, and Hepatocellular Carcinoma==
==Liver Injury and Cirrhosis, and Hepatocellular Carcinoma==
HCV is directly associated with hepatic [[steatosis]], which is fat accumulation in the liver. It seems that core proteins may play a role in regulating lipid accumulation in hepatocytes, contributing to steatosis. However, steatosis is not observed in all genotypes of HCV infection, it is classically described in genotype 3, which perhaps is the only genotype that has a direct role in the development of steatosis irrespective of alcohol or metabolic elements. Apart from steatosis, HCV per se has not been shown to have damaging effects on hepatocytes. The viral burden also does not seem to be directly related to the extent of liver injury.<ref name="pmid12829989">{{cite journal| author=Poynard T, Ratziu V, McHutchison J, Manns M, Goodman Z, Zeuzem S et al.| title=Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected with hepatitis C. | journal=Hepatology | year= 2003 | volume= 38 | issue= 1 | pages= 75-85 | pmid=12829989 | doi=10.1053/jhep.2003.50267 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12829989  }} </ref><ref name="pmid9037030">{{cite journal| author=Barba G, Harper F, Harada T, Kohara M, Goulinet S, Matsuura Y et al.| title=Hepatitis C virus core protein shows a cytoplasmic localization and associates to cellular lipid storage droplets. | journal=Proc Natl Acad Sci U S A | year= 1997 | volume= 94 | issue= 4 | pages= 1200-5 | pmid=9037030 | doi= | pmc=PMC19768 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9037030  }} </ref><ref name="pmid10905593">{{cite journal| author=Rubbia-Brandt L, Quadri R, Abid K, Giostra E, Malé PJ, Mentha G et al.| title=Hepatocyte steatosis is a cytopathic effect of hepatitis C virus genotype 3. | journal=J Hepatol | year= 2000 | volume= 33 | issue= 1 | pages= 106-15 | pmid=10905593 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10905593  }} </ref><ref name="pmid11322205">{{cite journal| author=Serfaty L, Andreani T, Giral P, Carbonell N, Chazouillères O, Poupon R| title=Hepatitis C virus induced hypobetalipoproteinemia: a possible mechanism for steatosis in chronic hepatitis C. | journal=J Hepatol | year= 2001 | volume= 34 | issue= 3 | pages= 428-34 | pmid=11322205 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11322205  }} </ref><ref name="pmid12524415">{{cite journal| author=Castéra L, Hézode C, Roudot-Thoraval F, Bastie A, Zafrani ES, Pawlotsky JM et al.| title=Worsening of steatosis is an independent factor of fibrosis progression in untreated patients with chronic hepatitis C and paired liver biopsies. | journal=Gut | year= 2003 | volume= 52 | issue= 2 | pages= 288-92 | pmid=12524415 | doi= | pmc=PMC1774979 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12524415  }} </ref><ref name="pmid12558359">{{cite journal| author=Sulkowski MS, Thomas DL| title=Hepatitis C in the HIV-Infected Person. | journal=Ann Intern Med | year= 2003 | volume= 138 | issue= 3 | pages= 197-207 | pmid=12558359 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12558359  }} </ref><ref name="pmid12118398">{{cite journal| author=Pol S, Vallet-Pichard A, Fontaine H, Lebray P| title=HCV infection and hemodialysis. | journal=Semin Nephrol | year= 2002 | volume= 22 | issue= 4 | pages= 331-9 | pmid=12118398 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12118398  }} </ref>
HCV is directly associated with hepatic [[steatosis]], which is fat accumulation in the liver. It seems that core proteins may play a role in regulating lipid accumulation in hepatocytes, contributing to steatosis. However, steatosis is not observed in all genotypes of HCV infection; it is classically described in genotype 3, which perhaps is the only genotype that has a direct role in the development of steatosis irrespective of alcohol consumption or metabolic elements. Apart from steatosis, HCV per se has not been shown to have damaging effects on [[Hepatocyte|hepatocytes]]. The viral burden also does not seem to be directly related to the extent of liver injury.<ref name="pmid12829989">{{cite journal| author=Poynard T, Ratziu V, McHutchison J, Manns M, Goodman Z, Zeuzem S et al.| title=Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected with hepatitis C. | journal=Hepatology | year= 2003 | volume= 38 | issue= 1 | pages= 75-85 | pmid=12829989 | doi=10.1053/jhep.2003.50267 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12829989  }} </ref><ref name="pmid9037030">{{cite journal| author=Barba G, Harper F, Harada T, Kohara M, Goulinet S, Matsuura Y et al.| title=Hepatitis C virus core protein shows a cytoplasmic localization and associates to cellular lipid storage droplets. | journal=Proc Natl Acad Sci U S A | year= 1997 | volume= 94 | issue= 4 | pages= 1200-5 | pmid=9037030 | doi= | pmc=PMC19768 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9037030  }} </ref><ref name="pmid10905593">{{cite journal| author=Rubbia-Brandt L, Quadri R, Abid K, Giostra E, Malé PJ, Mentha G et al.| title=Hepatocyte steatosis is a cytopathic effect of hepatitis C virus genotype 3. | journal=J Hepatol | year= 2000 | volume= 33 | issue= 1 | pages= 106-15 | pmid=10905593 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10905593  }} </ref><ref name="pmid11322205">{{cite journal| author=Serfaty L, Andreani T, Giral P, Carbonell N, Chazouillères O, Poupon R| title=Hepatitis C virus induced hypobetalipoproteinemia: a possible mechanism for steatosis in chronic hepatitis C. | journal=J Hepatol | year= 2001 | volume= 34 | issue= 3 | pages= 428-34 | pmid=11322205 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11322205  }} </ref><ref name="pmid12524415">{{cite journal| author=Castéra L, Hézode C, Roudot-Thoraval F, Bastie A, Zafrani ES, Pawlotsky JM et al.| title=Worsening of steatosis is an independent factor of fibrosis progression in untreated patients with chronic hepatitis C and paired liver biopsies. | journal=Gut | year= 2003 | volume= 52 | issue= 2 | pages= 288-92 | pmid=12524415 | doi= | pmc=PMC1774979 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12524415  }} </ref><ref name="pmid12558359">{{cite journal| author=Sulkowski MS, Thomas DL| title=Hepatitis C in the HIV-Infected Person. | journal=Ann Intern Med | year= 2003 | volume= 138 | issue= 3 | pages= 197-207 | pmid=12558359 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12558359  }} </ref><ref name="pmid12118398">{{cite journal| author=Pol S, Vallet-Pichard A, Fontaine H, Lebray P| title=HCV infection and hemodialysis. | journal=Semin Nephrol | year= 2002 | volume= 22 | issue= 4 | pages= 331-9 | pmid=12118398 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12118398  }} </ref>


