Reconstructing the origins of human hepatitis viruses

Infections with hepatitis B and C viruses (HBV, HCV) are widespread in huma n populations throughout the world, and are major causes of chronic liver d isease and liver cancer. HBV HCV and the related hepatitis G virus or GB vi rus C (referred to here as HGV/GBV-C) are capable of establishing persisten t, frequently lifelong infections characterized by high levels of continuou s replication. All three viruses show substantial genetic heterogeneity, wh ich has allowed each to be classified into a number of distinct genotypes t hat have different geographical distributions and associations with differe nt risk groups for infection. Information on their past transmission and ep idemiology might be obtained by estimation of the time of divergence of the different genotypes of HCV, HBV and HGV/GBV-C using knowledge of their rat es of sequence change. While information on the latter is limited to short observation periods and is therefore subject to considerable error and unce rtainty, the relatively recent times of origin for genotype of each virus p redicted by this method (HCV, 500 2000 years; HBV. 3000 years, HGV/GBV-C, 2 00 years) are quite incompatible with their epidemiological distributions i n human populations. They also cannot easily be reconciled with the recent evidence for species-associated variants of HBV and HGV/GBV-C in a range of non-human primates. The apparent conservatism of viruses over long periods implied by their epidemiological distributions instead suggests that nucle otide sequence change may be subject to constraints peculiar to viruses wit h single-stranded genomes, or with overlapping reading frames that defy att empts to reconstruct evolution according to the principles of the 'molecula r clock'. Large population sizes and intense selection pressures that optim ize fitness may be additional factors that set virus evolution apart from t hat of their hosts.