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: 10450183
• 负责人: SARAH BETH JOSEPH
• 金额: $ 65.32万
• 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/10450183
• 关键词: Acquired Immunodeficiency Syndrome; Animals; 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; Persons; 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.

项目总结/摘要 在未经治疗的感染中，HIV-1可以在CNS中建立群体，通常在长寿命的髓系细胞中。 在抗逆转录病毒治疗（ART）抑制的人类中检查这些组织储库是很少可能的; 需要一种非人灵长类动物（NHP）模型，以重现人类中NeuroHIV的许多特征。 本研究的目的是开发和使用一种新的猴-人免疫缺陷病毒（SHIV）模型 检查ART期间CNS中的病毒持久性，并确定CNS储库是否有助于病毒 当ART停止时反弹。该模型将以中等速度产生CNS疾病，类似于 在HIV感染者中观察到的，而不是大多数神经艾滋病的SIV模型的极快的速度。我们 已经产生了携带八种不同的HIV-1 env的可复制的新型SHIV克隆，每一种都是 从人CNS克隆，其中其适于在髓系细胞（M-SHIV）中复制，或 来自人血液，在那里它适应于在CD 4 + T细胞（R5 T-SHIV）中复制。另外我们有 在env中引入新发现的突变，大大增加了恒河猴中SHIV的复制。在 体内竞争实验将被用来鉴定能够稳健复制的SHIV并建立病毒种群 在感染后1年内的CNS中（目标1）。然后，高适应性SHIV将用于检验M- 和R5 T-SHIV都能够建立在ART期间持续存在的水库，但M-SHIV水库将 主要在CNS中发现，而R5 T-SHIV储库将主要在富含T细胞的组织（淋巴 节点和肠）（目标2）。然后，我们将研究这些变异对病毒反弹的贡献， ART中断（目标3）。这些目标的成功实现将建立一个现实的HIV-1中枢神经系统模型 这种疾病可以应用于未来的根除研究，它将扩大我们对病毒持久性的了解 通过确定在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 细胞作为潜伏的或活跃的复制库持续存在。