Studies of Gammaherpesvirus Infection and Host Response
Prepared under the direction of: Linda F. van Dyk, Ph.D.
Gammaherpesviruses cause a lifelong infection and are associated with lymphoproliferative disease and chronic inflammatory disease. Gammaherpesviruses are extremely host species specific, making it difficult to study the human viruses in vivo. Mouse gammaherpesvirus 68 (γHV68) provides an excellent model to study this family of viruses, due to their common biology, genome organization, and associated pathoglogies. I investigated the host response to gammaherpesvirus infection, and created tools to study γHV68 infection in vitro and in vivo.
I used BAC mutagenesis to construct recombinant viruses from which all future recombinants of the v-cyclin locus will be made. The marked viruses were constructed and found to be potentially suboptimal, but will serve as a framework for the construction of future marked viruses to track viral infection and gene expression.
I investigated the host immune response to γHV68 infection. I found evidence for continued antigen presentation from infected cells during latency, likely from sporadic reactivation events, as seen by the increased presence of T cells and T cell-produced cytokines, and the upregulation of activated macrophages in the peritoneal cavity. The differences found in the magnitude of the response in both spleen and peritoneal cavity, sites of viral latency, in IFNγR-/- mice compared to BL/6 mice support the hypothesis that the immune response in mice that develop chronic disease after γHV68 infection is different than in mice that remain healthy and control infection, and that the v-cyclin is a factor that links reactivation and chronic disease, via the host immune response.
I also investigated the role of a tumor suppressor protein p19Arf, in γHV68 infection, which appeared to play no significant role in replication of the virus in vitro or in reactivation from latency, but was induced during γHV68 infection in vitro and in vivo. These studies also revealed a population of immature peritoneal macrophages, elicited by viral infection and non-infectious inflammatory stimuli, in which p19Arf was induced, and appears to play an important role in their maturation and terminal differentiation. These studies are valuable in elucidating the host response to γHV68 infection, and may give insights into the immune control of the human gammaherpesvirus