Studies of host immunity to HIV demonstrate that the CD8+ HIV-specific CTL responses that are elicited after acute infection directly lyse virus infected cells and interfere with virus dissemination by the secretion of soluble mediators by fail to completely curtail virus replication. The reasons for the failure of CTL to control HIV may include mutational escape, clonal deletion, failure to migrate and eliminate reservoirs of infection, and the absence of CD4+ HIV-specific Th responses. Our lab has developed methods for isolating, genetically modifying and expanding virus-specific T cell clones enabling the evaluation the adoptive transfer as a strategy for augmenting T cell responses and studying mechanisms of virus evasion. The initial study in which HIV Gag-specific CTL clones were modified to express the HIV TK gene as a inducible suicide gene demonstrated that CTL infusions were safe but persistence of the infused CTL was limited due to the induction of host immune responses to the transgene product. To resolve this, unmodified Gag-specific CTL and CTL tagged with the LN retrovirus were administered. Using technology developed in the Virology Core for detection of cells by in situ hybridization, the transferred CTL were shown to migrate to lymph nodes and accumulate in the para-follicular microenvironment adjacent to cells expressing HIV RNA. Moreover, reductions in HIV RNA+ CD4+ T cells were observed in the peripheral blood with each CTL infusion. However, these effects were temporary similar to the limited survival of virus-specific CTL in CD4- Th deficient mice. Thus, the current proposal will investigate the administration of IL-2 to improve T cell persistence and antiviral efficacy, and develop genetic approaches for generating Th independent CD8+ CTL.
The specific aims are: (1). To determine the toxicity, effects on in vivo T cell persistence and migration, and antiviral efficacy of co- administering interleukin 2 (IL-2) with adoptively transferred CD8+ Gag- specific CTL clones to patients with established HIV infection; (2). To determine the safety and antiviral efficacy of adoptively transferred CD8+ CTL specific for multiple HIV antigens with IL-2 in patients with established HIV infection: (3). To determine in patients with primary HIV infection the effect of combined anti-retroviral drug therapy and adoptive immunotherapy with CD8+ HIV-specific CTL and IL-2; and (4). To develop retroviral vectors that provide high level expression of chimeric GM- CSF/IL-2 receptor genes and induce an antigen regulated helper independent phenotype in CD8+ HIV-specific CTL clones.
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