Reversal of HIV latency in vivo

HIV体内潜伏期的逆转

• 批准号: 8202574
• 负责人: STEVEN Grant DEEKS
• 金额: $ 39.51万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-08 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8202574
• 关键词: AIDS clinical trial group; Acquired Immunodeficiency Syndrome; Adult; Affect; Alcoholism; Anti-Retroviral Agents; Antibodies; Biological Assay; Biology; CCR5 gene; Cells; Clinic; Clinical Research; Clinical Trials; Collaborations; Data; Disulfiram; Dose; Drug usage; FDA approved; Funding; Genome; HIV; Institutional Review Boards; Intervention; Knowledge; Laboratories; Laboratory Finding; Pathogenesis; Pharmaceutical Preparations; Randomized Controlled Trials; Research; Scientist; Translating; Translational Research; Translations; Viral; Work; arm; base; design; in vivo; inhibitor/antagonist; member; phase 1 study; protocol development; virology

We propose to perform three small, focused clinical trials aimed at reversing HIV latency in long-term antiretroviral-treated adults. While our proposed studies seek to translate findings from the laboratory into the clinic, they are also designed to enable our laboratory-based scientists to further investigate the mechanisms that contribute to latency. We believe that this "reverse translation" is critical to advancing our knowledge about the biology of HIV persistence during therapy. In Specific Aim 1, we will perform a two-center, single arm, limited duration (two weeks) clinical study investigating the ability of disulfiram (an FDA-approved drug to treat alcoholism) to reverse HIV latency. This study is based on recent data from Dr. Siliciano and colleagues: using a primary cell assay for HIV latency developed by his laboratory to identify compounds that activate latent HIV, his group identified this drug as among the most promising agents. This study has received approval from the FDA and the Johns Hopkins IRB, and tentative approval from the UCSF IRB. In Specific Aim 2, we will perform a single-center, randomized, controlled study investigating the ability of maraviroc (a CCR5 inhibitor) to reverse latency. This study is based on emerging data from our group suggesting that this drug may directly affect latent HIV genomes independent of its effect on viral replication. We will work closely with Dr. Sharon Lewin (Project 5) to explore the potential mechanism for this effect. Our group has performed a similar study recently and expects to have no regulatory or logistical barriers to completing the study within one to two years. In Specific Aim 3, we will perform a limited center, dose-escalating phase I study of an anti-PD-1 antibody. This study is based on preliminary data outlined in Project 2 and 3, and will be performed within the ACTG using drug to be provided by Dr. Hazuda and her colleagues. This study has received ACTG approval for full protocol development. U19 funds will be used to support the intensive virology.

我们建议进行三项小型、集中的临床试验，旨在长期逆转艾滋病毒潜伏期 接受抗逆转录病毒治疗的成年人。虽然我们提出的研究试图将实验室的发现转化为 临床上，它们还旨在使我们实验室的科学家能够进一步研究其机制 这会导致延迟。我们相信这种“反向翻译”对于提升我们的知识至关重要 关于治疗期间艾滋病毒持续存在的生物学。 在具体目标1中，我们将进行一项两中心、单臂、有限持续时间（两周）的临床研究 研究双硫仑（FDA 批准的治疗酒精中毒的药物）逆转 HIV 潜伏期的能力。这 研究基于 Siliciano 博士及其同事的最新数据：使用原代细胞测定检测 HIV 潜伏期 由他的实验室开发来识别激活潜伏艾滋病毒的化合物，他的团队将这种药物鉴定为 是最有前途的代理商之一。该研究已获得 FDA 和约翰霍普金斯大学的批准 IRB 和 UCSF IRB 的初步批准。 在具体目标 2 中，我们将进行一项单中心、随机、对照研究，调查 maraviroc（一种 CCR5 抑制剂）可逆转潜伏期。这项研究基于我们小组的新数据 表明该药物可能直接影响潜伏的艾滋病毒基因组，而与其对病毒复制的影响无关。 我们将与Sharon Lewin博士（项目5）密切合作，探索这种效应的潜在机制。我们的 该小组最近进行了一项类似的研究，预计不会存在监管或后勤障碍 一到两年内完成学习。 在具体目标 3 中，我们将对抗 PD-1 抗体进行有限中心、剂量递增的 I 期研究。 这项研究基于项目 2 和 3 中概述的初步数据，并将在 ACTG 内进行 使用 Hazuda 博士和她的同事提供的药物。本研究已获得 ACTG 的全面批准 协议开发。 U19资金将用于支持强化病毒学研究。