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: 10629260
• 负责人: Katharine June Bar
• 金额: $ 81.25万
• 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/10629260
• 关键词: Acute; Address; Aftercare; Animal Model; Binding; Biodiversity; Biological; Biology; Blood; Blood Tests; Brain; CD4 Positive T Lymphocytes; CRISPR screen; Cells; Chronic; Clinical; Data; Disease remission; Frequencies; Genes; Goals; HIV-1; HIV/AIDS; Host Defense Mechanism; Human; Immune; Immune response; Individual; Infection; Integration Host Factors; Interferons; Interruption; Kinetics; Knowledge; Lymph; Lymphoid Tissue; Macaca mulatta; Macrophage; 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; knockout gene; lymphatic duct; 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. .

项目总结 艾滋病毒/艾滋病治疗研究的一个中心目标是预防或延缓分析治疗后的病毒反弹 中断(ATI)。人们普遍认为，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；然而， 反弹的病毒在很大程度上仍是未知的。在这里，我们建议利用我们的 小组以深入了解HIV-1复发的机制。采用“黄金标准”抽样方法 为了表征治疗中断(ATI)前后的潜伏库，我们发现病毒分离株 由定量病毒生长(QVOA)得出的不代表或预测在血浆中出现的病毒 治疗中断后(1、2)。我们还发现，反弹病毒，但不是QVOA派生的病毒库 病毒对1型干扰素(干扰素-I)具有高度抵抗力，表明宿主在 病毒复发(3)。令人惊讶的是，一些(但不是全部)反弹 建议 在巨噬细胞中复制到高滴度的分离株， 比以前所知的更大的生物多样性。最后，我们发现干扰素-I具有抗药性。 反弹的病毒有能力重新播种到水库，从而增加了长期临床后果的可能性。 ATI(2，3)。在这个应用中，我们将利用这些发现来阐明病毒和宿主因素 控制着HIV-1病毒的反弹。我们的假设是，通过(I)确定普适性、动力学和临床 干扰素-I抵抗在反弹过程中的影响，(Ii)确定干扰素-I抵抗的病毒决定因素和宿主 干扰素刺激的基因(ISG)对反弹的病毒施加压力，以及(Iii)追踪来源 在干扰素-I耐药反弹病毒中，我们将揭示控制HIV-1潜伏期重新激活的关键机制。 在目标1中，我们将把我们的研究扩大到更多不同的ATI试验参与者，包括妇女、少数族裔、急性 以及早期ART发起者和接受干扰素-I调节疗法的个人，以评估 反弹病毒的干扰素-I耐药表型。我们还将测试干扰素-I耐药性在多大程度上持续 延长的ATI，并确定这如何影响重新播种水库的干扰素-I抗性病毒的比率。在……里面 目的2，我们将阐明反弹HIV-1的生物学特性，绘制干扰素-I耐药的病毒决定因素图， 并确定对复发病毒施加压力的宿主干扰素刺激基因(ISG)。在《目标3》中， 我们将通过检测血液、胸管淋巴和淋巴组织来追踪反弹病毒的来源。 常规和改进的QVOA，检查长寿命的髓系细胞，包括脑巨噬细胞和 小胶质细胞，作为干扰素-I耐药病毒的储存库，并探索感染希沃克病毒的恒河猴 概述HIV-1储存和反弹病毒的干扰素-I表型。我们希望这些研究能有所改善。 我们对临床相关的、反弹能力强的HIV-1储存库的理解，潜在的机制 活体病毒重新激活和对反弹的病毒池施加压力的宿主因素，这应该会导致 以制定更合理有效的艾滋病毒/艾滋病治疗策略。 。