Characterizing the viral and host effector mechanisms that govern HIV-1 rebound

表征控制 HIV-1 反弹的病毒和宿主效应机制

• 批准号: 10332623
• 负责人: Katharine June Bar
• 金额: $ 81.23万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-25 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10332623
• 关键词: AIDS/HIV problem; Acute; Address; Aftercare; Animal Model; Antiviral Agents; Biodiversity; Biological; Biology; Blood; Blood Tests; Brain; CD4 Positive T Lymphocytes; CRISPR screen; Cells; Chronic; Clinical; Data; Disease remission; Frequencies; Genes; Goals; Gold; HIV-1; Host Defense Mechanism; Human; Immune; Immune response; Individual; Infection; Integration Host Factors; Interferons; Interruption; Kinetics; Knock-out; Knowledge; Lead; Lymph; Lymphoid Tissue; Macaca mulatta; Maps; Methods; Microglia; Minority; Molecular Cloning; Myeloid Cells; Participant; Pathway interactions; Phenotype; Plasma; Property; Proviruses; Recrudescences; Research; Resistance; Sampling; Site; Source; Testing; Thoracic Duct; Time; Tissues; Translating; Tropism; Variant; Viral; Viral Genes; Viral reservoir; Viremia; Virus; Woman; antiretroviral therapy; clinically relevant; cohort; cytokine; design; improved; in vivo; insight; lymphatic duct; macrophage; male; novel strategies; pressure; prevent; reactivation from latency; recruit; response; simian human immunodeficiency virus; viral rebound

PROJECT SUMMARY A central goal in HIV/AIDS cure research is preventing or delaying viral rebound following analytical treatment interruption (ATI). It is widely assumed that understanding the viral and host factors involved in in vivo latency reactivation would lead to new, more rational cure strategies; however, the biology and provenance of the rebounding virus remains largely unknown. Here, we propose to leverage four recent discoveries from our groups to gain insight into the mechanisms of HIV-1 recrudescence. Using “gold standard” sampling methods to characterize the latent reservoir before and after treatment interruption (ATI), we discovered that viral isolates derived by quantitative virus outgrowth (QVOA) do not represent or predict the viruses that emerge in the plasma following treatment interruption (1, 2). We also found that rebound viruses, but not QVOA-derived reservoir viruses, were highly resistant to type 1 interferons (IFN-I), indicating potent host innate responses at the site of viral recrudescence (3). Surprisingly, some, but not all, rebound suggesting isolates replicated to high titers in macrophages, a greater biological diversity than previously known. Finally, we discovered that IFN-I resistant rebound viruses have the ability to reseed the reservoir, raising the possibility of long-term clinical consequences of ATI (2, 3). In this application, we will leverage these discoveries to elucidate the viral and host factors that govern HIV-1 rebound. Our hypothesis is that by (i) determining the universality, kinetics and clinical impact of IFN-I resistance during rebound, (ii) defining the viral determinants of IFN-I resistance and the host interferon stimulated genes (ISGs) that place pressure on the rebounding virus, and (iii) tracing the provenance of IFN-I resistant rebound viruses, we will uncover key mechanisms that control HIV-1 reactivation from latency. In Aim 1, we will expand our studies to more diverse ATI trial participants, including women, minorities, acute and early ART initiators and individuals receiving IFN-I modulating therapies, to assess the generality of the IFN-I resistant phenotype of rebound viruses. We will also test to what extent IFN-I resistance persists during prolonged ATI and determine how this influences the rates of IFN-I resistant viruses that reseed the reservoir. In Aim 2, we will elucidate the biological properties of rebound HIV-1, map the viral determinants of IFN-I resistance, and identify the host interferon stimulated genes (ISGs) that place pressure on the recrudescing virus. In Aim 3, we will trace the provenance of rebound virus by testing blood, thoracic duct lymph and lymphatic tissue using regular and modified QVOAs, examine whether long-lived myeloid cells, including brain macrophages and microglia, serve as reservoirs of IFN-I resistant viruses, and explore whether SHIV-infected rhesus macaques recapitulate the IFN-I phenotypes of HIV-1 reservoir and rebound viruses. We expect these studies to improve our understanding of the clinically relevant, rebound competent HIV-1 reservoir, the mechanisms underlying in vivo viral reactivation and the host factors that place pressure on the rebounding virus pool, which should lead to more rational and effective HIV/AIDS cure strategies. .

项目摘要 艾滋病毒/艾滋病治疗研究的核心目标是预防或延迟分析治疗后病毒反弹 中断（ATI）。广泛认为了解体内潜伏期涉及的病毒和宿主因素 重新激活将导致新的，更合理的治疗策略；但是，生物学和出处 反弹病毒在很大程度上仍然未知。在这里，我们建议利用我们的四个最新发现 组以深入了解HIV-1复发的机理。使用“金标准”采样方法 为了表征治疗中断之前和之后的潜在储层（ATI），我们发现病毒分离株 通过定量病毒产物（QVOA）得出 治疗中断后（1，2）。我们还发现这种反弹病毒，但没有QVOA衍生的水库 病毒对1型干扰素（IFN-1）具有高度抗性，表明潜在的宿主先天反应 病毒复发（3）。令人惊讶的是，有些但不是全部反弹 建议 分离物在巨噬细胞中复制到高滴度， 比以前已知的更大的生物学多样性。最后，我们发现IFN-i耐药性 反弹病毒具有恢复水库的能力，从而增加了长期临床后果的可能性 ATI（2，3）。在此应用中，我们将利用这些发现来阐明病毒和宿主因素 控制HIV-1反弹。我们的假设是（i）确定宇宙，动力学和临床 反弹期间IFN-1耐药性的影响，（ii）定义IFN-1抗性的病毒决定剂和宿主 干扰素刺激基因（ISGS），将压力施加压力，并（iii）追踪出处 在IFN-I抗反​​弹病毒中，我们将发现控制潜伏期HIV-1重新激活的关键机制。 在AIM 1中，我们将把研究扩展到更多样化的ATI试验参与者，包括妇女，少数民族，急性 以及接受IFN-I调节疗法的早期艺术创始人和个人，以评估 IFN-I反弹病毒的抗性表型。我们还将测试IFN-I阻力在多大程度上持续 延长ATI并确定这如何影响回收储层的IFN-I抗性病毒的发生率。 AIM 2，我们将阐明HIV-1反弹的生物学特性，绘制IFN-1耐药性的病毒决定剂， 并识别宿主干扰素刺激的基因（ISGS），该基因（ISGS）对饲养病毒施加压力。在AIM 3中， 我们将使用血液，胸导管淋巴和淋巴组织来追踪反弹病毒的出处 定期和修改的QVOA，检查长寿细胞是否（包括脑巨噬细胞和）是否 小胶质细胞，作为IFN-I耐药病毒的储量，并探索Shiv感染的恒河猕猴是否 概括了HIV-1储层和反弹病毒的IFN-I表型。我们希望这些研究能改善 我们对临床上相关的，反弹有能力的HIV-1储层的理解， 体内病毒重新激活和将压力施加压力的宿主因素，应引导 更合理有效的艾滋病毒/艾滋病治疗策略。 。