This application focuses on the role of CD8+ T cells recognizing latent gammaherpesvirus proteins in the control of the latent infection. Latent infection with human gammaherpesviruses predisposes towards severe diseases such as Kaposi's sarcoma, Hodgkin's disease and lymphoproliferative disease. It is therefore crucial to understand the immunological mechanisms underlying the long-term control of gammaherpesviruses during latency. We propose to examine fundamental mechanisms behind the control of the latent infection in a mouse model, murine gammaherpesvirus. This model is highly tractable for immunological studies, and we have mapped an epitope recognized by CD8+ T cells within the latency-associated M2 protein. We have also demonstrated that M2-specific T cells can reduce the number of latently infected cells during the establishment of latency. The studies proposed address the mechanism of CD8+ T cell control of latency.
Aim 1 : We will determine the role of the M2-specific CD8+ T cell response in the control of M2 expression in the latent infection.
This aim builds on our preliminary data and seeks to gain a clearer understanding of the induction of the M2-specific CD8+ T cell response and it's role in both the early and long-term stages of the latent infection.
Aim 2 : We will test the hypothesis that vaccination with M2 can reduce the load of latently infected cells. We will vaccinate mice with M2 to determine if prior immunity to M2 interferes with either the establishment or maintenance of viral latency. We will also test whether therapeutic vaccination with M2 is possible. Finally we will identify further epitopes in putative latency-associated proteins, with the aim of developing multivalent vaccines incorporating several viral antigens. Data obtained from these studies will contribute to the development of more effective vaccines for gammaherpesviruses. In addition they will increase our knowledge of the host-virus interaction during latent/chronic viral infections in general.
