The role of the host immune system in the control of gamma-herpesvirus latency: Vaccination against, and surveillance of, latent infection

Unlike most viruses, the gamma-herpesviruses establish a latent infection within the host. This infection is never fully eliminated by the immune system and thus persists for the lifetime of the host. Latent gamma-herpesvirus infection is associated the induction of several diseases, including malignancies. There is thus a need for a more complete understanding the immune response to latent infection. Murine gamma-herpesvirus 68 (gammaHV68), a natural pathogen of rodents, has provided a tractable small animal model with which to study the gamma-herpesviruses. Studies outlined here utilize the gammaHV68 model to (a) examine the effect of vaccination on the establishment of latency and (b) identify immune mechanisms critical to controlling established latent infection.; An important component of a vaccine directed against a gamma-herpesvirus would be robust protection against the establishment of latent infection. Using an attenuated virus as a vaccine, we demonstrated that vaccination could produce significant and durable protection against the establishment of latency. In wild type mice, T cells were not required to mediate the protective effect of vaccination. In mice unable to produce anti-viral antibody, CD4 T cells, but not CD8 T cells, were required for protective vaccination. These studies provide insight into the design of effective vaccines against these viruses.; Once latency is established, the host immune system acts to limit this infection and prevent reactivation. To identify the mechanisms responsible for this control, we depleted various immune components from latently infected mice. Using this strategy, we observed that both CD4 and CD8 T cells are important in the surveillance of latent infection. These studies provided evidence that the immune mechanisms that limit latency are remarkably redundant.; The availability of mice with targeted deletions in components of the immune system has provided another tool with which to study immunity to latent infection. Using these animals, we demonstrated that, while CD8 T cells are crucial to control of latency, the classic ligands for these T cells, MHC Class la molecules, are not required to control latent infection. Instead, CD8 T cells appear to control latency via interaction with a nonclassical Class I molecule. These studies provide evidence that the immune system utilizes a novel mechanism to maintain latency in a quiescent state. This may provide insight into the development of novel therapies to combat gamma-herpesvirus-mediated disease.