Pathophysiology of lytic reactivation and spread of KSHV

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DESCRIPTION (Provided by the applicant): Kaposi's sarcoma (KS) is an endothelial neoplasm that is tightly linked to infection by KS-associated herpesvirus, KSHV. KSHV is a lymphotropic virus whose primary reservoir is the B cell. Spread to its endothelial targets in KS pathogenesis therefore requires reactivation from latently infected B cells and lytic replication. In addition, growing evidence suggests that the KSHV lytic cycle may be the source of paracrine factors that influence KS angiogenesis and inflammation, two of the histologic signatures of KS. In this application, experiments are proposed to examine the molecular basis of lytic KSHV reactivation and spread, by examining (i) the biochemical mechanisms by which the viral RTA protein, a key regulator of the latent-lytic switch, regulates viral gene expression and is itself regulated; (ii) the consequences of lytic viral reactivation on host cell survival and gene expression; and(iii) identifying host cell surface molecules involved in KSHV entry and spread.