Processes of genomic change in herpesviruses

Lead Research Organisation: MRC Virology Unit

Abstract

Eight members of the herpesvirus family naturally infect humans, including herpes simplex virus types 1 and 2, varicella-zoster virus, Epstein-Barr virus and cytomegalovirus. Most are very common in human populations, and infection is lifelong. In a healthy person herpesviruses typically have quite mild effects, but in some situations they cause serious diseases, including devastating general infection, birth defects, cancers, encephalitis, shingles and glandular fever.||The DNAs of herpesviruses are large by virus standards and contain many genes. In several human herpesviruses, most notably cytomegalovirus, some of the genes occur in a range of distinct versions in different strains of the virus. At present we do not understand in any detail how this diversity arises or the ways in which variations benefit the virus.||We are studying cytomegalovirus and other herpesviruses by determining DNA sequences for many virus strains, then using computer-based methods to analyse characteristics of gene variation. Our aim is to describe the patterns of variation in detail, and then to identify possible effects of variation on the course of infection. This work will form a fundamental part of understanding herpesviral infections of humans, and should underpin efforts to control and treat these agents.

Technical Summary

Herpesviruses have DNA genomes in the range 125 kbp to 236 kbp, containing up to approximately 165 genes. There are eight herpesviruses with humans as natural hosts: herpes simplex virus types 1 and 2 (HSV1 and HSV2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), human cytomegalovirus (HCMV), and human herpesviruses 6, 7 and 8 (HHV6, HHV7 and HHV8). Most infect a substantial proportion of the human population, and all give rise to lifelong infections. In healthy people herpesviruses typically exist in a minimally pathogenic state, but in appropriate conditions they cause a range of diseases, including encephalitis (HSV1 and HSV2), zoster (VZV), mononucleosis (EBV), congenital defects (HCMV) and cancers (EBV and HHV8). In immuno-compromised persons disseminated infections arise; for instance with HCMV in transplant patients and AIDS patients. We are analysing processes of variation and evolution in populations of human herpesviruses. In recent years complex or idiosyncratic patterns of genomic variation within herpesvirus species have been detected, for EBV, HHV8 and, most notably, HCMV. Descriptions of these phenomena remain incomplete and their basis in evolutionary processes and implications for virus biology and pathogenesis are unexplored. Acquiring such knowledge will provide a fundamental component in building a detailed understanding of the capabilities and behaviour of herpesviruses as human pathogens. The viruses to be studied include HCMV, EBV, HHV8, HSV1 and HSV2, which present a range of patterns of variation. A major focus, pursued jointly with Dr A Davison in the Unit, is to investigate gene content of HCMV and sequence variation in HCMV isolates. The genome sequence of a near-clinical HCMV isolate was determined and interpreted to give a much improved account of gene content. There is a subset of some 20 HCMV genes which are highly variable among strains, and we have undertaken comparative analyses of these. The underlying phenomena are complex, and include many recombination events. In the past year Dr Davison has been using next generation sequencing methods very productively to determine HCMV genome sequences, and we have analysed these to give novel insights into sequence diversity and constancy in HCMV. As a complementary approach to understanding the HCMV genome, we undertook complete genomic sequence determinations of chimpanzee CMV, two Old World monkey CMVs and two New World monkey CMVs. We have sequenced the genome of an EBV type 2 strain and compared it to two available type 1 strains, to give a precise delineation of type differences, now seen definitively to be restricted to four latent cycle genes. This study revealed the occurrence of distinct genome-wide lineages and recombination events between them. In addition we have discovered that certain of the latent cycle genes of EBV are evolving under global positive selection, which is presumed to reflect selection against presentation of T cell epitopes in latently infected lymphocytes, and this phenomenon is being studied further. Dr R Bowden in the group demonstrated diversity at locations in the HSV1 genome that correlated with prehistoric movements of human populations. This work is being developed to examine variation in HSV1 at the whole genome level, now using next generation sequencing methods.

Publications

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Davison AJ (2009) The order Herpesvirales. in Archives of virology

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Gatherer D (2009) The 2009 H1N1 influenza outbreak in its historical context. in Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology