KSHV infection of human tonsillar B cells

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DESCRIPTION (provided by applicant): Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV8) establishes lifelong infection and is the etiologic agent underlying primary effusion lymphoma, multicentric Castleman's disease, and Kaposi's sarcoma, an endothelial cell-based angiogenic tumor that remains the most prevalent AIDS-associated malignancy worldwide. Although the site for a definitive latent reservoir(s) remains unclear, KSHV can infect B cells in the oral cavity and express a number of viral proteins capable of modulating B cell signaling and survival. Shedding of KSHV in the saliva is frequent in infected individuals and concentrations are often higher than in the peripheral blood. Further, epidemiologic work implicates saliva as a major source for person-to-person viral transmission with infected tonsillar B cells also providing a potential source of spread to distal sites within individuals. In contrast, KSHV-infected B cells in the peripheral circulation are extremely rare in asymptomatic individuals and only slightly less infrequent in patients with early stages of disease. These observations suggest that KSHV may preferentially infect a subset of B cells present in the lymphatic organs of the oral cavity. Our overarching hypothesis is that oral exposure to KSHV leads to selective infection of a specific subset of human tonsillar B cells, effecting phenotypic and functional changes favorable to viral persistence and predictive of pathologic potential. Very little is known about the critical identity and character of KSHV-susceptible B cells in the oral cavity, the nature of the infection, the mechanism underlying differential tropism, or the characteristics of KSHV-induced changes in B cell phenotype and function. We propose to answer these questions. It is our long-term goal to causally link these changes with the expression of specific viral genes and identify those alterations potentially responsible for initiating and sustaining KSHV pathogenesis.)