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: 10319986
• 负责人: Mario Stevenson
• 金额: $ 38.38万
• 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: 2018-03-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10319986
• 关键词: AIDS/HIV problem; Affinity; Antibodies; Biological Assay; Bone Marrow Transplantation; Boston; CD4 Positive T Lymphocytes; Cell surface; Clinical; Clinical Research; Disadvantaged; Disease remission; Exhibits; Frequencies; Genome; Growth; HIV-1; Individual; Infection; Interruption; Light; Molecular; Molecular Cloning; Myelogenous; Myeloid Cells; Nature; Patients; Phylogenetic Analysis; Plasma; Play; Property; Proviruses; Recombinants; Research; Role; Sampling; Shapes; Supporting Cell; Tissues; Tropism; Variant; Viral; Viremia; Virus; antiretroviral therapy; catalyst; design; falls; fitness; insight; macrophage; viral rebound

Abstract Assessing whether myeloid cells support HIV-1 persistence in the face of effective ART represents a significant technical challenge. As a result, there is as yet, no direct evidence that myeloid cells play any role in viral persistence in the face of effective ART. As a consequence, research on myeloid cell reservoirs is falling into obscurity. Infection of macrophages can only be initiated by HIV-1 variants that have the ability to use low levels of CD4 on the cell surface. Therefore, if a functional myeloid reservoir contributes to viral persistence under effective ART, we would predict that viremia that rebounds following analytic treatment interruption (ATI), would contain viral variants that have a high affinity for CD4. We have developed an approach that allows identification of low frequency macrophage-tropic variants in rebounding viremia post ATI. Through single genome amplification (SGA), we cloned a large number of viral envelopes from plasma of individuals who underwent ATI. When these envelopes were used to construct recombinant molecular clones, they conferred the ability to fuse with, and replicate within primary macrophages. We believe that these results provide definitive evidence for the existence of a myeloid cell reservoir in infected individuals on suppressive ART and furthermore, that this reservoir contributes to viral rebound when ART is interrupted. We hypothesize that the myeloid cell reservoir is stable, permits long term viral persistence under suppressive ART and fuels viral rebound upon treatment interruption. To pursue this hypothesis, we propose to: 1: Assess the frequency of macrophage-tropic viruses through longitudinal sampling of rebounding viremia post-ATI. 2: Assess the persistent nature of the myeloid cell reservoir from individuals with prolonged remission intervals following bone marrow transplant (Boston patients) as well as sampling of rebounding viremia from individuals who underwent sequential ATI. 3: Evaluate whether macrophage-tropic viruses have a CNS origin and whether they are less fit relative to T tropic viruses. This proposal will integrate clinical, virologic and molecular studies to reveal the existence of a myeloid cell reservoir in individuals on suppressive ART and to shed light on the dynamics of this reservoir. The critical information gained from this study will provide whether there is rationale for an expanded effort to develop strategies to target the myeloid cell reservoir and to accelerate the path to a viral cure.

摘要 评估骨髓细胞是否支持HIV-1在有效的ART面前的持久性， 技术挑战。因此，目前还没有直接证据表明骨髓细胞在病毒感染中起任何作用。 因此，对骨髓细胞储库的研究正在陷入困境。 默默无闻巨噬细胞的感染只能由具有使用低水平的能力的HIV-1变体启动 细胞表面的CD 4分子。因此，如果一个功能性的骨髓储库有助于病毒持续存在， 有效的ART，我们预测分析性治疗中断（ATI）后反弹的病毒血症， 含有对CD 4具有高亲和力的病毒变体。我们已经开发出一种允许识别的方法 低频率巨噬细胞嗜性变异体在ATI后反弹病毒血症中的作用通过单个基因组 通过快速扩增（SGA），我们从经历ATI的个体的血浆中克隆了大量的病毒包膜。 当这些包膜用于构建重组分子克隆时，它们赋予了融合的能力， 在原代巨噬细胞内复制。我们相信这些结果提供了明确的证据 在接受抑制性ART的感染个体中存在骨髓细胞储库，此外， 当抗逆转录病毒治疗中断时，这个储存库会导致病毒反弹。 我们假设髓系细胞库是稳定的，在抑制性免疫抑制下允许病毒长期存在。 ART和燃料病毒反弹后，治疗中断。为了实现这一假设，我们建议： 1：通过反弹纵向采样评估嗜巨噬细胞病毒的频率 ATI后病毒血症 2：评估缓解期延长个体骨髓细胞库的持续性 骨髓移植后间隔（波士顿患者）以及反弹病毒血症采样 连续性ATI的患者。 3：评价嗜巨噬细胞病毒是否具有CNS来源，以及它们是否是较不适合的相对 T嗜性病毒。 该提案将整合临床、病毒学和分子研究，以揭示骨髓细胞的存在 在抑制性ART的个人水库，并阐明这个水库的动态。临界 从这项研究中获得的信息将提供是否有理由扩大努力， 针对骨髓细胞库和加速病毒治愈的策略。