The role of gammaherpesvirus protein kinase in lytic and latent infection

Medical College Of Wisconsin, Milwaukee WI

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Abstract

DESCRIPTION (provided by applicant): Gammaherpesviruses, including human Epstein-Barr virus (EBV) and Kaposi's Sarcoma associated herpesvirus (KSHV) are associated with the development of both solid and lymphoid malignancies, many arising in the immunocompromised host. Unfortunately, the exquisite species specificity of EBV and KSHV limits investigations of primary infection and long term virus-host interactions in vivo. We utilize mouse gammaherpesvirus-68 (MHV68) as an experimental model to study gammaherpesvirus-host interactions and viral lymphomagenesis. MHV68 encodes a viral protein kinase (orf36) that is related to protein kinases encoded by other herpesviruses, including EBV and KSHV. Investigations of the function of MHV68 orf36 in viral infection should offer important insights in the biology of herpesvirus kinases. We have shown that MHV68 orf36 is required for virus replication in vitro and in vivo. Furthermore, our preliminary data indicate that MHV68 kinase contributes to the efficient establishment of MHV68 latency. Orf36 effects on multiple viral life cycles may be based on its ability to regulate MHV68 gene expression. These observations have formed the basis for the following specific aims. Aim 1. Determine orf36 transcript structure and transcriptional regulation in lytic and latent infection. Aim 2. Determine mechanism by which orf36 facilitates MHV68 lytic replication in primary cells. Aim 3. Determine the mechanism by which MHV68 orf36 facilitates establishment of viral latency. PUBLIC HEALTH RELEVANCE: Studies proposed here will provide new insights into the role of viral protein kinase in gammaherpesvirus infection. Further understanding of the regulation of gammaherpesvirus infection by viral factors will eventually lead to the development of new treatment approaches for gammaherpesvirus-associated malignancies.