The tale of two receptors: Determining the role of lipoprotein receptors, SR-BI and LDL-R, in gammaherpesvirus infection

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Proposal Summary Gammaherpesviruses are ubiquitous pathogens that establish life-long infections in most adults and are associated with several cancers, including B cell lymphomas. While the risk factors supporting viral tumorigenesis remain poorly understood, elevated viral latency and reactivation often precede oncogenesis. Recent studies have demonstrated that endogenous lipid synthesis supports gammaherpesvirus replication and latency. However, the role of exogenous cholesterol exchange during infection remains unknown. Therefore, this proposal aims to determine how exogenous cholesterol impacts viral latency and reactivation. Due to the high prevalence and species specificity of human gammaherpesviruses, the mouse pathogen murine herpesvirus 68 (MHV68) is widely utilized as the small animal model of gammaherpesvirus pathogenesis. A strength of this model is the ability to genetically modify the host to examine the cellular and molecular mechanism by which infection is controlled. Using this model, we have recently discovered an exciting role for lipoprotein receptors during gammaherpesvirus infection. Specifically, we have found that SR- BI, the high-density lipoprotein (HDL) receptor, supports MHV68 reactivation. While LDL-R, the low-density lipoprotein (LDL) receptor, suppresses MHV68 latency and reactivation. Therefore, we hypothesize that SR-BI exerts pro-viral effects, while LDL-R exerts anti-viral effects in infection. The in vitro and in vivio experiments proposed here will provide an extensive, yet focused analysis of the cellular and molecular importance of SR-BI and LDL-R expression in the spleen of the host during gammaherpesvirus infection. Importantly, successful completion of these studies will provide insight into the control of gammaherpesvirus infections, which would offer potential therapeutic targets for infected individuals particularly susceptible to the associated oncogenic effects of gammaherpesviruses.