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

项目摘要/摘要 在未经治疗的感染中，HIV-1可以在中枢神经系统建立种群，通常是在长寿的髓系细胞中。 在抗逆转录病毒疗法(ART)抑制的人类中检查这些组织储存库几乎是不可能的；创造 需要一种非人类灵长类动物(NHP)模型来概括人类神经艾滋病毒的许多特征。 本研究的目的是建立和使用一种新的猴-人类免疫缺陷病毒(SHIV)模型 检查抗逆转录病毒治疗期间中枢神经系统的病毒持久性，并确定中枢神经系统的病毒储存库是否对病毒有贡献 当艺术停止时，反弹。这个模型将以温和的速度产生中枢神经系统疾病，类似于 在感染艾滋病毒的人身上观察到的，而不是大多数神经艾滋病SIV模型的极快速度。我们 已经产生了携带8个不同HIV-1环境的具有复制能力的新型SIV克隆，每个环境都是 克隆自人类中枢神经系统，在那里它适合在髓系细胞(M-SHIV)中复制，或者 从人的血液中提取，在那里它适合在CD4+T细胞(R5T-SHIV)中复制。此外，我们还有 在环境病毒中加入新发现的突变，极大地增加恒河猴的SHIV复制。在……里面 活体竞争实验将被用来识别复制能力强的SHIV并建立病毒种群 在感染后1年内在中枢神经系统(目标1)。然后将使用高适应度刀来测试M-M- 和R5 T-Shiv都能够建立在ART期间持续存在的储油层，但M-Shiv储油层将 主要在中枢神经系统发现，而R5 T-Shiv储存库主要在T细胞丰富的组织(淋巴组织)中发现 节点和肠道)(目标2)。然后我们将研究这些变异对病毒反弹的贡献 艺术中断(目标3)。这些目标的成功完成将建立一个现实的HIV-1 CNS模式 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知识 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细胞 细胞作为潜伏的或活跃的复制储存库持续存在。

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.