In chronic hepatitis C infections, local immune response lead to portal lymphoid infiltration and chronic inflammation that lead to bridging necrosis and degenerative lobular lesions.<ref name="pmid15036326">{{cite journal| author=Pawlotsky JM| title=Pathophysiology of hepatitis C virus infection and related liver disease. | journal=Trends Microbiol | year= 2004 | volume= 12 | issue= 2 | pages= 96-102 | pmid=15036326 | doi=10.1016/j.tim.2003.12.005 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15036326  }} </ref> Hepatic injury is directly associated with the degree of Th1 cytokine expression. Adaptive immune system, namely cytotoxic T-cell response, injures infected cells, as well as bystander cells. Nonetheless, it has not been confirmed whether increased number of cytotoxic T cells is associated with extent of liver injury.
In chronic hepatitis C infections, the local immune response leads to portal lymphoid infiltration and [[chronic inflammation]], which give way to bridging necrosis and degenerative lobular lesions.<ref name="pmid15036326">{{cite journal| author=Pawlotsky JM| title=Pathophysiology of hepatitis C virus infection and related liver disease. | journal=Trends Microbiol | year= 2004 | volume= 12 | issue= 2 | pages= 96-102 | pmid=15036326 | doi=10.1016/j.tim.2003.12.005 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15036326  }} </ref> Hepatic injury is directly associated with the degree of Th1 cytokine expression. The [[adaptive immune system]], namely the [[cytotoxic T-cell]] response, injures infected cells as well as bystander cells. Nonetheless, it has not been confirmed whether the number of [[Cytotoxic T cell|cytotoxic T cells]] is associated with the extent of liver injury.


