Revealing HIV-1 persistence in myeloid cell reservoirs

揭示骨髓细胞储存库中 HIV-1 的持久性

• 批准号: 10709063
• 负责人: Mario Stevenson
• 金额: $ 53.83万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10709063
• 关键词: Affinity; Anatomy; Area; Binding; CD4 Antigens; CD4 Positive T Lymphocytes; Cell membrane; Cells; Cellular Immunity; Chronic; Clinical; Cytoprotection; Evolution; Frequencies; Funding; Glean; Glycoproteins; HIV Genome; HIV-1; HIV/AIDS; Immunity; Immunologic Surveillance; Individual; Infection; Interruption; Kinetics; Ligands; Location; Longevity; Lymphoid; Macrophage; Male Genital Organs; Mediating; Membrane; Methods; Microglia; Myelogenous; Myeloid Cells; Nature; Plasma; Plasma Cells; Play; Population; Proteomics; Research; Role; Sampling; Source; T-Lymphocyte; T-Lymphocyte Epitopes; Tissues; Variant; Viral; Viral reservoir; Viremia; Virion; Virus; acute infection; antiretroviral therapy; cell mediated immune response; cohort; defined contribution; design; high risk population; high throughput analysis; insight; molecular clock; novel; novel strategies; pressure; reproductive tract; tool; viral rebound

Abstract. HIV-1 persistence in ART is maintained predominantly by tissue reservoirs. However, due to challenges in sampling anatomic sites, particularly in living subjects, most of the information on viral reservoir composition and dynamics has been gleaned from studies with circulating CD4+ T cells. As a result, the contribution of tissue resident macrophages to viral persistence, remains elusive. Therefore, there is a need for new approaches that can reveal the composition and dynamics of anatomic reservoirs in living subjects. In the previous funding period, we developed new methods capable of interrogating myeloid cell reservoirs in living subjects. One approach, termed liganded virion immunocapture, gauges the origins of virions in plasma from their proteomic content. It exploits the fact that the virion membrane is derived from the plasma membrane and that virions in plasma will therefore contain tags that reflect their host cell origin. With this approach, we provided evidence that some virions in plasma of individuals undergoing analytic treatment interruption (ATI) had a myeloid cell origin [1]. In this renewal, we propose to identify some anatomic sources of the myeloid reservoir, as well as the longevity and dynamics of the myeloid reservoir. Our objectives are to: Aim 1: Examine the composition of post-ATI viremia to assess the presence of infected myeloid cells, including CNS microglia, under suppressive ART. 1a: Track the relative frequencies of myeloid-cell-originating virions (liganded virion immunocapture and macrophage fusogenicity, molecular clock) across an ATI interval to gain insight into the kinetics of myeloid reservoir reactivation. 1b: Use liganded immunocapture with microglia-specific tags to assess whether microglial-cell-originating virions populate post-ATI viremia. Aim 2: Establish the chronicity of the myeloid reservoir, timing of its establishment and its role in evasion of host cell immunity. 2a: Track the re-emergence of related, myeloid-originating viral variants across sequential ATIs conducted over a two year period. 2b: Assess T cell epitope escape frequencies in temporally matched (molecular clock), myeloid-derived and lymphoid-derived virus populations. 2c: Evaluate whether myeloid cell-derived virions populate post-ATI viremia in early ART subjects. This proposal leverages important and unique clinical cohorts assembled from subjects undergoing single and sequential ATIs as well acute infection subjects and employs novel methods of examining post-ATI viremia to gain insight into anatomic myeloid reservoirs that have thus far, remained elusive.

抽象。 抗逆转录病毒疗法中的HIV-1持久性主要由组织库维持。然而，由于在 取样解剖部位，特别是活体，大部分关于病毒储库组成的信息， 从循环CD 4 + T细胞的研究中收集到了这种动力学。因此，组织的贡献 从巨噬细胞到病毒的持久性，仍然难以捉摸。因此，需要新的方法， 可以揭示活体解剖储库的组成和动态。 在上一个资助期，我们开发了能够在骨髓细胞库中询问骨髓细胞库的新方法。 活着的人一种称为配体病毒体免疫捕获的方法，测量血浆中病毒体的起源 从它们的蛋白质组含量。它利用了病毒体膜来源于质膜的事实 并且血浆中的病毒体将因此含有反映其宿主细胞来源的标签。通过这种方法，我们 提供了证据表明，接受分析治疗中断（ATI）的个体血浆中的一些病毒体 骨髓细胞起源[1]。在这次更新中，我们建议确定髓系储库的一些解剖学来源， 以及骨髓储库的寿命和动力学。我们的目标是： 目的1：检查ATI后病毒血症的组成以评估受感染的骨髓细胞的存在， 包括CNS小胶质细胞。 1a：追踪骨髓细胞源性病毒粒子（配体病毒粒子免疫捕获和 巨噬细胞融合性，分子钟），以深入了解髓系造血干细胞的动力学。 储层再活化 1b：使用带有小胶质细胞特异性标签的配体免疫捕获来评估小胶质细胞来源的病毒体是否 感染ATI后病毒血症。 目的2：确定髓系储库的慢性化，其建立的时间及其在逃避中的作用 宿主细胞免疫力。 2a：在2011年至2012年期间进行的连续ATI中，跟踪相关的骨髓源性病毒变异的重新出现 两年期。 2b：评估时间匹配的（分子钟）、骨髓来源的和骨髓来源的T细胞表位逃逸频率。 淋巴衍生的病毒群体。 2c：评估骨髓细胞衍生的病毒体是否在早期ART受试者中填充ATI后病毒血症。 该提案利用了从接受单次和多次治疗的受试者中收集的重要和独特的临床队列， 连续ATI以及急性感染受试者，并采用新的方法检查ATI后病毒血症， 深入了解解剖骨髓水库，迄今为止，仍然难以捉摸。