The long-term objective of this application is to define the role and effect of the soluble T cell product, gamma interferon (IFN- gamma), in the AIDS immune defect which predisposes AIDS patients to fatal opportunistic infections (01). Our studies have demonstrated that IFN-gamma is a key T4+ cell-derived lymphokine generated during the antigen-stimulated cell- mediated immune response which is critical for successful activation of mononclear phagocytes to exert enhanced antimicrobial activity. In addition, we have established that T4+ cells from AIDS patients with 01 fail to secrete antigen-induced IFN-gamma, a state which renders them vulnerable to and unable to control opportunistic pathogens. In parallel, we have also demonstrated, however, that the AIDS peripheral blood monocyte, monocyte-derived macrophage, and tissue (alveolar) macrophage is fully responsive to activation by exogenous IFN-gamma in vitro, and in a recent in vivo trial, showed that AIDS monocytes respond to intravenous recombinant (r) IFN-gamma with clear evidence of activation and enhanced antimicrobial capacity. In an on-going longitudinal prospective study of patients at high risk for AIDS which is being conducted in our well-established Immune Deficiency Research Unit (IDRU), we have also reported that the capacity to secrete antigen-stimulated IFN-gamma is an accurate predictor of the risk of progressing to AIDS and developing an 01. In the renewal of this application, we propose to extend our work using two basic specific aims: (1) continue and expand our IDRU longitudinal study of at-risk patients, and (2) determine in two controlled trials, if a combination regimen of immunotherapy (IFN-gamma) plus antiviral therapy (AZT) is superior to AZT alone in the treatment of AIDS patients with a prior 01. Although AZT (azidothymidine) appears to be the current anti-HIV agent of choice and has strikingly reduced short-term mortality in AIDS, 30% of AZT-treated patients were still subject to new or recurrent 01 and 25-40% experienced severe (grade 3) hematologic toxicity. Thus, we have designed our trials to determine if the addition of rIFN-gamma therapy to AZT can act synergistically to (1) significantly decrease the occurrence of new or recurrent 01 and (2) permit a reduction in AZT dose to diminish toxicity while preserving clinical efficacy. The prediction that there will be 300,000 cases of AIDS by 1991 in the country and the known mortality and morbidity which will accompany 01 in these patients clearly rationalize the critical need for new and necessarily experimental therapeutic approaches.
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