Our preliminary studies over the last 14 months have shown that interruption of Highly Active Anti-Retroviral Therapy (HAART) may boost patients' immune responses to HIV-1. Here, we propose a formal proof-of-concept study, to investigate the safety, immunologic and virologic outcomes of HIV-1 therapy interruption. The long-range goal of this proposal is to determine if intermittent Highly Active Anti-Retroviral Therapy (HAART) can be a safe and effective strategy to enhance anti-HIV-1 immunity. We will test the hypothesis that repeated structured treatment interruptions in chronically suppressed patients will increase HIV-1 immunity and result in control of viral replication in the absence of therapy for a minimum of 4 weeks more than that measured in interrupted controls who have remained continually suppressed while on antiretroviral therapy. We will test this hypothesis by determining time to viral rebound after withdrawal of antiretroviral therapy in a well-characterized subject population from a single center, randomized, non-blinded study. We will monitor adherence to therapy and determine changes in the immune status of patients following HAART interruption, such as CD4 T-cell percentage, CD4 and CD8 T-cell medicated anti-HIV-1 responses, cell surface T-cell antigen expression and thymic function. We will also monitor viral outcomes by determining genotypic changes in the HIV-1 protease and reverse transcriptase regions, and effect on the latent reservoirs. Completion of this study will determine if the concept of intermittent HAART therapy should be investigated further as a novel approach to increase anti-HIV-1 immunity. This hypothesis-driven proposal represents a collaborative multidisciplinary research effort by the Wistar Institute, the Aaron Diamond AIDS Research Center, the Jonathan Lax Immune Disorder Clinic, University of Pennsylvania's Center for Clinical Epidemiology and Biostatistics and the Gladstone Institute of Virology and Immunology.
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