ln this proposal we outline plans to investigate the immunopathogenesis of acute and early HIV-1 infection using sequential therapeutic interventions with antiretroviral chemotherapeutic agents and therapeutic vaccination in an attempt to manipulate the virus-host interaction to the benefit of the host. Our group consists of clinical sites in the United States (Denver arid Atlanta), Brazil and Zimbabwe and an interactive group of laboratory investigators based at the Universities of Colorado and Minnesota and at Rush Medical School. We plan to enroll 30 acutely infected and 90 patients with early HIV infection into an integrated program of randomized clinical trials that will feature early initiation of potent chemotherapeutic combination antiretroviral regimens designed to maximize tolerability, convenience and adherence and to minimize toxicity. Study participants achieving undetectable levels of plasma HIV-1 RNA will be offered entry into controlled clinical trials of therapeutic vaccination using several different vaccine approaches designed to maximize virus specific cellular immunity .The impact of therapeutic interventions will be evaluated by the extent to which viral replication is controlled by host effector mechanisms following therapeutic interruption. The immunopathogenesis of acute HIV-1 infection will be intensively evaluated in the context of these sequential therapeutic interventions by a coordinated series of laboratory studies that will evaluate the role of cellular and humoral HIV-1 specific effector mechanisms and soluble mediators in controlling HIV-1 expression in plasma and lymphoid tissues and in facilitating immune reconstitution following establishment of control of viral replication. Studies of the role of viral fitness and diversity will also be undertaken. The goals of these investigations are to better understand virus-host interactions in the context of acute HIV-1 infection, to improve therapeutic approaches to HIV-1 infection and to provide insights that will prove useful in AIDS vaccine development.
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