The AIDS epidemic was recognized in part because of a 20,000-fold increase in the occurrence of unusual malignancies such as Kaposi's Sarcoma (KS) in gay men. Despite success in controlling HIV levels in Western countries with HAART, as well as empiric advances in the treatment of AIDS malignancies, affected patients are rarely cured of their malignancies. Furthermore, because of the spread of HTV, Kaposi's Sarcoma in particular has now become the most prevalent tumor encountered in Southern Africa. The presence of Kaposi's Sarcoma-Associated Herpesvirus (KSHV or HHV8) in KS, Epstein-Barr virus (EBV) in a large subset of AIDS-associated lymphomas, and both viruses in primary effusion lymphomas (PELs) provide an important target for the investigation of the pathogenesis and ultimately the specific treatment of these neoplasms. The overall goal of this Program Project is to investigate how KSHV takes control of vascular endothelial cells and B-lymphocytes, with a mechanistic focus on viral and cellular genes expected to be elevant to tumorigenesis, prevention, and treatment of KS and PEL. Project 1 (Gary Hayward) will focus on control of latency, reactivation and spindle cell conversion in KSHV-infected dermal microvascular endothelial cells in culture, including the role of the tyrosine kinase signaling proteins VIP (Kl) and TMP (K15). Project 2 (Paula Pitha-Rowe) will focus on the mechanism of action of a KSHV latency protein vIRFS (or LANA2) that is homologous to cellular interferon response factors (IRF). Project 3 (John Nicholas) will focus on KSHV homologues of cellular beta-chemokines, which induce VEGF and include autocrine interactions with vGPCR that may play a role in supporting neoplastic proliferation. Project 4 (S. Diane Hayward and Richard Ambinder) will focus on repression of cellular gene expression by the key latent state LANAI protein involved in KSHV genome maintenance and in driving cell proliferation. Current models of KSHV pathogenesis envisage roles for the combined activities of both constitutively expressed KSHV latency gene products plus the occasional expression of abortive lytic cycle gene products These four Projects all address several different and overlapping aspects of the role of viral and cellular genes in maintenance of latency, the role of the early lytic cycle chemokines and the processes that controls switching between the two states. Collecting them together as a PPG centered around extensive utilization of the expertise and reagents generated by the skilled personnel in the two Laboratory Cores involving KSHV genetics and DNA and Viral vector driven gene expression and analysis, provides synergy, reagent sharing and overall beneficial interactions that would not otherwise occur. ?
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