Molecular evolution and origins of hepatitis B virus in humans and non-human primates

Abstract

Infection with hepatitis B virus (HBV) has been detected in most populations throughout the world, as well as in a number of non-human primate species. In humans HBV infection represents a major global health problem, with an estimated 1 million deaths per year due to hepatocellular carcinoma and chronic hepatitis. HBV variants infecting humans can be classified into at least 7 different genotypes differing from each other by 11-13% in nucleotide sequences. A range of distinct genotypes also infect African apes, Asian apes and possibly New World monkeys. Studies of HBV epidemiology and the geographical species associations of different HBV genotypes have led to a number of hypotheses for the origin of HBV in humans and primates. These are the "Out of Africa" hypothesis, the hypothesis that HBV originated in South America and spread in Africa and Western countries in the last 200-300 years, and more recently, proposed origins from cross-species transmission and/or co-evolution of HBV in their current host. The main aim of this thesis is to investigate the molecular evolution of human and non-human primate HBV to gain further insights into the origin of HBV in these species. This investigation was carried out in three main sections.The first comprised an extensive and detailed genetic analysis of the distribution of human HBV genotypes in HBV endemic areas in sub-Saharan Africa and South East Asia. In the second section complete genome sequences of HBV variants were analysed for recombination between different HBV genotypes. This analysis included the use of a novel method based on the calculation of association scores for phylogenetic groups, an approach that helps resolve many of the uncertainties and difficulties of interpretation of results arising from conventional methods, such as SimPlot.The third section investigated the frequencies of HBV infection in non-human primates, and the relationship between HBV genotype, primate species and geographical range. In my survey, HBV infection was confined to African and Asian apes, and uniformly absent from a wide range of African monkey species. Phylogenetic analysis of chimpanzee-, gibbon- and orangutan-derived HBV variants indicated that a geographical rather than a species correlation with genotypes, implying the co-circulation and cross-species transmission of HBV between species of overlapping habitats. However, in no cases were primate-associated HBV variants found in humans, nor human genotypes in non-human primates. These findings and the interspersed nature of human and non-human primate HBV genotypes deepens the mystery of HBV origins and evolution in humans. The findings, however, provide a context for ongoing studies of HBV biological variability and genotype-associated differences in pathogenicity and outcomes of infection.