IMMUNOLOGIC APPROACHES TO THE THERAPY OF HIV 1 INFECTION

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We evaluated the potential therapeutic aspects of immunologic interventions in HIV infected patients. Studies evaluating the immunologic and antiviral effects of intermittent administration of IL-2 and nucleoside analogues were continued. IL-2 therapy resulted in sustained increases in numbers of CD4+ T cells, decreased expression of activation markers on CD8+ T cells, and preferential increase in naive (CD45RA+) CD4+ T cells. The probability of manifesting an immunologic response was directly associated with baseline CD4+ T cell count. A randomized controlled trial comparing IL-2 plus nucleoside analogs to nucleosides alone was completed and confirmed that the CD4+ T-cell increases associated with IL-2 were real and did not result in sustained increases in viral load. A second randomized controlled multicenter trial was completed comparing 3-, 4-, and 5-day infusions of IL-2 plus nucleosides to nucleosides alone; duration of infusion rather than total dose of IL-2 was shown to be better associated with CD4+ T-cell response. A dose escalation trial evaluating subcutaneously administered IL-2 was expanded to include less advanced patients and demonstrated substantial increases in CD4+ T cell counts. Toxicities of subcutaneous IL-2 were identical to those seen with intravenous IL-2, but less severe. A study evaluating indinavir, an inhibitor of HIV-1 protease, plus intravenous IL-2 showed this to be an active regimen in patients with advanced disease. A study was continued to determine whether timing IL-2 therapy around laboratory correlates of immune activity produces greater responses than IL-2 on a fixed regimen. A study comparing IL-2 alone to IL-2 plus either anti-TNF antibody or thalidomide was continued. A study generating random recombinatorial libraries of human immunoglobulin genes from HIV-infected individuals was continued. An anti-gp120 antibody is being prepared for clinical development. A study evaluating the survival and distribution of adoptively transferred, genetically marked, syngeneic lymphocytes was expanded to evaluate the effects of indinavir and IL-2; persistent detection of gene-marked cells supports peripheral expansion of existing CD4 cells. The first phase of a gene therapy study testing single infusions of syngeneic CD8+ T cells engineered with a chimeric HIV-specific receptor was completed.