The objective of this proposal is to establish an AIDS Clinical Study Group (CSG) to unify and maximize the effectiveness of the future AIDS clinical research carried out at The New York Hospital-Cornell Medical Center. The emphasis in this application is on new and improved treatments for AIDS and AIDS-related opportunistic infections (OI), and our principal focus will be to determine if immune reconstitution with gamma interferon (IFN-gamma) can act synergistically with anti-HIV chemotherapy (azidiothymidine (AZT), ribavirin) to prevent (a) new OI in AIDS patients or (b) progression to AIDS and OI in immunodeficient ARC patients. Our studies have demonstrated that IFN-gamma is a key T4+ cell-derived lymphokine critical for successful activation of mononuclear phagocytes to exert enhanced antimicrobial activity. In addition, we have established that T4+ cells from AIDS patients with OI 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) macrophages 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 (Tau) IFN-gamma with clear evidence of activation and enhanced antimicrobial capacity. In an on-going prospective study of patients at high risk for AIDS 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 OI. We now propose to extend our work using several specific aims: (1) Continue and expand our IDRU longitudinal study of at-risk patients. (2) Determine in two trials, if combination immunotherapy (IFN-gamma) plus antiviral therapy (AZT) is superior to AZT alone in the treatment of AIDS patients with a prior OI in (a) decreasing the occurrence of new OI and (b) permitting a reduction in AZT dose to diminish toxicity while preserving clinical efficacy. (3) Determine if rIFN-gamma plus ribavirin is superior to ribavirin alone in preventing the progression of ARC to AIDS. And (4) Determine the efficacy of new treatments for OI: (a) spiramycin in cryptosporidiosis, (b) Fansidar prophylaxis in reactivated toxoplasmosis, and (c) fluconazole in cryptococcosis. The morbidity and mortality of AIDS-related OI clearly rationale the need for new experimental approaches.
Showing the most recent 10 out of 16 publications
