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

基本信息

批准号：
10437036
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
项目类别：
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/10437036
关键词：
AIDS/HIV problem Acute Address Aftercare Animal Model 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

项目摘要

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. .

项目概要 HIV/艾滋病治疗研究的中心目标是预防或延迟治疗后的病毒反弹分析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，其生物学和起源在此，我们建议利用我们最近的四项发现。小组使用“黄金标准”采样方法深入了解 HIV-1 复发的机制。为了描述治疗中断（ATI）前后的潜伏病毒库特征，我们发现病毒分离株由定量病毒生长 (QVOA) 得出的结果并不代表或预测血浆中出现的病毒治疗中断后 (1, 2)，我们还发现病毒反弹，但不是 QVOA 来源的病毒库。病毒对 1 型干扰素 (IFN-I) 具有高度抗性，表明宿主在其位点具有强大的先天反应令人惊讶的是，病毒复发（3）。建议分离株在巨噬细胞中复制到高滴度，最后，我们发现 IFN-I 具有抗性。反弹病毒有能力重新播种储存库，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。我们的假设是通过 (i) 确定普遍性、动力学和临床。反弹期间 IFN-I 耐药性的影响，(ii) 定义 IFN-I 耐药性和宿主的病毒决定因素干扰素刺激基因（ISG）对反弹的病毒施加压力，以及（iii）追踪来源 IFN-I 抗性反弹病毒的研究，我们将揭示控制 HIV-1 从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展到更多样化的 ATI 试验参与者，包括女性、少数族裔、急性以及早期 ART 发起者和接受 IFN-I 调节疗法的个人，以评估我们还将测试反弹病毒的 IFN-I 抗性表型。延长 ATI 并确定这如何影响重新接种储存库的 IFN-I 抗性病毒的速率。目标 2，我们将阐明反弹 HIV-1 的生物学特性，绘制 IFN-I 耐药性的病毒决定因素，并确定对复发病毒施加压力的宿主干扰素刺激基因 (ISG)。我们将通过检测血液、胸导管淋巴液和淋巴组织来追踪反弹病毒的来源常规和改良的 QVOAs，检查长寿的骨髓细胞，包括脑巨噬细胞和小胶质细胞，作为 IFN-I 抗性病毒的储存库，以及是否探索感染 SHIV 的恒河猴概括 HIV-1 储存病毒和反弹病毒的 IFN-I 表型，我们期望这些研究能够得到改进。我们对临床相关的、具有反弹能力的 HIV-1 储存库的理解，以及其背后的机制体内病毒重新激活以及对病毒库反弹造成压力的宿主因素，这应该会导致制定更合理、有效的艾滋病治疗策略。。