Successful early antiviral intervention for HIV-1 infection requires a better understanding of potential biologically relevant and reliable markers of viral burden. The correlation between the detection of a particular virologic marker and evidence of clinical disease progression and/or antiretroviral effects is unclear. The significance of the detection of drug-resistant virus variants from patients is unknown. Our hypothesis is that improved virologic markers and an understanding of their relationship to the natural history of HIV-1 infection will provide a more reliable indication of clinical disease progression and antiretroviral activity. To identify the optimal surveillance of virologic markers and detection of drug-resistant virus variants during antiretroviral trials, the goal of this research effort will be to characterize, compare, and validate newer virologic markers with respect to viral burden, natural history of HIV-1 infection, clinical disease progression, and therapeutic intervention. Specifically, we will: a) quantify virus from both patient plasma and PBMC, b) quantify HIV-1 p24 antigenemia and validate whether dissociation of p24 antigen/antibody immune complexes by acid hydrolysis enhances sensitivity of detection, c) quantitate cell-associated proviral DNA, unintegrated closed circular HIV-1 DNA, and plasma-derived genomic RNA are particularly relevant to clinical antiviral trials because they represent the earliest products of reverse transcription during active replication. The significance of detection of drug-resistant virus variants derived from patients at different time points during infection and treatment will be evaluated by: a) identifying the optimal methodology for detection and the viral reservoirs (PBMC versus plasma) required for surveillance, b) comparing the detection of these variants to quantitative measurements of viral burden, c) determining the mechanism(s), timing, and stability of the emergence of these variants (both phenotypically and genotypically), and d) identifying alternative therapeutic strategies in vitro against drug-resistant virus variants using single agent or combined therapy. These studies will contribute significantly to our understanding of HIV-1 disease pathogenesis and the role of therapeutic interventions with single agent and combined drug regimens in vivo.
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