IMMUNOLOGIC APPROACHES TO THE THERAPY OF HIV 1 INFECTION

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An intensive effort was directed toward studying the potential therapeutic aspects of immunologic approaches to HIV infection. Studies evaluating the effects of interleukin (IL)-2 therapy continue to reveal sustained (i.e., up to 4 years in duration) increases in CD4+ T cells and decreased expression of activation markers on CD8+ T cells. The probability of manifesting an immunologic response was directly associated with baseline CD4+ T-cell count. Continued follow up of patients on a randomized controlled trial comparing IL-2 plus nucleoside analogs to nucleosides alone confirmed the durability of the CD4+ T-cell response and the absence of chronic HIV activation associated with cytokine treatment. Despite transient and consistent increases in viral load at the end of each IL-2 infusion, sustained increases in viral load were not present after 2 years of IL-2 treatment. A dose escalation trial evaluating the safety and immunologic activity of subcutaneously administered IL-2 comparing different doses and dose intervals was completed, and a phase II randomized controlled study was begun. Substantial increases in CD4+ T-cell counts were observed, and the magnitude of CD4+ T-cell rise correlated directly with baseline CD4+ T-cell counts. Toxicities of subcutaneous IL-2 were similar to those of intravenous IL-2, but less severe. A multicenter, randomized controlled study of subcutaneous IL-2 in more advanced subjects was initiated. A study evaluating the protease inhibitor indinavir plus intravenous IL-2 was continued and revealed persistent immunologic responses in patients previously unresponsive to IL-2 plus nucleosides. A study was continued in order to determine whether timing of IL-2 therapy around in vitro correlates of immune activity results in greater and more durable responses than administering IL-2 on a fixed regimen. A study generating random recombinatorial libraries of human immunoglobulin genes from HIV-infected individuals was continued. An anti-gp120 antibody that was identified is now being readied for clinical study. Evaluation of a candidate DNA vaccine in HIV uninfected individuals was initiated. Utilizing plasmid DNA containing the HIV env and rev genes as the immunizing agent, the study will determine the safety and immunogenicity of this agent, including the ability of immunization with this agent to generate cytotoxic T cell responses. Study of bacteriophage phi X174 immunization in both healthy and HIV-infected individuals was begun to assess whether bacteriophage clearance and immune responses will serve as useful correlates of immune competence. A study evaluating the survival and distribution of adoptively transferred, syngeneic, genetically modified lymphocytes, was expanded to evaluate the effect of repeated infusions and showed that immune clearance may account for shortened cell survival on re-exposure. A randomized controlled study testing multiple infusions of syngeneic CD8+ T cells genetically engineered with a chimeric CD4-zeta T cell receptor (TCR) was continued, demonstrating the safety and feasibility of this approach and the long-term persistence of transferred cells in the circulation and lymphoid tissues. A pilot study testing infusions of syngeneic CD4+ T cells genetically engineered with transdominant Rev and/or anti-sense TAR genes was initiated.