Pathogenesis and Cell Biology of HBV Infection

28 May

HBV belongs to a group of hepatotropic DNA viruses known as the hepadnaviruses, which are found in a number of mammalian and avian species (Chapter 4). A diagram of the structure of the virus shows the major antigens (Ags) to which the host develops antibodies. The DNA ge- nome is small, about 3200 bp, and occurs as a circular complete minus (–) strand with a comple- mentary plus (+) strand that is incomplete (Chapter 4). As with other animal hepadnaviruses, the virion contains a DNA polymerase/reverse  transcriptase that is utilized during its complex life cycle, as described in more detail in Chapter 4. Since the life cycle of the virus involves an RNA intermediate,  as in retroviruses,  one might expect to find integrated  viral DNA in the host genome. This is true, although in many instances the integration of the viral genome into host cell DNA appears to involve rearrangement  and recombination  of the viral genome (Takada et al., 1990; Zhou et al., 1987). Other studies have indicated that incorporation of the viral genome into the host genome results in genetic instability of the host cell genome (Hino et al., 1991; Matsuzaki et al., 1997), indicating that virus infection in the hepatocyte may mimic the action of a  progressor  agent (Chapter  9). Although  there is no known  “oncogene”  within  the HBV

Figure 12.13 Outline of the modes of HBV transmission in countries where the infection is endemic as compared with where it is non-endemic.  The rates of progression to chronicity and the HCC incidence in endemic and non-endemic  regions are noted in the figure as % of the population affected. (Adapted from Buendia, 1992, with permission of the author and publisher.)

genome, an interesting gene termed the X gene, giving rise to a protein with a similar designa- tion, occurs in all hepadnaviruses.  Mutation of the X gene results in loss of viral replication in the animal host (cf. Yen, 1996). The X protein functions as a transcriptional transactivator for a number of cellular genes (cf. Koike and Takada, 1995) and may also be involved in the processes of cellular DNA repair (Feitelson and Duan, 1997; Prost et al., 1998) and signal transduction (Cong et al., 1997).

As noted above, chronic infection with HBV is a prolonged, lifelong process that may be dramatically modified by appropriate therapy (Hoofnagle and di Bisceglie, 1997; Terrault, 1996) but probably never completely cured. The natural history of HBV infection, leading ultimately to cirrhosis and/or hepatocellular  carcinoma,  is seen in Figure 12.15. Furthermore,  it is quite likely that the immune response of the host to the chronic infection with HBV plays a major role

Figure 12.14 Diagrammatic  structure  of the hepatitis  B virus. The envelope  is noted as consisting  of several proteins, which are the surface antigens to which antibodies are produced. The nucleocapsid  core contains the partially double-stranded  viral genome and the DNA polymerase/reverse transcriptase  (large, filled circle). The boxes indicate the positions of direct repeats (DR1 and DR2). The core antigen protein (HbcAg) may also serve as an antigen for the host immune system. (Adapted from Blum et al., 1989, with permission of the authors and publisher.)

in the ultimate development of hepatocellular carcinoma. Transgenic mice that overproduce the hepatitis B virus large-envelope polypeptide and accumulate toxic quantities of hepatitis B sur- face antigen within the hepatocyte develop extensive, prolonged hepatocellular injury involving inflammation,  regenerative  hyperplasia,  aneuploidy,  and ultimately  hepatocellular  carcinoma (Chisari et al., 1989). This finding has implied that the immune response induced by HBV infec- tion is perhaps equal to or more important in the development of hepatocellular carcinoma in the human than is the integration of the viral genome into the host DNA (Chisari and Ferrari, 1995). Thus, the immune response resulting in chronic viral hepatitis, cell proliferation, and apoptosis may be analogous to tumor promotion in rodent hepatocarcinogenesis  (Chapter 7), and the pro- gressor action of the virus transits such promoted cells into the stage of progression and malig- nant neoplasia in the human host.

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