THERAPY OF EARLY HIV INFECTIONS IN HEMOPHILIACS

本申请的临床研究部分描述了 在一个连续的I期后期和II期早期研究中， 一组150到200名艾滋病毒血清阳性血友病患者。 这些患者 是400名多次输血的血友病患者的亚群， 在大西洋中部的三个中心接受全面护理 他们的性格和他们的免疫力都很好。 缺乏状态。 拟定的AZT初始治疗的疗效 和阿昔洛韦将在一项同期病例对照研究中进行评价 通过测量T细胞亚群、血清IFN α水平、抗原 捕获分析，蛋白质印迹分析，并通过神经精神 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） 一种体外流式细胞检测系统， 1万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)我们提出了一种体内人组织异种移植系统， 在裸鼠宿主中开发和验证。 研究 免疫反应性的天然抗体，艾滋病毒DNA 构建表达文库。 如果临床状态可以 与受感染个体的抗体反应相关 在治疗过程中，将使用细菌合成的蛋白质， 来生产针对特定HIV抗原决定簇的单克隆抗体。 这些抗体随后将被测试其阻断艾滋病毒的能力 在体外和体内的感染。 中和和 天然存在的抗体的细胞毒性能力，以及它们的 特异性，将使用我们的两个实验模型进行研究 系统. 将在体外和体内评估耐药性， 裸小鼠宿主。 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，他们将导致更好的发展， 抗病毒药物或疫苗的早期干预策略。

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.