IMMUNOLOGIC APPROACHES TO THE THERAPY OF HIV-1 INFECTION

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HIV infection is associated with a progressive decline in immune function as evidenced by a progressive decline in the number and the repertoire of the CD4 T lymphocyte pool of the immune system. A major focus of this project is attempting to reverse this process through the use of interleukin-2 to increase the number of CD4 T lymphocytes in the setting of HIV infection. Over the past year, four phase II trials have been completed. Each of these has demonstrated that IL-2 is capable of inducing a substantial increase in CD4+ T cell count without major changes in levels of HIV. In addition, a pooled analysis of the first 157 patients enrolled in randomized, controlled trials of IL-2 have demonstrated long term substantial increases in CD4+ T cell counts, small decreases in levels of HIV and a trend towards fewer AIDS-defining illnesses. The potential of the T cell limb of the immune system to respond to different antigens is defined through the diversity of the T cell repertoire. HIV infection leads not only to a decrease in the total number of CD4 T lymphocytes, but also to a decline in the diversity of the T cell repertoire. In an attempt to expand the ability of the T cell repertoire to recognize and respond to HIV infected cells, the tools of gene therapy were utilized to create chimeric human T cells that express not only their native receptor but also a second receptor with specificity for HIV. The feasibility of this approach for the treatment of patients with HIV infection was established in a clinical trial utilizing syngeneic twin pairs discordant for HIV infection, in which cells from the healthy twin were removed, genetically modified to include a second receptor with specificity for the coat protein of HIV and then infused to the HIV-infected twin. While there did not appear to be any clinical benefit to this approach it did demonstrate that such cells could survive in vivo and that their survival was enhanced when both CD4 and CD8 T cells were transferred as opposed to the transfer of CD8 T cells alone.