Failure to completely suppress viral replication with combination antiretroviral therapy results in the selection of drug-resistant HIV-1. Although high-level drug-resistance eventually emerges in most patients who remain on stable therapy, plasma HIV RNA levels generally remain below the pre-therapy viral load """"""""set-point"""""""". The virologic and immunologic determinants of this lower steady-state level of viremia have not been defined. Preliminary data from our group indicate that: (1) drug-resistant variants have reduced replicative capacity in vitro and pathogenic potential in vivo, (2) the presence of drug-resistant viremia is associated with reduced T cell activation and T cell turnover compared to the presence of wild-type viremia, and (3) HIV-specific CD4+ T cells are often observed in patients who durably maintain low to moderate levels of drug-resistant viremia, but are absent in patients with higher levels of viremia. Based on these preliminary observations, we postulate that the emergence of a poorly fit, drug-resistant variant results in the generation and preservation of an effective HIV-specific CD4+ T cell response, and that this response contributes to the establishment of a lower steady-state level of viremia. ? ? We will test this hypothesis in the setting of a rigorously defined and managed longitudinal cohort of 50 patients who are remaining on a stable antiretroviral regimen despite low to moderate levels of drug-resistant viremia (plasma HIV RNA level of 200 to 10,000 copies/mL). Each patient will be followed carefully for two years, or until therapy is modified or discontinued. Based on preliminary data from our group, we anticipate that 50 percent of the cohort will maintain stable levels of viremia and 50 percent will experience virologic progression (increase to >10,000 copies RNA/mL). We will measure the breadth and magnitude of the HIV specific CD4+ and CD8+ T-cell responses as a function of viral load, viral replicative capacity, drug resistance phenotype, T cell turnover, and thymic function. These studies will provide insights into the management of drug-resistant viremia (i.e., when to switch therapy and when to stop therapy), and may lead to new therapeutic strategies to enhance immunologic control of drug-resistant viremia. ? ? Finally, since we will estimate the relative in vivo thresholds for HIV-mediated immunogenicity and pathogenicity, these studies may also have implications for vaccine development.
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