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 analogues was continued. IL-2 therapy resulted in sustained increases in numbers of CD4 cells, decreased expression of activation markers, and restoration of blastogenesis responses. A new plasma HIV RNA detection assay was employed; this revealed transient and consistent increases in viral load at the end of each infusion. In follow up of these findings, a randomized controlled trial comparing IL-2 plus nucleoside analogues to nucleosides alone was initiated. Adoptive immunotherapy using transfers of activated and expanded syngeneic polyclonal lymphocytes was begun. Marked but transient increases in CD4 counts have been seen in the post transfer period, sometimes in association with increased viral replication in plasma. A phase I trial administering a nef-specific CTL clone to its donor was continued; no clinical benefit was demonstrated, and this patient~s immune function has steadily declined. A protocol evaluating the safety and pharmacokinetics of N-acetylcysteine (NAC) was modified to examine long term safety and antiviral activity. Systemic bioavailability with oral NAC was too low to make oral dosing practical; intravenous NAC was intolerable at doses that achieve concentrations shown to be inhibitory in vitro. No antiviral effects were seen with up to one year of oral therapy. A study generating random recombinatorial libraries of human immunoglobulin genes from HIV infected individuals was continued. Protocols using recombinant gp160 and p24 immunization of seropositive patients were concluded; both proteins were found to be safe, but no immunologic or antiviral benefit was seen.