HEPATITIS C VIRUS (HCV)
 
Table of contents :

  • Epidemiology
  • Genomics
  • Proteomics
  • Transmission
  • Pathogenesis
  • Symptoms & signs
  • Laboratory examinations
  • Prognosis
  • Prevention
  • Therapy
  • Web resources


  • Epidemiology : prevalence = 3% of the world's population (180 million people worldwide ; 3 million Americansref) remain chronically infected. The virus claims 10,000 to 12,000 U.S. lives annually. Routine screening of blood donors for HBsAg and the elimination of commercial blood sources in the early 1970s reduced the frequency of, but did not eliminate, transfusion-associated hepatitis. Although the frequency of transfusion-associated hepatitis C fell as a result of blood donor screening, the overall frequency of hepatitis C remained the same until the early 1990s, when the overall frequency fell by 80%, in parallel with a reduction in the number of new cases in injection drug users. After the exclusion of anti-HCV-positive plasma units from the donor pool, rare, sporadic instances have occurred of hepatitis C among recipients of immune globulin (IG) preparations for intravenous (but not intramuscular) use. Serologic evidence for HCV infection occurs in 90% of patients with a history of transfusion-associated hepatitis (almost all occurring before 1992, when second-generation HCV-screening tests were introduced), hemophiliacs and others treated with clotting factors, and injection drug users; 60 to 70% of patients with sporadic "non-A, non- B" hepatitis who lack identifiable risk factors; 0.5% of volunteer blood donors; and 1.8% of the general population in the USA, which translates into 4 million persons. Comparable frequencies of HCV infection occur in most countries around the world, but extraordinarily high prevalences of HCV infection occur in certain countries :

    Hepatitis C accounts for 40% of chronic liver disease, is the most frequent indication for liver transplantation, and is estimated to account for 8,000 to 10,000 deaths per year in the USA. Most asymptomatic blood donors found to have anti-HCV and approximately 20 to 30% of persons with reported cases of acute hepatitis C do not fall into a recognized risk group; however, many such blood donors do recall risk-associated behaviors when questioned carefully.
    Genomics : the complete HCV sequence has been available since 1989ref; genes coding for structural proteins (C, E1, E2/NS1) undergo antigenic drift (=> quasi-species). It replicates from a ribonucleoprotein (RNP) complex that is associated with the ER membrane : in response to this stress, the unfolded protein response (UPR) is initiated by the proteolytic cleavage of a transmembrane protein, activating transcription factor 6 (ATF6), leading to increased transcriptional levels of heat shock 70kDa protein 5 (HSPA5) / GRP78, an ER luminal chaperone protein. However, the overall level of GRP78 protein is decreased. While ER stress is also known to affect translational attenuation, cells expressing HCV replicons have lower levels of phosphorylation of eIF2a. Interestingly, cap-independent internal ribosome entry site-mediated translation directed by the 5' noncoding region of HCV and GRP78 is activated in cells expressing HCV replicons.
    There are 4 hierarchical strata in the genetic heterogeneity of HCV: group above subgroup above isolates above quasispecies. The entire genome sequence has so far been reported for 16 isolates which are classifiable into 3 groups and 6 subgroups. Provisional classification of HCV is also possible using a partial sequence of the HCV genome : Okamoto's serotypesref of core protein : useful in cases where serum samples were not stored under conditions to preserve RNA or in infected hosts who have cleared the virus and therefore have only antibodies remaining to identify the infection. Proteomics :
    The polarized nature of hepatocytes and the tight junction roles of OCLN and CLDN1 suggest an entry pathway similar to that of the group B coxsackieviruses, where the virion initially binds readily accessible factors that then provide a mechanism for migration of the virion into the tight junction region, just prior to internalization. Indeed, cellular factors are utilized by the incoming HCV virion in a temporal manner. At least GAGs and LDL-R appear to mediate virion binding. Conflicting evidence has shown that SR-BI acts as either a binding or postbinding entry factor, while CD81 and CLDN1 play postbinding roles in the HCV cell entry process.
    CD81 and SR-BI are essential for HCVpp entry. However, these 2 proteins are not sufficient to provide entry functions in non permissive cells, suggesting that additional unidentified cellular factor(s) are necessary for HCVpp entryref.


