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 interventions in patients with HIV infection. Ongoing studies evaluating the immunologic and antiviral effects of intermittent administration of interleukin (IL-2) and nucleoside analogues were continued. IL-2 therapy resulted in sustained increases in numbers of CD4 cells and decreased expression of activation markers on CD8 cells; the probability of manifesting these immunologic responses was shown to be directly associated with baseline CD4 count. Transient and consistent increases in viral load at the end of each infusion were revealed. Attempts to block cytokine induction by IL-2 with pentoxifylline in vivo failed to produce a clinical benefit. A randomized controlled trial comparing IL-2 plus nucleoside analogues to nucleosides alone was continued; a second randomized controlled multicenter trial was also continued comparing 3-, 4-, and 5-day infusions of IL-2 plus nucleosides to nucleosides alone. A dose escalation trial evaluating the safety and immunologic activity of subcutaneously administered IL-2 was expanded to include patients with less advanced disease. A study evaluating the immunologic and antiviral activity of intravenous IL-2 in combination with an inhibitor of HIV-1 protease was initiated. A study was begun to determine whether timing IL-2 therapy around laboratory correlates of immune activity produces greater and more durable responses than administering IL-2 on a fixed regimen. Studies evaluating the safety and activity of an anti-TNF antibody and a soluble TNF receptor were completed. A study comparing IL-2 administration alone to IL-2 combined with either anti-TNF antibody or thalidomide was begun. An anti-gp120 antibody derived from a recombinatorial library was identified and is being prepared for clinical development. A study evaluating the survival and distribution of adoptively transferred, genetically marked, syngeneic lymphocytes was undertaken; cells containing the marker gene continue to be detected in the peripheral blood of all 6 recipients from 28 to 48 weeks post- transfer. A gene therapy study was begun testing the safety and activity of repeated infusions of syngeneic CD8 cells engineered with a chimeric CD4 -zeta TCR receptor.