The genetics controlling the course of herpes virus infection in humans

Herpes viruses have evolved over time developing a complex strategy for maintaining persistent infection in humans. This sophisticated group of viruses usually persists asymptomatically for the life of the host, controlled by constant immune surveillance. These viruses stimulate a large number of T cells which suppress the virus and protect the host from herpes-related pathologies. However, if the immune system is weakened, the virus may become lytic, proliferate and initiate pathogenesis. The outcome of infection with these viruses is highly variable, and an unfortunate minority suffer major life threatening clinical problems. For this reason, it is important to understand the complicated machinations involved in T cell immunology and how it works to actively control virus. Viral peptide epitopes are present on the surface of virus-infected cells and are recognised by the cytotoxic T lymphocytes (CTL) of the immune system only when bound to cell surface molecules called human leukocyte antigens (HLA) in humans. These HLA molecules are highly polymorphic, with each different HLA capable of binding a distinct set of viral peptides. Over the last 2 decades, various studies have identified the viral peptides that are recognised in the CTL response to herpes viruses Epstein-Barr virus (EBV) and human Cytomegalovirus (HCMV). The critical molecule on the surface of CTLs that is involved in specific recognition of viral peptides is the T cell receptor (TCR). To accommodate the huge variety of viral peptides presented by infected cells, millions of different TCR molecules are expressed by CTLs to ensure an appropriate TCR is available for binding to most viral peptides. Interestingly, some viral peptides are recognised by a large variety of TCR molecules while others are targeted by very few. This restriction in TCR usage is sometimes so extreme that the same “public TCRs” emerge in different individuals through mechanisms that are unclear. Polymorphism within the various levels of these immune responses may alter or compromise immunogenic competence. Highly polymorphic HLA molecules and viral genome sequence variability, in addition to TCR gene polymorphism could represent an important mechanism for inter-individual differences in antiviral T cell responses and disease progression. A more complete understanding of the influence these factors have on the immune system and disease pathogenesis will likely enhance both theoretical and clinical immunology