Chronic inflammation ultimately leads to [[fibrogenesis]] due to deposition extracellular matrix elements in hepatic parenchyma. It is unknown whether viral components are directly responsible in the particular mechanism of hepatic cirrhosis in chronic HCV infection; although cirrhosis is definitely worsened in HCV patients who are also exposed to other risk factors, such as alcohol, obesity, and HIV.<ref name="pmid15036326">{{cite journal| author=Pawlotsky JM| title=Pathophysiology of hepatitis C virus infection and related liver disease. | journal=Trends Microbiol | year= 2004 | volume= 12 | issue= 2 | pages= 96-102 | pmid=15036326 | doi=10.1016/j.tim.2003.12.005 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15036326  }} </ref>
[[Chronic inflammation]] ultimately leads to [[fibrogenesis]] due to deposition extracellular matrix elements in hepatic [[parenchyma]]. It is unknown whether viral components are directly responsible in the particular mechanism of hepatic [[cirrhosis]] in chronic HCV infection; although cirrhosis is definitely worsened in HCV patients who are also exposed to other risk factors, such as alcohol, [[obesity]], and [[HIV]].<ref name="pmid15036326">{{cite journal| author=Pawlotsky JM| title=Pathophysiology of hepatitis C virus infection and related liver disease. | journal=Trends Microbiol | year= 2004 | volume= 12 | issue= 2 | pages= 96-102 | pmid=15036326 | doi=10.1016/j.tim.2003.12.005 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15036326  }} </ref>


