Immune surveillance in murine gammaherpesvirus infection

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DESCRIPTION (provided by applicant): Human gammaherpesviruses are associated with significant disease, and these are particularly prevalent in AIDS patients. In these patients virus-transformed cells can grow uncontrolled into tumors such as non-Hodgkin's lymphoma, primary CNS lymphoma and Kaposi's sarcoma. Such diseases occur as a consequence of latent infection by the virus, and it is therefore critical to understand the immunological control during latency. We propose to investigate several aspects of the immune surveillance mechanism using a mouse gammaherpesvirus model. Specifically we will test the following hypotheses: (i) That lytic and latent antigen-specific CD8 T cells make different contributions to the control of gammaherpesvirus latency. We will reconstitute latently-infected immunodeficient mice with T cell lines specific for either latent or lytic virus antigens and determine which ones are able to maintain control of the virus. We will also determine the mechanism by which these cells to control the virus. (ii) That different effector/memory T cell population play different roles in the control of latent infection. Effector/memory T cells have been found to be heterogeneous with respect to surface markers, effector function and migration. One marker that partly defines these populations in is CD62L. We will examine the roles of CD62Lhi and CD62LIo cells during latent infection using an adoptive transfer system. (iii) That virus-specific CD8 T cells involved in immune surveillance are regulated in a different manner to conventional memory CD8 T cells. Our preliminary data indicates that, unlike conventional memory T cells, MHV-68-specific CD8 T cells do not require IL-15 for proliferative renewal. We will therefore determine what regulates these CD8 T cells during the latent infection, with specific focus on the cytokines involved and the role of regulatory CD4+CD25+ T cells. The work described in this proposal will provide essential information to the poorly understood process of immune surveillance in gammaherpesvirus infections. In addition some of this information may also lead to a greater understanding of immune surveillance to other chronic virus infections or tumor cells. This work will lead to better therapies to combat tumor-associated virus infections.