THERAPY OF EARLY HIV INFECTIONS IN HEMOPHILIACS

血友病患者早期 HIV 感染的治疗

• 批准号: 2063189
• 负责人: M E EYSTER
• 金额: $ 73.67万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-09-30 至 1995-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2063189
• 关键词: AIDS; AIDS therapy; HIV infections; acyclovir; antiAIDS agent; antibody formation; antibody neutralization test; antiviral agents; antiviral antibody; blood cell count; clinical chemistry; clinical trials; combination chemotherapy; communicable disease diagnosis; cooperative study; disease /disorder proneness /risk; dosage; drug adverse effect; enzyme linked immunosorbent assay; flow cytometry; gel electrophoresis; helper T lymphocyte; hemophilia As; human immunodeficiency virus 1; human subject; human therapy evaluation; interferons; microorganism disease chemotherapy; neuropsychological tests; virus antigen; virus infection mechanism; virus replication; zidovudine

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.

该应用程序的临床研究部分描述了 顺序后期 I 期和早期 II 期研究的方法 由 150 至 200 名 HIV 血清阳性血友病患者组成的小组。 这些患者 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 地区和谁的免疫特征良好 缺乏状态。 拟议的 AZT 初始治疗的疗效 和阿昔洛韦将在并行病例对照研究中进行评估 通过测量 T 细胞亚群、血清 IFN α 水平、抗原 捕获测定、蛋白质印迹分析和神经精神学 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) 体外流式细胞术检测系统，可识别少至 10,000 个外周血淋巴细胞中的一个 HIV 感染细胞 （目前正在根据与 NHLBI 的合同进行开发），以及 (2) 我们建议的体内人体组织异种移植系统 在裸鼠宿主中开发和验证。 为了研究 天然存在的抗体（HIV DNA）的免疫反应性 将构建表达库。 如果临床状态可以 与感染个体的抗体反应相关 接受治疗时，将使用细菌合成的蛋白质 生产针对特定 HIV 表位的单克隆抗体。 然后将测试这些抗体阻断 HIV 的能力 体外和体内感染。 中和和 天然抗体的细胞毒能力及其 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 裸鼠主机。 希望这些临床和基础知识 研究研究将有助于更好地了解 分子遗传学、免疫生物学和艾滋病毒自然史 感染，并且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。