NEW TREATMENTS FOR AIDS AND AIDS-RELATED INFECTIONS

这项建议的目的是建立一个艾滋病诊所， 研究小组（CSG），以统一和最大限度地提高 在纽约进行的未来艾滋病临床研究 医院-康奈尔医疗中心。 在这方面的重点是 申请是关于艾滋病的新的和改进的治疗方法， 艾滋病相关的机会性感染（OI），以及我们的主要重点 是确定伽马射线免疫重建 干扰素（IFN-γ）可与抗HIV协同作用 化疗（叠氮胸苷（AZT），利巴韦林），以防止（a） AIDS患者中的新OI或（B）AIDS患者中的进展为AIDS和OI 免疫缺陷ARC患者。 我们的研究表明 IFN-γ是一种关键的T4+细胞衍生的淋巴因子， 成功激活单核吞噬细胞， 增强的抗菌活性。 此外，我们还建立了 来自患有OI的艾滋病患者的T4+细胞不能分泌抗原， 诱导的IFN-γ，一种使他们容易受到 无法控制机会性病原体。 同时，我们有 然而，也证明了艾滋病外周血 单核细胞、单核细胞衍生的巨噬细胞和组织（肺泡） 巨噬细胞对外源性IFN-γ的激活有充分的反应。 体外和最近的体内试验表明，艾滋病 单核细胞对静脉内重组（Tau）IFN-γ的应答 具有明显的活化证据和增强的抗微生物 容量 在一项正在进行的高风险患者前瞻性研究中， 艾滋病在我们公认的免疫缺陷 研究股（IDRU），我们还报告说， 分泌抗原刺激IFN-γ是准确预测因子 发展成艾滋病和OI的风险。 我们现在建议利用几个具体目标来扩展我们的工作： (1)继续并扩大我们的IDRU风险纵向研究 患者 (2)在两次试验中确定，如果组合 免疫治疗（IFN-γ）加抗病毒治疗（AZT）， 上级优于AZT单独治疗艾滋病患者， （a）减少新OI的发生，以及（B） 允许减少AZT剂量以减少毒性， 保持临床疗效。 (3)确定rIFN-γ + 利巴韦林上级单独的利巴韦林， ARC发展为艾滋病。 （4）确定 OI的新治疗方法：（a）螺旋霉素治疗隐孢子虫病，（B） 凡西达预防再活化弓形虫病，和（c） 氟康唑治疗隐球菌病 的发病率和死亡率 艾滋病相关OI明确理据，需要新的实验 接近。

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.