==Hepatocellular Carcinoma==
==Hepatocellular Carcinoma==
[[Hepatocellular carcinoma]] ([[HCC]]) occurs following chronic HCV infection complicated by liver cirrhosis. The true role of HCV components in the development of HCC is poorly understood. Pinpointing which viral protein is directly related to carcinogenesis has been difficult, but studies have shown that NS3, NS4B, and NS5A all have oncogenic properties.<ref name="pmid12407572">{{cite journal| author=National Institutes of Health| title=National Institutes of Health Consensus Development Conference Statement: Management of hepatitis C: 2002--June 10-12, 2002. | journal=Hepatology | year= 2002 | volume= 36 | issue= 5 Suppl 1 | pages= S3-20 | pmid=12407572 | doi=10.1053/jhep.2002.37117 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12407572  }} </ref><ref name="pmid8676467">{{cite journal| author=Ray RB, Lagging LM, Meyer K, Ray R| title=Hepatitis C virus core protein cooperates with ras and transforms primary rat embryo fibroblasts to tumorigenic phenotype. | journal=J Virol | year= 1996 | volume= 70 | issue= 7 | pages= 4438-43 | pmid=8676467 | doi= | pmc=PMC190377 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8676467  }} </ref><ref name="pmid7745741">{{cite journal| author=Sakamuro D, Furukawa T, Takegami T| title=Hepatitis C virus nonstructural protein NS3 transforms NIH 3T3 cells. | journal=J Virol | year= 1995 | volume= 69 | issue= 6 | pages= 3893-6 | pmid=7745741 | doi= | pmc=PMC189112 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7745741  }} </ref><ref name="pmid10631105">{{cite journal| author=Park JS, Yang JM, Min MK| title=Hepatitis C virus nonstructural protein NS4B transforms NIH3T3 cells in cooperation with the Ha-ras oncogene. | journal=Biochem Biophys Res Commun | year= 2000 | volume= 267 | issue= 2 | pages= 581-7 | pmid=10631105 | doi=10.1006/bbrc.1999.1999 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10631105  }} </ref><ref name="pmid10355764">{{cite journal| author=Ghosh AK, Steele R, Meyer K, Ray R, Ray RB| title=Hepatitis C virus NS5A protein modulates cell cycle regulatory genes and promotes cell growth. | journal=J Gen Virol | year= 1999 | volume= 80 ( Pt 5) | issue=  | pages= 1179-83 | pmid=10355764 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10355764  }} </ref>
[[Hepatocellular carcinoma]] ([[HCC]]) occurs following chronic HCV infection complicated by liver [[cirrhosis]]. The precise role of HCV components in the development of HCC is poorly understood. Pinpointing which viral protein is directly related to carcinogenesis has been difficult, but studies have shown that NS3, NS4B, and NS5A all have [[oncogenic]] properties.<ref name="pmid12407572">{{cite journal| author=National Institutes of Health| title=National Institutes of Health Consensus Development Conference Statement: Management of hepatitis C: 2002--June 10-12, 2002. | journal=Hepatology | year= 2002 | volume= 36 | issue= 5 Suppl 1 | pages= S3-20 | pmid=12407572 | doi=10.1053/jhep.2002.37117 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12407572  }} </ref><ref name="pmid8676467">{{cite journal| author=Ray RB, Lagging LM, Meyer K, Ray R| title=Hepatitis C virus core protein cooperates with ras and transforms primary rat embryo fibroblasts to tumorigenic phenotype. | journal=J Virol | year= 1996 | volume= 70 | issue= 7 | pages= 4438-43 | pmid=8676467 | doi= | pmc=PMC190377 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8676467  }} </ref><ref name="pmid7745741">{{cite journal| author=Sakamuro D, Furukawa T, Takegami T| title=Hepatitis C virus nonstructural protein NS3 transforms NIH 3T3 cells. | journal=J Virol | year= 1995 | volume= 69 | issue= 6 | pages= 3893-6 | pmid=7745741 | doi= | pmc=PMC189112 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7745741  }} </ref><ref name="pmid10631105">{{cite journal| author=Park JS, Yang JM, Min MK| title=Hepatitis C virus nonstructural protein NS4B transforms NIH3T3 cells in cooperation with the Ha-ras oncogene. | journal=Biochem Biophys Res Commun | year= 2000 | volume= 267 | issue= 2 | pages= 581-7 | pmid=10631105 | doi=10.1006/bbrc.1999.1999 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10631105  }} </ref><ref name="pmid10355764">{{cite journal| author=Ghosh AK, Steele R, Meyer K, Ray R, Ray RB| title=Hepatitis C virus NS5A protein modulates cell cycle regulatory genes and promotes cell growth. | journal=J Gen Virol | year= 1999 | volume= 80 ( Pt 5) | issue=  | pages= 1179-83 | pmid=10355764 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10355764  }} </ref>


