(PQ 6) New Models of KSHV Oncogenesis and KS Immune Environment

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PROJECT SUMMARY Kaposi's common (KSHV, Castleman's KSHV-associated cells related of numerous been superficially ex will sarcoma (KS) is the most common cancer globally in people living with HIV, and among the most cancers in Sub-Saharan Africa, and is caused by infection by the Kaposi sarcoma herpesvirus also called HHV-8). This virus also causes primary effusion lymphoma (PEL) and multicentric disease (MCD). While PEL is rare, it is an aggressive malignancy with few therapeutic options. diseases are difficult to model because this virus is species-specific, it does not transform in in culture, in vitro infection frequently leads to a mixture of latent and lytic viral gene expression, and animal viruses do not cause the same pathologies. Furthermore, KS lesions are composed of a mixture cells that include latently KSHV-infected spindle cells and a mixed inflammatory infiltrate that includes CD8+ and CD4+ T cells, plasma cells, macrophages, and mast cells. While substantial attention has given to the histogenesis of the spindle cells, the immune infiltrates in KS lesions have only been and incompletely described. The overarching goal is this application is develop preclinical in vitro, vivo and in vivo models of KSHV-associated diseases, including KS, MCD and lymphoma. To model KS, we applyobservations from human lesions, and include the immune elements of this disease. This will be accomplished through the following specific aims: 1) conditional expression of major latency transcript genes in immunocompetent mice; 2) examine of engineer synthetic, in vitro and ex vivo Kaposi sarcoma-like tissue niches for controlled growth of healthy and diseased primary endothelial cells. We will examine the effects of first line therapeutic approaches, targeted therapy and immunotherapy in these models to validate them for preclinical use. major immune subsets in mice; the tumor immune environment in KS lesions in patients and test the role and 3)