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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 (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-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>  


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>
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>

Revision as of 18:34, 25 October 2016

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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]

Overview

In isolated acute HCV infection, the host immune system stimulates the secretion of interferon alpha and the activation of natural killer cells, 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 causes 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

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 Jak-Stat 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 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.[16]

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.[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 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.[17][18][19][20]

Similarly, activation of CD4+ and CD8+ T-cell response is required for viral clearance. This cellular response allows 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 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, local immune response lead to portal lymphoid infiltration and chronic inflammation that lead to bridging necrosis and degenerative lobular lesions.[16] 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.

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 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.[34][35][36][37][38]

Histology

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

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.
  7. ↑ Alter MJ (2008). "Healthcare should not be a vehicle for transmission of hepatitis C virus". J. Hepatol. 48 (1): 2–4. doi:10.1016/j.jhep.2007.10.007. PMID 18023493.
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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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  22. ↑ Bain C, Fatmi A, Zoulim F, Zarski JP, Trépo C, Inchauspé G (2001). "Impaired allostimulatory function of dendritic cells in chronic hepatitis C infection". Gastroenterology. 120 (2): 512–24. PMID 11159892.
  23. ↑ Wedemeyer H, He XS, Nascimbeni M, Davis AR, Greenberg HB, Hoofnagle JH; et al. (2002). "Impaired effector function of hepatitis C virus-specific CD8+ T cells in chronic hepatitis C virus infection". J Immunol. 169 (6): 3447–58. PMID 12218168.
  24. ↑ Lechner F, Wong DK, Dunbar PR, Chapman R, Chung RT, Dohrenwend P; et al. (2000). "Analysis of successful immune responses in persons infected with hepatitis C virus". J Exp Med. 191 (9): 1499–512. PMC 2213430. PMID 10790425.
  25. ↑ Appay V, Dunbar PR, Callan M, Klenerman P, Gillespie GM, Papagno L; et al. (2002). "Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections". Nat Med. 8 (4): 379–85. doi:10.1038/nm0402-379. PMID 11927944.
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  27. ↑ Poynard T, Ratziu V, McHutchison J, Manns M, Goodman Z, Zeuzem S; et al. (2003). "Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected with hepatitis C." Hepatology. 38 (1): 75–85. doi:10.1053/jhep.2003.50267. PMID 12829989.
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