NEW TREATMENTS FOR AIDS AND AIDS-RELATED INFECTIONS

这项提议的目标是建立一个艾滋病诊所 研究小组(CSG)统一并最大限度地发挥 未来在纽约进行的艾滋病临床研究 医院-康奈尔医疗中心。这一点的重点是 申请新的和改进的艾滋病治疗方法和 艾滋病相关机会性感染(OI)和我们的主要关注点 将决定是否使用伽马进行免疫重建 干扰素(干扰素-γ)与抗艾滋病毒具有协同作用 预防(A)的化疗(AZT、利巴韦林) 艾滋病患者的新OI或(B)进展为AIDS和OI 免疫缺陷的ARC患者。我们的研究表明 干扰素是一种关键的T4+细胞来源的淋巴因子，对 成功激活单核巨噬细胞发挥作用 增强了抗菌活性。此外，我们还建立了 艾滋病合并OI患者的T4+细胞不能分泌抗原- 诱导的干扰素-γ，这种状态使他们容易患上和 无法控制机会性病原体。与此同时，我们有 然而，也证明了艾滋病患者的外周血液 单核细胞、单核细胞来源的巨噬细胞和组织(肺泡) 巨噬细胞对外源性干扰素-1的激活完全有反应 伽玛在体外和最近的体内试验中表明，艾滋病 单核细胞对静脉注射重组(Tau)干扰素-γ的反应 有明显的激活证据和增强的抗菌剂 容量。在一项对高危患者进行的前瞻性研究中 对于艾滋病进行的免疫缺陷是我们公认的 研究股(IDRU)，我们还报告说， 分泌型抗原刺激的干扰素-γ是一个准确的预测因子 对进展为艾滋病和发展成OI的风险。 我们现在建议通过几个具体目标来扩展我们的工作： (1)继续和扩大我们的IDRU风险纵向研究 病人。(2)在两次试验中确定是否合并 免疫疗法(干扰素-伽马)加抗病毒疗法(AZT)是 AZT治疗艾滋病合并多发性硬化疗效优于单用AZT 先前OI在(A)减少新OI发生和(B) 允许减少AZT的剂量以减少毒性，同时 保存临床疗效。(3)检测重组人干扰素-γ+ 利巴韦林在预防血吸虫病方面优于单用利巴韦林。 ARC进展为艾滋病。和(4)测定其疗效。 OI的新疗法：(A)螺旋霉素治疗隐孢子虫病，(B) Fansidar预防复发性弓形虫病，以及(C) 氟康唑在隐球菌病中的应用该病的发病率和死亡率 与艾滋病相关的OI清楚地表明需要新的实验 接近了。

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.