==Histology==
==Histology==
Click on the arrow to view the pathologic findings in viral hepatitis:
Click on the arrow to view the pathologic findings in viral hepatitis:
{{#ev:youtube|_hXvbpSxFZw}}
{{#ev:youtube|_hXvbpSxFZw}}
==Mechanisms involved in extra-[[hepatic]] manifestations==
*[[Cryoglobulinemia|Cryoglobulinemic vasculitis]]: [[Chronic]] antigen stimulation reduces the threshold for activation and proliferation of B-[[lymphocyte]] and induces Bcl-2 activation and t(14;18) translocation. It results in decreased [[apoptosis]]. As a result, CD21−CD27+ cells produce [[antibodies]] against the Fc portion of [[IgG]], forming [[immune complexes]] that precipitate in small [[blood]] [[vessels]].<ref name="pmid29703790">{{cite journal |vauthors=Cacoub P, Desbois AC, Comarmond C, Saadoun D |title=Impact of sustained virological response on the extrahepatic manifestations of chronic hepatitis C: a meta-analysis |journal=Gut |volume=67 |issue=11 |pages=2025–2034 |date=November 2018 |pmid=29703790 |doi=10.1136/gutjnl-2018-316234 |url=}}</ref>
*[[B-cell lymphoma]]: A continuous HCV [[antigen]] stimulation and permanent [[genetic]] damage caused by [[virus|viral]] [[proteins]] cause clonal proliferation of CD21−CD27+. It also down-regulates [[tumor]]-suppressive signals (such as, microRNA-26b). [[cancer|Oncogenic]] signals are further enhanced and additional tumor suppressor [[genes]] such as Bcl-6, p53, and β-catenin undergo [[mutation]]. Hence, the reduced levels of [[caspase]] 3, 7, and 9 reduce their sensitivity to Fas-induced [[apoptosis]].<ref name="pmid29703790">{{cite journal |vauthors=Cacoub P, Desbois AC, Comarmond C, Saadoun D |title=Impact of sustained virological response on the extrahepatic manifestations of chronic hepatitis C: a meta-analysis |journal=Gut |volume=67 |issue=11 |pages=2025–2034 |date=November 2018 |pmid=29703790 |doi=10.1136/gutjnl-2018-316234 |url=}}</ref>
* [[CVS|Cardiovascular]] [[disease]]: Local [[vessel|vascular]] damage is caused by an increased expression of adhesion molecules on [[endothelium|endothelial]] surface. Smooth cells in the media proliferate and [[apoptosis]] is inhibited, with local [[macrophages]] producing [[inflammation|proinflammatory]] [[cytokines]] and free radicals. These processes result in accelerated [[atherosclerosis]], procoagulant effects, and lead to major cardiovascular events.<ref name="pmid29703790">{{cite journal |vauthors=Cacoub P, Desbois AC, Comarmond C, Saadoun D |title=Impact of sustained virological response on the extrahepatic manifestations of chronic hepatitis C: a meta-analysis |journal=Gut |volume=67 |issue=11 |pages=2025–2034 |date=November 2018 |pmid=29703790 |doi=10.1136/gutjnl-2018-316234 |url=}}</ref>
*[[Chronic kidney disease]]: Direct [[HCV]] cytopathic effect, [[chronic]] [[inflammation]] from [[atherosclerosis]] and [[insulin resistance]], [[endothelium|endothelial]] and mesangial [[inflammation]], and [[podocyte]] and tubular [[injury]] caise [[CKD]]. [[Cryoprecipitates]] deposit at [[glomeruli]] also manifested as type I [[membranoproliferative glomerulonephritis]].<ref name="pmid29703790">{{cite journal |vauthors=Cacoub P, Desbois AC, Comarmond C, Saadoun D |title=Impact of sustained virological response on the extrahepatic manifestations of chronic hepatitis C: a meta-analysis |journal=Gut |volume=67 |issue=11 |pages=2025–2034 |date=November 2018 |pmid=29703790 |doi=10.1136/gutjnl-2018-316234 |url=}}</ref>
*[[Type 2 diabetes]]: Caused by both hepatic and peripheral [[insulin]] resistance. In the [[liver]], [[HCV]] leads to [[phosphatidylinositol 3-kinase|PI3K]]-AKT insulin-signaling pathway reduction via [[insulin]] receptor substrate 1 inhibition and impaired [[Sodium-glucose transport proteins|Glut2]]–mediated [[hepatic]] [[glucose]] intake. In the extra[[hepatic]] tissue, [[insulin]] resistance is a consequence of soluble endocrine mediators released by [[hepatocytes]]. Up-regulation of [[tumor necrosis factor|TNF]], [[glucose 6-phosphate|G6P]], and [[resistin]], with an imbalance in the adipocytokine profile, increases [[gluconeogenesis]] in these sites.<ref name="pmid29703790">{{cite journal |vauthors=Cacoub P, Desbois AC, Comarmond C, Saadoun D |title=Impact of sustained virological response on the extrahepatic manifestations of chronic hepatitis C: a meta-analysis |journal=Gut |volume=67 |issue=11 |pages=2025–2034 |date=November 2018 |pmid=29703790 |doi=10.1136/gutjnl-2018-316234 |url=}}</ref>


