Hepadnaviruses

Hepatitis B Virus

Hepatitis B virus (HBV) is the prototype of a new family of closely related DNA viruses, the Hepadnaviruses. This family comprises the woodchuck hepatitis virus (WHV), the ground squirrel hepatitis virus, and the duck hepatitis B virus as well as several other avian and mammalian strains. As in humans infected with HBV, chronic hepatitis and hepatocellular carcinoma (HCC) are commonly observed in persistently infected woodchucks and less frequently in infected ground squirrels and ducks.178 All the hepadnaviruses show hepa-totropism and similar life cycles in their hosts. They all start the replication cycle by reverse transcription of viral RNA to form DNA within core particles of the virus. The partially double-stranded circular DNA encodes four overlapping open reading frames179: 5 for the surface or envelope gene, C for the core gene, P for the polymerase gene, and X for the X gene. The 5 and C genes have upstream regions designated pre-5 and pre-C. The whole virion, or Dane particle, is a 42-nm spherical body that contains the nucleocapsid. The viral envelope, coded by the 5 gene, contains three distinct components (large, middle, and small proteins) that are synthesized by beginning transcription within the pre-5 or 5 gene, respectively. HBV can produce a large excess of the envelope surface antigen (HBsAg), consisting of both rods and small spheres with an average diameter of 22 nm, that can be found in patients' blood. The hepatitis B core antigen (HBcAg) is the nucleocapsid that encloses the viral DNA. When HbcAg-derived peptides are processed and expressed on the surface of hepatocytes, a T-cell-mediated immune response is induced to kill infected cells and eliminate the virus. The hepatitis B antigen (HbeAg) is a circulating peptide derived from the core gene and secreted by liver cells. Its presence in serum is a marker of active viral replication. The X gene encodes two proteins that have transactivating activity on the HBV enhancer to support viral replication. The X proteins can also transactivate cellular genes that may play a role in hepa-tocellular carcinoma.

Chronic HBV infection and cirrhosis are conditions leading to the development of HCC.180-183 This concept emerged from evidence that (1) the greatest incidence of HCC is detected in areas of the world (tropical and equatorial regions) where HBV infection is widespread and (2) most patients affected by HCC bear markers of a long-lasting HBV infection. Based on prospective epidemiologic studies, it is estimated that chronic HBV carriers exhibit a 100-fold-increased risk for HCC development.184 In sub-Saharan Africa with a high incidence of HCC, endemic infection by HBV cooperates in HCC together with exposure to aflatoxins derived from fungi of the Aspergillus genus, which grow on improperly stored foods.181,185 The mechanisms of hepatocar-cinogenesis by HBV are both direct and indirect. The direct mechanisms are related to integration of the HBV genome into cellular DNA and to potential oncogenic functions expressed by some viral genes (Figure 17.1). The role of HBV integration is most clearly observed in animal models. In more than 50% of HCCs arising in woodchucks, the WHV sequences specifically integrate 5' or 3' to the proto-oncogenes c-myc or n-myc, inducing a steady-state level overexpression of their mRNA, due to near insertion of the WHV enhancers.180 In human HCC, the HBV DNA integrates randomly in the cellular genome, and direct effects of inser-tional mutagenesis on oncogene activation were observed. In one such rare case, HBV DNA was integrated within an exon of the gene of the retinoic acid receptor p,180-186 disrupting the gene sequence. Because retinoic acid is important in inducing terminal cell differentiation, the inappropriate expression of one of its receptors may disturb the normal control of cell growth. In a second HCC, HBV DNA integration occurred in an intron of the cyclin A gene,180,185,187 leading to its truncation and to the production of a cyclin A/HBV fusion gene. The N-terminus of the cyclin A protein, containing the signal for protein degradation, was deleted and replaced by HBV pre-S sequences (including the strong pre-S2/S promoter). The resulting fusion protein was expressed in a high amount, and it was resistant to degradation.180,185,187 Constitutive expression of this chimeric form of cyclin A may lead to cell-cycle deregulation, uncontrolled DNA synthesis, and cell proliferation. In human HCC, deletions, rearrangements, and mutations at several chromosomal loci are frequently observed,180,185 inducing overexpression of c-myc and c-fos oncogenes and reduced expression of the most common tumor suppressor genes, such as p53, pRb, and p16INK4.185 None of these chromosomal alterations, however, seems to be a direct consequence of HBV DNA integration.

A more relevant direct viral mechanism of human hepa-tocyte transformation is related to the expression of the HBV X gene.183 Its products, the X protein, transform NIH3T3 and other immortalized mouse cells to the neoplastic pheno-type,188,189 and transgenic mice expressing the HBV X gene from the HBV promoter develop HCC.190 HBV X can tran-scriptionally activate a broad array of cellular genes, including epidermal growth factor and cellular proto-oncogenes, such as c-myc, c-fos, and c-jun. Because HBV X does not bind to DNA, HBV X-mediated transcriptional alterations may

Direct mechanisms

Insertional mutagenesis due to integration of HBV DNA into the sequence of cellular genes: retinoic acid receptor p and cyclin A. Transcriptional alterations due to the HBV X protein, affecting cellular genes EGF, c-myc, c-fos, c-jun, p53 and DNA repair genes.

Indirect mechanisms

Infection by HBV Chronic hepatitis

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