Flaviviruses

Hepatitis C Virus

The hepatitis C virus (HCV) belongs to a genus of the family Flaviviridae. The virion is spherical and enveloped. The genome is a single-stranded linear RNA molecule of about 9.5 kb encoding a single large polyprotein precursor of about 3,000 amino acids from which three structural and seven non-structural proteins are generated by specific cleavage. The capsid protein or core protein is located at the amino-terminus of the polyprotein precursor. Similarly to HIV-1, HCV shows a great genomic variability, thus representing a quasi-species, that is, a population of closely related, yet heterogeneous, viral genomes.204-206 Nevertheless, HCV can be subdivided into six major genotypes. HCV genetic heterogeneity may have important implications because it could influence the immunologic and therapeutic responses as well as represent a major obstacle in the preparation of an effective anti-HCV vaccine.30,204-207 Epidemiologic studies have shown that HCC is associated with HCV infection, but the proportion of cases related to HCV varies considerably.208 In countries of southern Europe such as Italy, Spain, and Portugal, as well as in Japan, HCV infection appears to be the most frequent underlying cause of HCC, because from 50% to 70% of patients with HCC show anti-HCV antibodies. In the United States, the proportion of patients with HCC who are seropositive for anti-HCV antibodies is much lower, about 30%,208,209 but still very significant.

The process of hepatocarcinogenesis caused by HCV results mainly from indirect mechanisms.183 Similar to HBV infection, when the cell-mediated immune response fails to eradicate HCV infection, the acute hepatitis may evolve toward chronic persistent hepatitis, cirrhosis, and HCC. As for HBV infection, the host immune response plays the major role in causing the hepatocellular damage.182,205,206,208,210 During the evolution from acute infection to chronic hepatitis and cirrhosis, the repeated bouts of inflammation, necrosis, and hepatocyte regeneration favor the emergence of a neoplastic liver cell population. Cirrhosis is found in about 90% of HCC patients with HCV markers,182,205 although there are patients with HCV-related HCC without liver cirrhosis.211 This observation suggests a possible direct role of HCV in hepatocarcinogenesis. Various mechanisms appear possible. The HCV nonstructural protein NS3 transforms to the neoplastic phenotype in the NIH3T3 mouse fibroblasts.212 Moreover, the HCV core protein suppresses apoptosis183,213 and, in cooperation with the human activated c-H-ras oncogene, causes malignant transformation of primary rat embryo fibroblasts.214 Finally, HCV core gene transgenic mice develop HCC.215 The HCV genotype 1b has been associated with more severe and rapidly progressive liver disease and a higher risk of HCC.182,208

HCV infects other tissues besides the liver, and it is associated with several diseases,216,217 such as sialadenitis, membranoproliferative glomerulonephritis, and mixed cryoglobulinemia, a disorder characterized by the presence in the serum of a mixture of polyclonal immunoglobulins of various isotypes that reversibly precipitate at temperatures below 37°C. Most of these immunoglobulins are complexes of polyclonal IgG and polyclonal rheumatoid factor that are mainly IgM.216,217 Because mixed cryoglobulinemia is considered the expression of a low-grade malignant lymphoproliferative disease, an association was postulated between HCV and lym-phoproliferative disorders. Epidemiologic studies showed a significant association between HCV infection and B-cell non-Hodgkin's lymphoma (NHL).217 HCV-related markers (HCV RNA and anti-HCV antibodies) were detected in 34% of B-cell NHL, compared to 3% Hodgkin's lymphomas and 1.5% healthy controls.217 Comparable values of association between B-cell NHL and HCV infection were confirmed in subsequent studies,217,218 although HCV markers were not detected in NHL cells in HCV-infected patients.216,219,220 A case-control study demonstrated that HCV infection increases by 50-fold the risk of B-cell NHL involving the liver and the major salivary glands (the most common sites of HCV infection) and by four fold the risk of lymphomas at other sites.221 Although HCV has been widely detected in peripheral blood mononuclear cells of patients with mixed cryo-globulinemia and B-cell NHL with HCV infection, the virus replicates poorly in lymphoid cells.216,219 Therefore, the postulated oncogenic role of HCV in lymphoproliferative disorders is presently unclear. According to other models of B-cell lymphomagenesis,13 HCV may act as an exogenous prolonged antigenic stimulus inducing a mitogenic effect and proliferation of B lymphocytes in HCV-infected patients.219 Treatment with IFN of HCV infection in patients with splenic lymphomas led to strikingly complete responses of the lymphomas, but not in noninfected patients.

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