==References==
==References==
{{Reflist|2}}
{{Reflist|2}}


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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Yazan Daaboul, Serge Korjian, Seyedmahdi Pahlavani, M.D. [2], Javaria Anwer M.D.[3]

Overview

In isolated acute HCV infection, the host immune system stimulates the secretion of interferon alpha and the activation of natural killer cells, which is followed by the activation of the adaptive immune system. Chronic HCV is characterized by the impairment of these mechanisms. Eventually, chronic HCV infection leads to local inflammation and fibrogenesis, which cause hepatic injury and cirrhosis. Hepatocellular carcinoma, a known complication of chronic HCV infection, arises in cases of cirrhosis; the role of oncogenic proteins of HCV in the pathogenesis of hepatocellular carcinoma has yet to be elucidated.

Transmission

The transmission of HCV can be defined as percutaneous, sexual, healthcare-associated, or maternal-infant in nature.

Percutaneous Transmission

  • Blood and blood components transfusion
    • More than 90% of seronegative recipients who are transfused with blood from HCV-antibody positive donors will acquire infection.[1]
  • Contaminated shared needles among intravenous drug users
    • Before 1992, at least two-thirds of new HCV infections in the United States were associated with illicit drug use; the number has since decreased significantly.[2]
  • Chronic hemodialysis
    • The frequency of anti-HCV in patients on hemodialysis ranges from less than 10% in the United States to 55% to 85% in Jordan, Saudi Arabia, and Iran.[3]

Sexual Transmission

  • HCV RNA has been detected in semen and saliva.[4] People with multiple sexual partners and commercial sex workers have a high HCV prevalence.[5]

Health care Associated

  • Nosocomial transmission has been observed under several different conditions (e.g. needle stick, organ transplant, during surgery); now, however, because of infection control protocols, nosocomial transmission of HCV is rare except in cases of breach of protocols.[6][7]

Maternal Infant Transmission

  • Perinatal transmission frequency ranges from 0% to 4% in larger studies.[8][9]

HCV Clearance and Persistence

Acute viral infection and HCV replication triggers the activation of host immune responses, first by secretion of type I interferon alpha (IFN-alpha) and activation of natural killer (NK) cells. Nonetheless, secretion of endogenous IFN does not seem to effectively inhibit HCV replication.[10][11][12]

HCV proteins play a crucial role in inhibiting IFN-alpha effectors, such as IFN regulatory factor-3 (IRF-3), double stranded RNA-dependent protein kinase (PKR), and the JAK-STAT signaling pathway.[13][14][15] More importantly, chronic carriage of HCV is associated with impaired activation of NK cells despite IFN-alpha secretion. It is believed that the cross-linking of CD81 and the envelope protein E2 of the virus is a key mechanism by which NK cells are inactivated and INF-gamma is not produced by these cells.[16]

The activation of IFN-gamma is a prerequisite for the appropriate clearance of HCV. When activation occurs normally, antibodies start to form 7-31 weeks later.[17][18][19][20] While most epitopes for antibodies have not been discovered yet, hypervariable region 1 (HVR1) of the E2 envelope glycoprotein was found to be a target for anti-HVR1 antibodies. Antibodies play a role in clearing the virus from the host. It is currently unknown whether "escape" mechanisms are present in HCV that favor persistent HCV infection despite an adequate antibody response.[17][18][19][20]

Similarly, the activation of the CD4+ and CD8+ T-cell response is required for viral clearance. This cellular response allows for the development of long-term immunity against HCV.[21] Studies also proved that delayed or inadequate activation of T-cell response is associated with persistence of infection. It is not known why T-cell response may fail in response to acute infection, but it is hypothesized that persistence might be related to viral inhibition of T-cell maturation, defective dendritic cells, and/or failure of interleukin (IL) 12 activation.[21][22][23][24][25][26]

