HIV 1 TATS PROMOTION OF KAPOSIS SARCOMA

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DESCRIPTION (Applicant's Description): The Principal Investigator plans to develop his intellectual and analytical skills to become a successfully funded independent investigator. A program of didactic and laboratory training in virology and mentoring by senior investigators with expertise in virology and immunology will be used. The long term goal of the PI is to establish himself as a nationally recognized investigator in Human herpesvirus 8 [HHV8]-Kaposi's sarcoma biology. The presence of either human immunodeficiency virus (HIV-1) or HHV8 alone is not associated with a high frequency of Kaposi's sarcoma. Their combined presence, however, leads to frequent development of KS. The applicants' hypothesis is that the high frequency and aggressiveness of KS in HIV-I- infected individuals is due to a direct effect of HIV-I Tat on cells or HHV8. Preliminary studies show Tat signals through binding to cell surface integrin receptors through its RGD integrin binding motif in a manner that mimics the integrin ligands, fibronectin and vitronectin. The investigators will test for activation of focal adhesion kinase (FAK) and involvement of the integrin-FAK- Ras-MAP kinase signaling pathway by blockade at steps along the integrin pathway and the use of dominant negative mutants of ras. Further studies will employ single exon Tat, which is still competent for trans-activation of the HIV-1 promoter, but lacks the RGD motif, versus full length Tat. Initial studies have shown that Tat activates HHV8 replication in vitro. Tat transgenic mice will be used for studies on whether Tat also promotes HHV8 replication in vivo. The elucidation of the effects of Tat on integrin- dependent cell signaling, and HHV8 replication will provide insights into HIV- 1 pathogenesis in KS and could lead to the identification of sites for intervention in the commonest cancer seen in HIV-1 infected people.