    NS3. The serine protease, NS4A cofactor and RNA helicase domains are shown in pink, green and blue, respectively. The serine protease and RNA helicase active site residues are indicated in red. b, NS5A domain I. Shown is a dimer, as seen in the crystal structure. Individual subunits are shown in blue and green, with their C termini (that is, leading into domain II) pointing upwards. The N termini, which presumably face the membrane, are at the bottom. The purple spheres represent Zn2+ ions. Disulphide bonds are indicated in red. Brackets indicate highly conserved surfaces. A basic groove, which may bind RNA, is also indicated. c, NS5B. Shown is the typical 'right hand' model of the RdRP, with palm, fingers and thumb domains in pink, blue and green, respectively. The C-terminal region, which is not part of the RdRP, is shown in yellow. Note the extensive interactions between the finger and thumb domains. In addition, a -hairpin is shown in purple, and active site residues Asp 220 and Asp 318 are shown in red.
    Transmission : Environmental survival : RNA in plasma or serum has been found to be stable at 4°C for 7 days
    Resistance : Pathogenesis : primed CD8 T cells are critical for antiviral immunity and subsets of circulating CD8 T cells have been defined in blood but these do not necessarily reflect the clonality or differentiation of cells within tissue. Current models divide primed CD8 T cells into effector and memory cells, further subdivided into central memory (CCR7+, L-selectin+), recirculating through lymphoid tissues and effector memory (CCR7-, L-selectin-) mediating immune response in peripheral organs. D8 T cells derived from organ donors and patients with end-stage HCV infection showed that: 1) all liver-infiltrating CD8+ T cells express high levels of CD11a, indicating the effective absence of naive CD8 T cells in the liver. 2) The liver contains distinct subsets of primed CD8+ T cells including a population of CCR7+ L-selectin- cells, which does not reflect current paradigms. The expression of CCR7 by these cells may be induced by the hepatic microenvironment to facilitate recirculation. 3) The CCR7 ligands CCL19 and CCL21 are present on lymphatic, vascular, and sinusoidal endothelium in normal liver and in patients with HCV infection. The recirculation of CCR7+/L-selectin- intrahepatic CD8 T cells to regional lymphoid tissue will be facilitated by CCL19 and CCL21 on hepatic sinusoids and lymphatics. This centripetal pathway of migration would allow restimulation in lymph nodes, thereby promoting immune surveillance in normal liver and renewal of effector responses in chronic viral infectionref. Compared with peripheral cells, intrahepatic T cells from patients with chronic hepatitis C were selectively enriched with CD45RO+ memory T cells but had a lower percentage of CD4+ T cells expressing the differentiation markers CD27 and CD28. The percentage of intrahepatic CD45RO+ and CD28+ T cells correlated with the degree of liver inflammation, which suggests that memory T cells at relatively early stages of differentiation are directly involved in liver inflammation. Despite their memory phenotype, intrahepatic T cells were defective in proliferation capability, produced less IFN-g in response to stimulation by TcR, and contained less perforin but expressed higher levels of Fas and FasL, compared with their counterparts in peripheral blood. The distinct characteristics of intrahepatic T cells suggest that they play an important role in the immunopathogenesis of chronic hepatitis Cref.
    Incubation 15÷160 days =>
    => asymptomatic in babies
    => acute or protracted hepatitis C (a.k.a. non-A, non-B hepatitis) from immune-mediated damage Associated diseases : although HCV is a hepatotropic virus, the HCV genome and its replicative intermediates have also been detected in peripheral blood mononuclear cells (PBMCs) and in lymphoid tissues of chronically infected patientsref1, ref2, ref3, ref4, ref5, ref6, ref7. This evidence, however, has been questioned, as commonly used techniques are limited in their ability to discriminate between positive and negative RNA strands, the presence of the latter being regarded as a direct evidence of viral replicationref. Importantly, in several studies that used assays carefully optimized for strand specificity, HCV RNA negative strand was not detected in PBMCs from infected patientsref1, ref2, ref3. Similarly, although the presence of active replication in bone marrow (BM) was suggested by in situ detection of viral RNA and viral antigensref, it was not confirmed by an investigation using strand-specific assayref. However, the latter study was relatively small, as it included only 6 patients. It was found in 38% of serum and 31% of bone marrow in a US clinicref Laboratory examinations : ... confirmed by testing for HCV RNA : 1 international unit equals to 2.7 copies of viral genome.
    Research on HCV has been hampered by the lack of a virion-capable cell culture system : most existing models rely on strains isolated from chronic carriers and only a few HCV strains can replicate in this system and these strains need adaptive mutations in their viral genome to replicate efficiently in cultured cells. Since 2005 several strains have been cultivated in the human hepatoma cell line Huh7 : Prognosis : HCV RNA may persist and replicate in the liver (genomic strand : 83%; antigenomic strand : 100%) and PBMCs (genomic strand : 50%; antigenomic strand : 83%) of healthy, anti-HCV antibody–positive, serum HCV RNA–negative patients who have persistently normal ALT levels. These patients should be followed up, because they have an ongoing viral infectionref.

    Prevention :

    Therapy : Web resources : LANL HCV Databases (LANLHCV)

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