Pathogenesis and Cell Biology of HCV Infection

29 May

Hepatitis C virus is a positive-strand RNA virus related to the flaviviruses on the basis of molec- ular and biophysical  characteristics  (cf. IARC, 1994). A diagrammatic  characterization  of the virion and its genome and genomic products is seen in Figure 12.22. After infection, the posi- tive-strand RNA of the virus is translated by ribosomes producing the various proteins, including the RNA-dependent RNA polymerase necessary for the production of the minus strand and sub- sequent replication to produce the positive strand that interacts with the various structural pro- teins and is released from the cell by a budding mechanism (Koff, 1998). The core protein (p21,

Figure 12.21 World map illustrating  the prevalence  of antibodies  to hepatitis C virus (HCV) in blood donors measured by modern technologies.  (From Heintges and Wands, 1997, with permission  of the au- thors and publisher.)

Figure 12.22 Schematic  features of the HCV virion, its RNA, and functional  products thereof. (After

Esumi and Shikata, 1994; modified by authors with newer findings.

Figure 12.22) is the antigen inducing the predominant antigenic response in patients with hepato- cellular carcinoma (Watanabe et al., 1991), and there is some evidence that this protein has the ability to transform rat fibroblasts in culture as well as to suppress apoptosis (cf. DiBisceglie,

1997). A number of different genotypes of the virus have been reported and are now classified into types I to VI with various subtypes (IARC, 1994). The host range or species specificity of HCV infection is limited to humans and chimpanzees. The nucleotide divergence of the various genotypes may be as high as 20%, and there is substantial evidence that the virus exhibits ex-treme genetic variability  with an estimated rate of nucleotide  change of 10–3  substitution/site year (cf. Bréchot, 1997). Such extreme genetic variability, which is comparable to that seen with the AIDS virus (see below), markedly reduces the effectiveness of the development of any vac- cine for the virus infection. Still, the viral gene products are quite immunogenic and are associ- ated with chronic infection of the target organ, the liver, ultimately leading to cirrhosis and HCC. Since the HCV genome does not integrate into the host cell genome but its gene products may serve to transactivate  cellular genes (e.g., Ray et al., 1997), the virus serves the function of a complex promoting agent in inducing HCC.

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