Development and Use of Novel SHIVs Bearing Clinically Relevant HIV-1 Envs for Examining HIV Persistence and Eradication in the CNS of Nonhuman Primates

携带临床相关 HIV-1 包膜的新型 SHIV 的开发和使用，用于检查非人类灵长类动物中枢神经系统中 HIV 的持续存在和根除情况

• 批准号: 10219924
• 负责人: SARAH BETH JOSEPH
• 金额: $ 62.12万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-16 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10219924
• 关键词: Acquired Immunodeficiency Syndrome; Animals; Biological; Biological Assay; Biological Models; Blood; Blood - brain barrier anatomy; CCR5 gene; CD4 Positive T Lymphocytes; Cell Lineage; Cells; Central Nervous System Diseases; Central Nervous System Infections; Collaborations; Development; Disease; Disease Progression; Evolution; Future; HIV; HIV-1; Human; Human Cloning; Immune system; Immunosuppression; In Situ; Individual; Infection; Interruption; Knowledge; Laboratories; Macaca; Macaca mulatta; Malignant Neoplasms; Microglia; Modeling; Modernization; Mutation; Myelogenous; Phenotype; Population; Recrudescences; Research Personnel; SIV; Severities; Source; Systemic infection; T-Lymphocyte; Testing; Tissue Sample; Tissues; Ursidae Family; Variant; Viral; Viral reservoir; Virus; Virus Diseases; Virus Replication; antiretroviral therapy; cell type; clinically relevant; deep sequencing; design; experimental study; fitness; in vivo; lymph nodes; macrophage; nervous system disorder; neuroAIDS; nonhuman primate; novel; prevent; programs; screening; simian human immunodeficiency virus; treatment duration; viral rebound

PROJECT SUMMARY/ABSTRACT In untreated infection, HIV-1 can establish populations in the CNS, often in long-lived myeloid lineage cells. Examining these tissue reservoirs in antiretroviral therapy (ART)-suppressed humans is rarely possible; creating a need for a nonhuman primate (NHP) model that recapitulates many of the features of NeuroHIV in humans. The objective of this study is to develop, and use, a novel simian-human immunodeficiency virus (SHIV) model to examine viral persistence in the CNS during ART and to determine whether CNS reservoirs contribute to viral rebound when ART is stopped. This model will generate CNS disease at a moderate pace, similar to that observed in HIV-infected humans, rather than the extremely rapid pace of most SIV models of NeuroAIDS. We have generated replication competent novel SHIV clones carrying eight different HIV-1 envs, each of which was cloned from either the human CNS, where it was adapted to replicating in myeloid lineage cells (M-SHIVs), or from the human blood, where it was adapted to replicating in CD4+ T cells (R5 T-SHIVs). In addition, we have incorporate newly discovered mutations in env that greatly increase SHIV replication in rhesus macaques. In vivo competition experiments will be used to identify SHIVs that replicate robustly and establish viral populations in the CNS within 1 year of infection (Aim 1). High fitness SHIVs will then be used to test the hypothesis that M- and R5 T-SHIVs are both able to establish reservoirs that persist during ART, but that M-SHIV reservoirs will primarily be found in the CNS, while R5 T-SHIV reservoirs will primarily be found in T cell-rich tissues (lymph nodes and gut) (Aim 2). We will then examine the contribution that these variants make to viral rebound after ART interruption (Aim 3). Successful completion of these aims will both establish a realistic model of HIV-1 CNS disease that can be applied to future studies of eradication and it will expand our knowledge of viral persistence in the CNS by identifying the types of infected cells that persistent during antiretroviral therapy and whether these cells persist as latent or actively replicating reservoirs.

项目概要/摘要 在未经治疗的感染中，HIV-1 可以在中枢神经系统中建立群体，通常是在长寿的骨髓谱系细胞中。 在接受抗逆转录病毒治疗（ART）抑制的人类中检查这些组织库几乎是不可能的。创造 需要一种能够概括人类 NeuroHIV 的许多特征的非人类灵长类动物 (NHP) 模型。 本研究的目的是开发和使用一种新型猿猴人类免疫缺陷病毒 (SHIV) 模型 检查 ART 期间中枢神经系统中的病毒持续性，并确定中枢神经系统储存库是否会导致病毒传播 ART 停止时反弹。该模型将以中等速度产生中枢神经系统疾病，类似于 在 HIV 感染者中观察到的速度，而不是大多数 NeuroAIDS SIV 模型中的极快速度。我们 已经产生了具有复制能力的新型 SHIV 克隆，其携带八种不同的 HIV-1 envs，其中每一个都是 从人类 CNS 克隆，适应于在骨髓谱系细胞 (M-SHIV) 中复制，或者 它来自人类血液，适合在 CD4+ T 细胞（R5 T-SHIV）中复制。此外，我们还有 纳入新发现的 env 突变，大大增加了恒河猴中 SHIV 的复制。在 体内竞争实验将用于识别复制能力强的 SHIV 并建立病毒种群 感染后 1 年内出现在中枢神经系统中（目标 1）。然后，高适应度的 SHIV 将被用来检验以下假设：M- 和 R5 T-SHIV 都能够建立在 ART 期间持续存在的病毒库，但 M-SHIV 病毒库将 主要存在于 CNS 中，而 R5 T-SHIV 储存库主要存在于富含 T 细胞的组织（淋巴 节点和肠道）（目标 2）。然后我们将检查这些变异对病毒反弹的贡献 ART 中断（目标 3）。成功完成这些目标将建立 HIV-1 CNS 的现实模型 可以应用于未来根除研究的疾病，它将扩大我们对病毒持久性的了解 通过识别抗逆转录病毒治疗期间持续存在的感染细胞类型以及这些细胞是否在中枢神经系统中 细胞作为潜在或活跃复制的储存库持续存在。