HBV and Immunoprophylaxis

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The host--cell interactions that allow for the persistence of a virus, and the failure of the immune system to eliminate it in an immunocompetent individual, is a topic of considerable relevance for the DNA tumour virus field. For largely noncytopathic viruses, such as HPV, EBV, KSHV and HBV, they must either overwhelm an effective immune response or adopt mechanisms that allow for avoidance, as suggested by one or more of the hypothesized routes for progression from infection to generation of hepatocellular carcinoma (Figure 18). One approach for EBV therapy, as discussed elsewhere, assumes that the immune system may need to, and can, be stimulated specifically to recognize viral genes that might be expressed in its associated tumours, with beneficial effects. As noted, however, realistically such an approach is aimed at reducing morbidity, rather than effecting cure (Khanna et al., 1999). Such an approach may be even more valid for HBV, which can infect virtually all the hepatocytes in the liver, suggesting that the number of infected cells might actually outnumber relevant antigen-specific T-cells by several orders of magnitude in acute hepatitis infections and HCC. Thus, in individual situations where there are not sufficient cytotoxic T cells to contain infection, stimulation of the immune system might prove effective. On the other hand, there are studies to suggest that in some individuals with acute hepatitis, even in the presence of a vigorous T cell response, not all virus may be cleared. This has been explored using sensitive PCR assays where, several decades after complete clinical and serological recovery from this disease, low levels of viral DNA were detected in sera and PBMCs in some cases. Whether this result represents individuals at risk of reinfection and/or developing HCC for other, possibly genetic reasons, remains to be assessed. Notably, in HBV vaccine studies in Taiwan on children of different ethnic origins, unidentified host factors were postulated to explain the hyporesponsiveness seen among some populations (Hsu, 1996).

For HBV, it was earlier demonstrated that serum containing HBsAg retained its immunogenic properties even after heat inactivation. This observation proved the basis for plasma-derived, and later recombinant, s-antigen vaccines against HBV. In the 1980s, large-scale vaccination studies on children were initiated in both Taiwan and China, countries with the highest rates of HBV endemicity in the world, with the reasonable expectations that universal childhood immunization would allow HBV infections to be controlled in these areas within a few generations. In some high-risk areas, vaccination programmes to immunize every newborn child have been initiated and subsequent HCC incidence in these areas is being carefully monitored. As this malignancy, as with

Figure 18 Hypothesis. Route from HBV infection to the genesis of hepatocellular carcinoma (HCC). (Adapted from Chisari, 2000.)

EBV-associated NPC, is mainly confined to adult populations, the data on this topic are not yet available. However, in Taiwan 10 years on, for children who completed a complete course of vaccination (four doses), anti-HBV antigen antibodies were detectable in a high proportion (82%) of them. Interestingly, in China it has now been found that tree shrews (Tupaia belangeri chinenesis) can be infected with human HBV and the infection passed to offspring in a high proportion of cases. Thus, a useful model may evolve for studying many of the unanswered questions about the relationship of HBV infection, the development of HCC and the variable responses to vaccination that have been observed.

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