We propose to form an HIV-I Acute Infection and Early Disease Research Unit that will use innovative approaches to recruit and retain at least 25 persons with acute HIV and 40 with early HIV infection each year for 4 years. These subjects will constitute a cohort for longitudinal assessment of Clinical, immunologic and virologic endpoints of HIV infection. Consenting cohort members will be randomized to receive combination antiviral treatment (zidovudine, lamavudine and nelfinavir) with or without IL-2. We will assess whether IL-2 enhances the ability of combination therapy to improve immunologic measures and maintain suppression of virus below detectable levels. Those declining randomization will be followed and assessed as observational controls. The specifiC objectives in the investigation of early HIV pathogenesis will be to study treated and untreated persons to: Evaluate whether viral load in blood, PBMCs, tonsil, and other sites influences pathogenesis and assess whether kinetics of viremia can be used to estimate time from infection; Determine the pattern of immunologic activation as measured by cell surface markers, levels of apoptosis, soluble and cell-associated cytokines, and reactivation of herpes viruses; Examine whether the extent of CD8+ cell antiviral activity as measured by non-cytotoxic and cytotoxic responses affects the kinetics of viral replication and viral load; Determine whether a broad cellular immune response to HIV infection, measured by T cell repertoire, correlates with the patterns of cellular immune antiviral responses. These virologic and immunologic studies will provide insights into the pathogenesis of HIV infection and contribute to the development new approaches for its treatment.
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