Evolutionary history, cross-species transmission and host adaptation of human viruses and their primate homologues

Abstract

At present the origins of major human pathogens associated with hepatic disease are poorly understood. The absence of such information pertaining to the evolutionary history of hepatitis B virus (HBV) and hepatitis C virus (HCV) and its genetically related viruses impacts upon the development of vaccines and effective eradication strategies. Studies are currently limited by the absence of historical samples from which to date the emergence of human infections and therefore the evolution of human hepatic viruses relies on epidemiological studies and genetic analysis of contemporary virus populations worldwide. Approximately one third of the world’s population is infected with HBV, and despite the availability of a vaccine, the virus is attributed with over 1 million deaths per year through liver disease. HBV variants infecting humans show genetic and antigenic heterogeneity and are currently classified into 8 genotypes A-H with nucleotide divergence of between 9-13%. In addition to these variants, recombination has been detected between genotypes A and D, and B and C, which can generate novel variants. The past 10 years has seen the detection of HBV in chimpanzees, gorillas and other non-human primates (NHPs) at frequencies comparable to those observed in regions of endemic human HBV infection. Despite the genetic divergence between human and NHP HBV variants the detection of recombination between human genotype C and chimpanzee and gibbon variants suggests that HBV can share hosts in nature. The evolutionary process that may have given rise to the distinct species-specific variants of NHP HBV within overlapping geographical regions has not been reconciled, with evidence supporting both allopatric speciation and co-speciation. HCV a member of the Flaviviridae family currently infects approximately 3% of the world’s population and is one of the major causes of chronic liver disease, hepatocellular carcinoma and liver cirrhosis. Human pegivirus (HPgV) a member of the Pegivirus genus of the Flaviviridae family infects approximately 5% of the world’s population, although it is of unknown disease association. Very recently, several studies of wild rodent and bat populations have revealed much greater viral diversity of members of both Hepacivirus and Pegivirus genera. Homologues of HCV have been detected in a range of species including domestic dogs (canine hepacivirus [CHV]) and horses (non-primate hepaciviruses [NPHV]). Similarly, several new pegiviruses have been described in horses (equine pegivirus, [EPgV] and Theiler’s Disease Associated Virus [TDAV]), several species of rodents (rodent pegivirus [RPgV]), and further species of bats (bat pegivirus, [BPgV]). Despite the differences in pathogenicity between HCV and HPgV infections, they share similar genomic organisation and are capable of establishing persistent infections in humans. Studies into bat, horse and rodent homologs of HCV and HPgV have yet to determine disease associations, transmission routes and seroprevalence. Studies presented within this thesis broaden our understanding of the clinical presentations and host range of NPHV and EPgV. Screening to determine the level of active and past infection to both viruses provides novel insight into infection frequencies, host range, disease progression and examines the correlation between infections and the presence or absence of hepatic disease. Research examining HBV variants circulating in NHPs in Cameroon provides novel evidence for the occurrence of recombination and cross species transmission between NHP variants of HBV and examines the role these findings play in expanding our understanding of the evolution of HBV.