We propose a multidisciplinary research program which will integrate substantial institutional expertise in infectious diseases, retrovirology and herpes viruses, antiviral agents, epidemiology, biostatistics, and numerous clinical resources, focusing on the evaluation of novel antiretroviral therapies in HIV-infected persons. In Project 1 a group of clinical investigators with diverse backgrounds will collectively study new antiviral compounds or novel antiviral combinations. Studies will determine the safety and tolerance of such therapies in small groups of patients who will be intensively studied for in vivo evidence of antiviral effects on HIV and other virus infections (EBV, CMV, hepatitis B) that may be cofactors in AIDS pathogenesis. Patients will include hemophiliacs from a large, well studied cohort, and HIV-infected individuals from other risk groups. The pharmacokinetics of antiviral compounds will be closely monitored, as will the impact of liver disease, common in hemophiliacs, on metabolism of antiviral compounds such as AZT. Projects 2-5 comprise a BASIC RESEARCH COMPONENT and explore aspects of HIV biology relevant to antiviral therapy. In Project 2, antiviral synergy and resistance and the mechanisms underlying these phenomena will be studied in different HIV isolates. Project 3 will examine biologic interactions between EBV, CMV and HIV in vitro, and Project 4 will study the role of CMV in progression of immunodeficiency among HIV-infected hemophiliacs. These related projects will provide important information concerning the role of putative cofactor viruses in AIDS pathogenesis, and their potential importance as targets for antiviral therapy. Project 5 will study the molecular evolution of HIV isolates recovered from sexual partners. This study will provide information concerning the sexual transmission of HIV and forces acting on evolution of the env gene. Project 6 (OUTREACH COMPONENT) will evaluate contact tracing among HIV-infected persons identified in a low prevalence state, important because effective contact tracing will be essential for broad application of antiviral therapy. All of the above projects will be supported by a Clinical Retrovirology Laboratory core with sophisticated virologic and serologic capabilities.
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