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 human immunodeficiency virus (HIV) infection. A study evaluating the immunologic and antiviral effects of repeated administration of interleukin-2 (IL-2) and nucleoside analogs was continued. IL-2 therapy resulted in sustained increases in numbers of CD4 cells and decreased expression of CD8 activation markers; the probability of manifesting these immunologic responses was shown to be directly associated with baseline CD4 count. Using a new plasma HIV RNA detection assay, transient and consistent increases in viral load at the end of each infusion were revealed. In follow-up of these findings, an in vitro model of IL-2-induction of viral replication in peripheral blood mononuclear cells was developed and investigations into the mechanisms of IL-2 induction of HIV were begun. A study of IL-2 in patients with Kaposi's sarcoma was initiated, in order to attempt to correlate immunologic and clinical responses. A randomized controlled trial comparing IL-2 plus nucleoside analogs to nucleosides alone was continued, and a randomized controlled multicenter trial comparing 3, 4, and 5 day infusions of IL-2 plus nucleosides to nucleosides alone was initiated. A dose escalation trial evaluating the safety and immunologic activity of subcutaneously administered IL-2 was initiated and an MTD was defined. Toxicities of IL-2 administered subcutaneously were identical to those seen with intravenous IL-2, but generally less severe. Adoptive immunotherapy using transfers of activated and expanded syngeneic polyclonal lymphocytes was completed. Marked but transient increases in CD4 counts were seen in the post-transfer period, often in association with increased viral replication in plasma. CD4 responses were directly related to baseline CD4 count. Studies with gene-marked cells were initiated as a prelude to attempts at gene therapy. A study generating random recombinatorial libraries of human immunoglobulin genes from HIV- infected individuals was continued. An anti-gp120 antibody was identified for clinical development. Studies evaluating the safety and activity of an anti-tumor necrosis factor (TNF-alpha) antibody and a soluble TNF-alpha receptor were initiated. Inhibition of circulating TNF-alpha was not associated with short-term toxicity; no appreciable immunologic or virologic benefit was seen.