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，重点的临床试验，旨在长期逆转HIV潜伏期 抗逆转录病毒治疗的成年人。虽然我们拟议的研究试图将实验室的发现转化为 诊所还旨在使我们的基于实验室的科学家进一步研究机制 这有助于潜伏期。我们认为，这种“反向翻译”对于促进我们的知识至关重要 关于治疗过程中HIV持久性的生物学。 在特定的目标1中，我们将执行一个两中心的单臂，有限的持续时间（两周）临床研究 研究二硫仑（一种由FDA批准的药物治疗酒精中毒）逆转艾滋病毒潜伏期的能力。这 研究基于Siliciano博士及其同事的最新数据：使用主要细胞测定艾滋病毒潜伏期 由他的实验室开发以识别激活潜伏艾滋病毒的化合物，他的小组确定该药物为 最有前途的代理商之一。这项研究已获得FDA和Johns Hopkins的批准 IRB和UCSF IRB的初步批准。 在特定的目标2中，我们将执行一项单中心，随机，对照研究，研究的能力 maraviroc（CCR5抑制剂）以逆转潜伏期。这项研究基于我们小组的新兴数据 表明该药物可能直接影响潜在的HIV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）紧密合作，以探讨这种效果的潜在机制。我们的 小组最近也进行了类似的研究，预计没有任何调节障碍或后勤障碍 在一到两年内完成研究。 在特定的目标3中，我们将对抗PD-1抗体进行有限的中心剂量提升的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中执行 使用Hazuda博士及其同事提供的药物。这项研究已获得ACTG的批准 协议开发。 U19资金将用于支持强化病毒学。