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: 10666563
• 负责人: Thomas Hope
• 金额: $ 154.89万
• 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/10666563
• 关键词: Animals; Antibodies; Antiviral Response; Aquila; Area; Autopsy; Binding; Biological Assay; Blood; Blood Cells; Blood specimen; CCR5 gene; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell Separation; Cells; Characteristics; Collaborations; Data; Dependence; Detection; Development; Disadvantaged; Goals; HIV; HIV Infections; Human; ImmunoPET; In Vitro; Infection; Interferons; Interruption; Investigation; Location; Macaca mulatta; Macrophage; Methods; Modeling; Mucous Membrane; Myelogenous; Myeloid Cells; Outcome; PET/CT scan; Patients; Phase; Plasma; Play; Population; Population Dynamics; Positron-Emission Tomography; Predisposition; Process; Proteins; 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; Viremia; Virus; Virus Replication; acute infection; cell type; critical period; granulocyte; human tissue; humanized mouse; in vivo; innovation; insight; lymph nodes; mast cell; nonhuman primate; nonhuman tissue; pressure; response; text searching; 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） 艾滋病毒感染目的地目的地长期抑制病毒血症的持久性构成了主要障碍 治愈艾滋病毒。不幸的是，即使对于急性感染期间在购物车中启动的患者也是如此。长期 感染后持续的艾滋病毒水库迅速播种，这在非人类私人中得到了证实 （NHP）艾滋病毒模型。此外，来自几个小组的数据强烈表明残留的病毒复制 正在进行的组织任务中，通过手推车完全抑制病毒血症。我们正在进行的研究调查了 卡车中断后，NHP模型中病毒反弹的“日食阶段”。这个“日食阶段”是 了解反弹过程，因为病毒在病毒血症之前正在组织中扩散，并且受到影响 自适应和天生的反应以及宿主微环境。在我们对早期的研究（4天后） 感染）CART计划，我们创新的SIV-ENV Immunopet-CT指导分析和采样导致了几个 重要的是，有时意外的发现：1）我们在整个主机中检测到SIV扩展> 1周 后车倡议，此后信号减少； 2）即使在6-8个月后，免疫集/CT也是 尽管血液中无法检测到的病毒血症，但敏感足以检测组织中残留的病毒（蛋白质）信号。 3）在艺术中断时，病毒信号最早在手推车中断后4天反弹（ATI），但也有2个 在血浆中发现病毒的前几周； 4）分析通过我们的PET-CT回弹收集的组织 引导性尸检工作流令人惊讶地表明，大多数感染细胞是髓样细胞的。后 广泛的分析，这些细胞揭示为肥大细胞（MC），这是一个主要组织居民粒细胞的肉芽细胞（MC） 我们演示表达CD4和CCR5。通过与本地MC专家合作，我们能够证明 原发性组织MC在体外容易受到HIV感染的影响，其敏感性和支持病毒的能力 复制受环境刺激的影响很大。在此PPG中，我们将利用一些重要的见解 以及在当前PPG期间开发的创新技术，以调查MC有助于的假设 卡车期间组织中的HIV持续性和/或在卡车中断时会导致病毒反弹。而且，我们 将通过组织和 通过我们创新的PET-CT指导采样工作流进行分离的细胞。这些时间也将被确定 通过分析我们通过当前认识的“反弹组织”的其他特征 研究。该PPG包括3个独立的，但高度相互联系的项目，1个科学NHP核心 和1个行政核心。这三个项目将以不同的方式使用NHP研究的组织以及 每个项目独有的资源，并将解决不同的完整问题，并以最终的方式解决 剖析艾滋病毒持久性和反弹机制的目标。