The use of effective antiretroviral therapy (ART) to treat HIV-infected individuals has dramatically changed the clinical outcome in many patients and has led to a substantial decline in the incidence of AIDS and in AIDS-related mortality. However, it is now clear that prolonged suppression of plasma viremia by ART is not likely to eradicate HIV in most infected individuals. In addition, long-term ART may lead to drug-induced toxicities, difficulties in adhering to drug regimens, and development of drug-resistant virus. Thus, development of alternative immunologic strategies aimed at efficient suppression of HIV in infected individuals is urgently needed. Over the past year, we conducted two research projects, one clinical and one basic, to develop alternative treatment strategies. 1. Identification of CD8+ T cell-associated antiviral factors in HIV-infected long-term non-progressors At least two types of CD8+ T cell-mediated antiviral activities play an important role in controlling HIV infection. The first is a suppressive activity against HIV involving lysis of infected cells in an antigen-specific, HLA-restricted fashion, while the second mechanism inhibits viral replication in the absence of cell killing, in a process that includes CC-chemokines. Whereas these CC-chemokines exert their antiviral activity on the binding and ultimate entry of HIV into CD4+ T cells and macrophages, another class of currently unidentified antiviral factor (s) suppresses post-entry viral replication by down-regulating transcription of HIV in infected cells. We have constructed a cDNA library from CD8+ T cells isolated from three HIV-infected long-term non-progressors and have begun screening for genes involved in inhibiting of HIV replication. Upon identification of such antiviral candidates, we plan to characterize their biological properties in vitro and pursue a clinical strategy aimed at utilizing these CD8+ T cell-derived antiviral factors in vivo. 2. Role of an immunosuppressive drug in HIV replication. Despite the development of successful therapeutic strategies, it has not been possible to eradicate HIV in infected individuals, mainly due to the persistence of various viral reservoirs. In particular, replication-competent virus, HIV-1 proviral DNA including 2 LTR circles, and spliced and unspliced HIV-1 RNA in CD4+ T cells, has been found in the majority of infected individuals in whom plasma viremia is below the limit of detection. This persistent viral reservoir has emerged as the major obstacle in preventing the eradication of HIV. In addition, we find a statistically significant inverse correlation between the frequency of CD4+ T cells carrying HIV-1 proviral DNA and the CD4+/CD8+ T cell ratios in aviremic infected individuals receiving ART (with plasma viremia levels below the limit of detection for prolonged periods of time (>2.5 years). Strategies aimed at minimizing cellular activation may further diminish residual viral replication in patients receiving ART. To address this question, we have begun a pilot clinical trial to examine the safety and tolerability of a mildly immunosuppressive agent, daclizumab, a humanized IgG1 monoclonal antibody that binds specifically to the alpha subunit (p55 alpha, CD25, or Tac subunit) of the human high-affinity IL-2 receptor expressed on the surface of activated lymphocytes. Considering the existence of an intimate relationship between the degree of immune activation and HIV replication, we aim to determine whether daclizumab can normalize immunologic profiles and reduce plasma viremia in study subjects.
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