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.

项目摘要/摘要 在未经治疗的感染中，HIV-1通常在中枢神经系统中建立种群，通常在长期寿命的髓样谱系细胞中。 在抗逆转录病毒疗法（ART）中检查这些组织储层很少是抑制人类的；创建 需要一个非人类灵长类动物（NHP）模型，该模型概括了人类神经hiv的许多特征。 这项研究的目的是开发和使用一种新型的猿猴 - 人类免疫缺陷病毒（SHIV）模型 检查ART期间中枢神经系统的病毒持久性，并确定中枢神经系统储层是否有助于病毒 当艺术停止时反弹。该模型将以中等速度产生CNS疾病，类似 在HIV感染的人类中观察到，而不是大多数SIV神经辅助模型的极快速度。我们 已经产生了携带八个不同HIV-1 Envs的复制胜任的小说Shiv克隆，每个克隆都 从人中枢神经系统中克隆，在该CNS中，它适用于在髓样谱系中复制（M-SHIVS）或 从人类血液中，该血液适应在CD4+ T细胞中复制（R5 T-SHIVS）。此外，我们还有 在ENV中纳入了新发现的突变，该突变大大增加了恒河猕猴中的Shiv复制。在 体内竞争实验将用于识别可重复复制并建立病毒种群的SHIV 在感染后的1年内，在中枢神经系统中（AIM 1）。然后将使用高健身SHIV来检验以下假设。 R5 T-Shivs都可以建立在艺术期间持续存在的储层，但是M-Shiv水库将 主要在中枢神经系统中找到，而R5 T-SHIV储层将主要在富含T细胞的组织中发现（淋巴 节点和肠道）（目标2）。然后，我们将研究这些变体对病毒反弹的贡献 艺术中断（目标3）。这些目标的成功完成都将建立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 在中枢神经系统中，通过识别在抗逆转录病毒治疗期间持续存在的感染细胞的类型以及这些是否存在 细胞持续为潜在或主动复制储层。