Liver Injury and Cirrhosis, and Hepatocellular Carcinoma

HCV is directly associated with hepatic steatosis, which is fat accumulation in the liver. It seems that core proteins may play a role in regulating lipid accumulation in hepatocytes, contributing to steatosis. However, steatosis is not observed in all genotypes of HCV infection; it is classically described in genotype 3, which perhaps is the only genotype that has a direct role in the development of steatosis irrespective of alcohol consumption or metabolic elements. Apart from steatosis, HCV per se has not been shown to have damaging effects on hepatocytes. The viral burden also does not seem to be directly related to the extent of liver injury.[27][28][29][30][31][32][33]

In chronic hepatitis C infections, the local immune response leads to portal lymphoid infiltration and chronic inflammation, which give way to bridging necrosis and degenerative lobular lesions.[16] Hepatic injury is directly associated with the degree of Th1 cytokine expression. The adaptive immune system, namely the cytotoxic T-cell response, injures infected cells as well as bystander cells. Nonetheless, it has not been confirmed whether the number of cytotoxic T cells is associated with the extent of liver injury.

Chronic inflammation ultimately leads to fibrogenesis due to deposition extracellular matrix elements in hepatic parenchyma. It is unknown whether viral components are directly responsible in the particular mechanism of hepatic cirrhosis in chronic HCV infection; although cirrhosis is definitely worsened in HCV patients who are also exposed to other risk factors, such as alcohol, obesity, and HIV.[16]

Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) occurs following chronic HCV infection complicated by liver cirrhosis. The precise role of HCV components in the development of HCC is poorly understood. Pinpointing which viral protein is directly related to carcinogenesis has been difficult, but studies have shown that NS3, NS4B, and NS5A all have oncogenic properties.[34][35][36][37][38]

Histology

Click on the arrow to view the pathologic findings in viral hepatitis: {{#ev:youtube|_hXvbpSxFZw}}

Mechanisms involved in extra-hepatic manifestations

References

  1. ↑ Vrielink H, van der Poel CL, Reesink HW, Zaaijer HL, Scholten E, Kremer LC, Cuypers HT, Lelie PN, van Oers MH (1995). "Look-back study of infectivity of anti-HCV ELISA-positive blood components". Lancet. 345 (8942): 95–6. PMID 7815889.
  2. ↑ Alter MJ (1997). "Epidemiology of hepatitis C". Hepatology. 26 (3 Suppl 1): 62S–65S. doi:10.1002/hep.510260711. PMID 9305666.
  3. ↑ Jadoul M, Barril G (2012). "Hepatitis C in hemodialysis: epidemiology and prevention of hepatitis C virus transmission". Contrib Nephrol. 176: 35–41. doi:10.1159/000333761. PMID 22310779.
  4. ↑ Liou TC, Chang TT, Young KC, Lin XZ, Lin CY, Wu HL (1992). "Detection of HCV RNA in saliva, urine, seminal fluid, and ascites". J. Med. Virol. 37 (3): 197–202. PMID 1331308.
  5. ↑ van Doornum GJ, Hooykaas C, Cuypers MT, van der Linden MM, Coutinho RA (1991). "Prevalence of hepatitis C virus infections among heterosexuals with multiple partners". J. Med. Virol. 35 (1): 22–7. PMID 1940879.
  6. ↑ Martínez-Bauer E, Forns X, Armelles M, Planas R, Solà R, Vergara M, Fàbregas S, Vega R, Salmerón J, Diago M, Sánchez-Tapias JM, Bruguera M (2008). "Hospital admission is a relevant source of hepatitis C virus acquisition in Spain". J. Hepatol. 48 (1): 20–7. doi:10.1016/j.jhep.2007.07.031. PMID 17998149.
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  20. ↑ 20.0 20.1 Puntoriero G, Meola A, Lahm A, Zucchelli S, Ercole BB, Tafi R; et al. (1998). "Towards a solution for hepatitis C virus hypervariability: mimotopes of the hypervariable region 1 can induce antibodies cross-reacting with a large number of viral variants". EMBO J. 17 (13): 3521–33. doi:10.1093/emboj/17.13.3521. PMC 1170689. PMID 9649423.
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