The highly activity combination anti-retroviral therapies (HAART) evaluated against HIV in the last two years have succeeded in reducing the level of plasma virions by multiple logs, below the current levels of detection in many individuals. This state can be maintained for months t years, if not indefinitely, in therapy compliant individuals. Interruption of therapy, however, has resulted in a rebound in plasma virus load, often to pretreatment levels. Nonetheless, the prospect of virus eradication may be plausible if virus suppression can be maintained until infected cells die off. A major impediment to realization of this goal is that whereas CD4+ T cell numbers increase on HAART, T cell numbers and function thus far have failed to recover to normal levels. The studies proposed here are aimed at analyzing reservoirs of residual virus in individuals undergoing successful or failed combination anti-retroviral therapy, treated with low dose-IL-2 therapy, and infused with HIV-specific CD8+ or CD4+ effector cells. To this end, re propose to determine the impact of adoptively transferred HIV-specific effector cells and low dose IL-2 on virus evolution in the blood and lymph nodes. We will address the hypotheses that: 1) Adoptive transfer of HIV-specific CTL will result in the selective elimination of HIV-infected cells expressing the targeted epitope; 2) Diversifying selection on env will increase as a result of therapy-induced immunologic pressure on the virus population, and 3) Virus spread, measured by the accumulation of mutations in proviral DNA, proceeds even when anti-retroviral therapy suppresses plasma viral load below thresholds of clinical assay detection.
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