Effects of Opioids on SIV Reservoirs in Brain Macrophages of Rhesus Macaques

阿片类药物对恒河猴脑巨噬细胞 SIV 储库的影响

• 批准号: 9848712
• 负责人: Marcelo J Kuroda
• 金额: $ 15.26万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9848712
• 关键词: Effects; Opioids; SIV; Reservoirs; Brain

 DESCRIPTION: HIV infection in combination with opiate drug addiction is an emerging and growing problem, partly due to a longer life expectancy afforded by HAART. Despite effective anti-retroviral therapy (ART) and extended longevity, opiate use exacerbates neurological abnormalities in HIV-infected patients. Our long-term goal is to ameliorate or reverse development of neurological abnormalities that arise despite ART in drug-addicted HIV-infected individuals. The purpose of this R21/R33 proposal is to verify and determine the contribution of perivascular macrophages (PVM) to the virus reservoir in the CNS of SIV-infected macaques following ART and to test if opiate addiction modifies the function of immune cell subsets, including PVM, to fuel the virus reservoir and exacerbate pathogenesis of SIV infection. Our central hypothesis is that long-lived PVM not only serve as major SIV reservoirs but also influence the establishment of virus reservoirs in other cells subsets of the CNS such as microglia and astrocytes in opioid-addicted macaques. To test this, we propose that in vivo depletion of long-lived PVM will reduce or eliminate the virus reservoir and consequently ameliorate the progression of neuropathology and neuroinflammation. The rationale for our hypothesis is that, (i) morphine- dependent SIV-infected macaques display exacerbation of neurological abnormalities observed in parallel in HIV-infected and addicted humans, (ii) reservoir sites of SIV can be examined in finer detail and under more controlled experimental conditions in macaques than in HIV-infected humans, and (iii) we established a safe protocol to eliminate PVM in vivo that will enable us to directly demonstrate their role in the virus reservoir and neuropathogenesis. We propose two aims in phase I (R21) of this application: Aim 1. Determine the effect of morphine on the size and host cell range of the CNS virus reservoir in SIV-infected macaques undergoing ART. Our working hypothesis is that morphine- treated SIV-infected macaques will develop a higher virus reservoir level in PVM and a higher monocyte turnover (indicative of disease progression) than in the SIV-infected-only group at the initiation of ART treatment. Aim 2. Define the specific contribution of PVM to the CNS viral reservoir in opioid-dependent SIV-infected macaques undergoing suppressive ART. Our working hypothesis is that in vivo depletion of PVM will reduce or eliminate the brain virus reservoir in morphine-treated SIV-infected macaques undergoing suppressive ART. To test this, SIV-infected macaques will begin ART after reaching virus set point. The PVM then will be selectively depleted via intrathecal liposomal bisphosphonate (BP) treatment that is expected to induce repopulation by recruiting fresh cells. This approach will also bring to light the magnitude of other cell types that may contribute to the SIV reservoir, such as microglia and astrocytes. These results will demonstrate cellular site(s) and magnitude of SIV reservoirs in the brain of morphine-treated SIV-infected rhesus macaques. Specifically, the outcomes will provide proof-of-concept for the in vivo depletion of PVM and their contribution to the virus reservoir that will lead to testing a treatment strategy targeting PVM to reduce disease progression. This will set the foundation for stud- ies in aim 3 of phase II (R33) to corroborate if targeting PVM earlier after infection and ART will re- duce or ameliorate exacerbation of CNS pathogenesis in morphine-treated SIV-infected macaques. Aim 3. Determine if early in vivo depletion of PVM prevents progression of neuropathogesis in opioid-dependent SIV-infected macaques undergoing suppressive ART. Our working hypothesis is that PVM serve as SIV reservoirs and/or promote development of reservoirs in other host cells. Here, we will determine if in vivo elimination of PVM early after initiating ART will control or re- duce progression of CNS pathogenesis in SIV-infected macaques with chronic morphine treatment. If successful, this study will lead to developing novel therapeutic strategies to effectively target persistent HIV infection of the brain and reverse HAND development.

 描述：艾滋病毒感染与阿片类药物成瘾是一个新出现且日益严重的问题，部分原因是高效抗逆转录病毒治疗（HAART）延长了预期寿命，尽管抗逆转录病毒治疗（ART）有效并延长了寿命，但阿片类药物的使用会加剧艾滋病毒感染者的神经系统异常。我们的长期目标是改善或逆转药物成瘾的 HIV 感染者在接受 ART 后出现的神经异常。目的是验证和确定血管周围巨噬细胞（PVM）对 ART 后感染 SIV 的猕猴中枢神经系统病毒库的贡献，并测试阿片成瘾是否会改变免疫细胞亚群（包括 PVM）的功能，为病毒库提供燃料，我们的中心假设是，长寿命的 PVM 不仅是主要的 SIV 储存库，而且还影响中枢神经系统其他细胞亚群（如小胶质细胞和细胞）中病毒储存库的建立。为了测试这一点，我们提出体内长寿 PVM 的消耗将减少或消除病毒库，从而改善神经病理学和神经炎症的进展。吗啡依赖性 SIV 感染的猕猴表现出神经系统异常的恶化，这与 HIV 感染者和成瘾人类中观察到的情况类似，(ii) SIV 的储存位点可以与感染艾滋病毒的人类相比，在猕猴身上进行更详细、更受控的实验条件下的检查，并且（iii）我们建立了一个安全的方案来消除体内 PVM，这将使我们能够直接证明它们在病毒库中的作用 我们提出了本申请第一阶段 (R21) 的两个目标： 目标 1. 确定吗啡对接受 ART 的 SIV 感染的猕猴中 CNS 病毒库的大小和宿主细胞范围的影响。与对照组相比，接受吗啡治疗的 SIV 感染的猕猴在 PVM 中会形成更高的病毒库水平，并且单核细胞更新率更高（表明疾病进展）。目标 2：在接受抑制性 ART 的阿片类药物依赖性 SIV 感染的猕猴中，确定 PVM 对 CNS 病毒库的具体贡献。减少或消除接受抑制性 ART 的吗啡治疗的感染 SIV 的猕猴体内的脑病毒库 为了测试这一点，感染 SIV 的猕猴将在接受抑制性 ART 后开始 ART。然后，PVM 将通过鞘内脂质体双磷酸盐 (BP) 治疗选择性地耗尽，预计通过招募新鲜细胞来诱导重新增殖，这种方法也将揭示可能有助于 SIV 储存的其他细胞类型的数量。 ，例如小胶质细胞和星形胶质细胞，这些结果将证明吗啡治疗的 SIV 感染的恒河猴大脑中 SIV 储存库的细胞位点和大小。结果将为 PVM 的体内消耗及其对病毒库的贡献提供概念验证 导致测试针对 PVM 的治疗策略以减少疾病进展，这将为 II 期目标 3 (R33) 的研究奠定基础，以证实感染后早期针对 PVM 和 ART 是否会减少或改善中枢神经系统发病机制的恶化。目的 3. 确定 PVM 的早期体内消耗是否可以阻止阿片类药物依赖的神经病理进展。感染 SIV 的猕猴接受抑制性 ART，我们的工作假设是 PVM 作为 SIV 储存库和/或促进其他宿主细胞中储存库的发育，在此，我们将确定在开始 ART 后尽早体内消除 PVM 是否会控制或重新抑制 SIV。如果成功，这项研究将导致开发新的治疗策略，以有效地持续靶向大脑的 HIV 感染并逆转 HAND。发展。