Unraveling the Mechanisms of HIV Persistence and Rebound

揭示艾滋病病毒持续存在和反弹的机制

• 批准号: 10460073
• 负责人: Thomas Hope
• 金额: $ 151.1万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10460073
• 关键词: Address; Animals; Antibodies; Antiviral Response; Aquila; Area; Autopsy; Biological Assay; Blood; Blood Cells; Blood specimen; CCR5 gene; CD4 Positive T Lymphocytes; Cell Differentiation process; Cells; Characteristics; Collaborations; Data; Dependence; Detection; Development; Disadvantaged; Goals; HIV; HIV Infections; Human; ImmunoPET; In Vitro; Infection; Interferons; Interruption; Investigation; Literature; Location; Macaca mulatta; Methods; Modeling; Mucous Membrane; Myelogenous; Myeloid Cells; Outcome; PET/CT scan; Patients; Phase; Plasma; Play; Population; Population Dynamics; Positron-Emission Tomography; Predisposition; Primary Infection; Process; Residual state; Resolution; Resources; Role; SIV; Sampling; Scanning; Shapes; Signal Transduction; Site; Skin; Source; Stains; Stimulus; T-Lymphocyte; Techniques; Technology; Testing; Time; Tissue Banks; Tissues; Tryptase; Viral; Viral Proteins; Viremia; Virus; Virus Replication; acute infection; base; cell type; critical period; granulocyte; human tissue; humanized mouse; in vivo; innovation; insight; lymph nodes; macrophage; mast cell; nonhuman primate; nonhuman tissue; pressure; response; therapy design; viral detection; viral rebound

PROJECT SUMMARY/ABSTRACT (Overall) The persistence of HIV infection despite long term suppression of viremia by cART constitutes the major obstacle to HIV cure. This is unfortunately true even for patients initiated on cART during acute infection. Thus, long-term persistent HIV reservoirs are seeded rapidly post infection, and this was confirmed in the nonhuman primate (NHP) model of HIV. In addition, data from several groups and ours strongly suggest that residual viral replication is ongoing despite in tissues despite full suppression of viremia by cART. Our on-going studies investigate the “eclipse phase” of viral rebound in the NHP model after cART interruption. This “eclipse phase” is key to understand the rebound process since the virus is spreading in tissues before viremia and it is influenced by adaptive and innate responses as well as the host microenvironment. In our studies of early (4 days post- infection) cART initiation, our innovative SIV-env ImmunoPET-CT guided analysis and sampling led to several important, sometimes unexpected findings: 1) we detected SIV expansion throughout the entire host for >1 week post cART initiation, with signal decreasing thereafter; 2) Even after 6-8 months of cART, immunoPET/CT was sensitive enough to detect residual viral (protein) signal in tissues in spite of undetectable viremia in the blood; 3) upon ART interruption, viral signals rebounded as early as 4 days post cART interruption (ATI) but also 2 weeks before detection of virus in plasma; 4) analysis of the tissues collected at rebound through our PET-CT guided necropsy workflow surprisingly showed that the majority of infected cells were of myeloid cells. After extensive analysis, these cells revealed to be mast cells (MC), a predominantly tissue resident granulocytes that we demonstrate expresses CD4 and CCR5. By teaming up with a local MC expert, we were able to demonstrate that primary tissue MC are susceptible to HIV infection in vitro and their susceptibility and ability to support viral replication is heavily influenced by environmental stimuli. In this PPG, we will leverage several important insights and innovative techniques developed during our current PPG to investigate the hypothesis that MC contribute to HIV persistence in tissues during cART and/or contribute to viral rebound upon cART interruption. Moreover, we will clarify virus-host dynamics through phyloanatomical analysis of viral populations in tissues using tissues and cells isolated through our innovative PET-CT guided sampling workflow. These tissues will be identified also through the analysis of additional features of “rebound tissues” that we have recognized through our current studies. This PPG comprises of 3 independent, although highly interconnected projects, 1 scientific NHP core and 1 administrative core. The 3 projects will all use in different ways tissues from the NHP studies as well as resources unique to each project and will address different although complementary questions with the ultimate goal to dissect the mechanisms of HIV persistence and rebound.

项目摘要/摘要(总体) 尽管CART长期抑制了病毒血症，但艾滋病毒感染仍持续存在，这是主要障碍 为了治愈艾滋病。不幸的是，即使是在急性感染期间接受CART治疗的患者也是如此。因此，从长远来看， 在感染后，持久的艾滋病毒储存库迅速播种，这在非人类灵长类动物中得到了证实 (NHP)HIV模型。此外，来自几个小组和我们的数据强烈表明，残留的病毒复制 尽管CART完全抑制了病毒血症，但组织中的病毒仍在继续。我们正在进行的研究调查了 病毒在NHP模型中断后的“月食阶段”反弹。这一“月食阶段”是 了解病毒的反弹过程，因为病毒在病毒血症之前在组织中传播，并受到 适应性和先天反应以及寄主微环境。在我们早期(4天后)的研究中 感染)CART启动后，我们创新的SIV-env免疫PET-CT引导分析和采样导致了几个 重要的、有时是意想不到的发现：1)我们在整个主机中检测到SIV扩展了1周 CART开始后，信号减弱；2)即使在CART后6-8个月，免疫PET/CT仍 足够灵敏，即使血液中没有检测到病毒血症，也能检测到组织中残留的病毒(蛋白质)信号； 3)在ART中断后，病毒信号最早在购物车中断(ATI)后4天反弹，但也有2 检测血浆中病毒的前几周；4)通过我们的PET-CT分析反弹时收集的组织 引导的尸检工作流程令人惊讶地显示，大多数感染细胞是髓系细胞。之后 广泛的分析表明，这些细胞是肥大细胞(MC)，主要是一种驻留在组织中的粒细胞， 我们演示了CD4和CCR5的表达。通过与当地的MC专家合作，我们能够展示 原代组织MC在体外对HIV感染及其易感性和支持病毒的能力 复制很大程度上受环境刺激的影响。在这篇PPG中，我们将利用几个重要的见解 以及在我们当前的PPG期间开发的创新技术，以调查MC对 在CART过程中艾滋病毒在组织中的持续存在和/或在CART中断时有助于病毒反弹。此外，我们 将通过使用组织和组织中的病毒种群的系统解剖学分析来阐明病毒宿主的动力学 通过我们创新的PET-CT引导采样工作流程分离细胞。这些组织也将被识别出来 通过分析我们通过目前所识别的“反弹组织”的其他特征 学习。该PPG由3个独立但高度关联的项目、1个科学NHP核心组成 和1个行政核心。这三个项目都将以不同的方式使用来自NHP研究的组织以及 资源对每个项目都是独一无二的，并将通过终极解决不同但互补的问题 目的剖析HIV持续和反弹的机制。