THERAPY OF EARLY HIV INFECTIONS IN HEMOPHILIACS

本应用程序的临床研究组件描述了一种 第一阶段和第二阶段早期序贯研究的方法 由150至200名HIV血清阳性血友病患者组成的小组。这些病人 是400名多次输血血友病患者的亚群 在大西洋中部的三个中心接受全面护理 地区和他们的免疫特点很好 缺乏状态。建议的AZT初始治疗的疗效 阿昔洛韦将在一项同时进行的病例对照研究中进行评估 通过检测T细胞亚群、血清干扰素水平、抗原 捕获分析、Western Blot分析和神经精神病学 评估和临床结果。抑制病毒复制 将通过两个独特的模型系统进行实验评估：(1) 一种体外流式细胞仪检测系统 万个外周血淋巴细胞中有1个HIV感染细胞 (目前正在与NHLBI签订合同进行开发)，以及 (2)我们提出的体内人体组织异种移植系统 在裸鼠宿主上进行开发和验证。为了研究 自然产生的抗体，一种艾滋病毒DNA的免疫反应性 将构建表达文库。如果临床状态可以 与感染者的抗体反应相关 在治疗过程中，细菌合成的蛋白质将被使用 生产针对特定HIV表位的单抗。 然后，这些抗体将被测试它们阻止艾滋病毒的能力。 在体外和体内的感染。中和和 自然产生的抗体的细胞毒性能力及其 具体情况，将使用我们的两个实验模型进行研究 系统。耐药性将在体外和体内进行评估 裸鼠主持人。希望这些临床和基础 研究将有助于更好地了解 HIV的分子遗传学、免疫生物学和自然史 感染，它们将导致更好的发展 使用抗病毒药物或疫苗进行早期干预的策略。

The clinical research component of this application describes an approach for sequential late Phase I and early Phase II studies in a group of 150 to 200 HIV seropositive hemophiliacs. These patients are a subpopulation of 400 multitransfused hemophiliacs who receive comprehensive care at three centers in the mid-Atlantic region and who are well characterized concerning their immune deficiency status. Efficacy of proposed initial therapy with AZT and Acyclovir will be evaluated in a concurrent case control study by measurement of T-cell subsets, serum IFN alpha levels, antigen capture assay, Western Blot analysis, and by neuropsychiatric assessment and clinical outcomes. Inhibition of viral replication will be assessed experimentally by tow unique model systems: (1) an in vitro flow cytometric detection system to identify as few as one HIV infected cell among 10,000 peripheral blood lymphocytes (currently under development by contract with the NHLBI), and (2) an in vivo human tissue xenograft system which we propose to develop and validate in a nude mouse host. To study the immunoreactivity of naturally occurring antibodies, an HIV DNA expression library will be constructed. If clinical status can be correlated with antibody response of infected individuals undergoing therapy, bacterially synthesized proteins will be used to produce monoclonal antibodies against specific HIV epitopes. These antibodies will then be tested for their ability to block HIV infections both in vitro and in vivo. The neutralizing and cytotoxic abilities of naturally occurring antibodies, and their specificities, will be studied using our two experimental model systems. Drug resistance will be assessed in vitro and in vivo in the nude mouse host. It is hoped that these clinical and basic research studies will contribute to a better understanding of the molecular genetics, immonobiology and natural history of HIV infections, and that they will lead to the development of better strategies for early intervention with antiviral drugs or vaccines.