Hepatitis delta virus. Genetics and pathogenesis.

After the discovery of HDV there have been significant advances in the understanding of the biology and disease of HDV infection. Analyses at the molecular level have revealed several fascinating features (ribozyme activity, RNA-dependent RNA polymerase activity of RNA polymerase II, HDAg isoprenylation, and RNA editing) that are of significant interest. Intensive investigation of the ribozyme elements has yielded important insights in both functional and structural features. However, there is information lacking about other aspects of the HDV replication cycle including the specific nature of the interaction between HDAg and HDV RNA, the function of HDAg in HDV RNA replication, transcription by RNA polymerase II, and the mechanisms of HDV RNA editing and its regulation. Further study of these and other aspects of the HDV replication cycle will continue to enrich our understanding of basic biology. Evaluation of the mechanisms of HDV disease remains an important goal in the study of this agent. Although both acute and chronic disease are commonly associated with unfavorable outcomes, it is clear that chronic infection is associated with a broad spectrum of disease. The interactions between HDV, HBV, and the host are necessarily complex, and it is likely that each contribute factors that influence disease and outcome. Recent analyses of HDV genotypes have suggested that disease variations may be associated with viral genetic factors. Consistent with the obligate role of HBV in the HDV life cycle, HBV replication is also an important determinant of HDV disease. It is still unclear if interactions between specific genotypes or variants of HBV and HDV influence disease. Recent data also suggest that infection with multiple hepatitis viruses (HBV, HDV, and HCV) can influence the severity of disease. It remains to be seen whether coinfection with the recently discovered hepatitis G virus is associated with altered disease patterns. Further advances in our understanding HDV disease and possible therapeutic approaches will rely on a combination of additional studies at the molecular, genetic, epidemiologic, and clinical levels. These studies will continue to elaborate the model of HDV infection and disease that can ultimately be tested by experimental infection of chimpanzees and woodchucks.