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：艾滋病毒感染与有效的药物相结合是一个新兴和增长的问题，部分原因是Haart提供了更长的预期寿命。尽管有效的抗逆转录病毒疗法（ART）和延长寿命，但优化使用HIV感染患者的神经系统异常。我们的长期目标是改善或逆转神经系统异常的发展，这些神经系统异常是在药物吸引的HIV感染者中出现的。 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 expanding addiction modifiers the function of immune cell subsets, including PVM, to fuel the virus reservoir and exacerbate pathogenesis of SIV infection.我们的中心假设是，长期寿命的PVM不仅是主要的SIV储层，而且还会影响其他中枢神经系统中其他细胞中的病毒储层的建立，例如小胶质细胞和阿片类药物成型猕猴。为了测试这一点，我们建议长寿命PVM的体内耗竭将减少或消除病毒储量，从而改善神经病理学和神经炎症的进展。 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消除体内PVM，这将使我们能够直接证明其在病毒储层中的作用 和神经病发生。我们在此应用的I阶段（R21）中提出了两个目标：AIM 1。确定吗啡对CNS病毒储层的大小和宿主细胞范围的影响，在SIV感染的猕猴中正在进行ART中。我们的工作假设是，在ART治疗的倡议中，与吗啡治疗的SIV感染的猕猴在PVM中的病毒储层水平更高，单核细胞更新（指示疾病进展）更高的单核细胞更新（指示疾病进展）。目标2。定义PVM对阿片类药物依赖性SIV感染的猕猴的特定贡献。我们的工作假设是，PVM的体内耗竭将减少或消除由吗啡处理的SIV感染的猕猴中的脑病毒储存剂，接受抑制作用。为了测试这一点，SIV感染的猕猴将在达到病毒设定点后开始艺术。然后，PVM将通过鞘内脂质体双膦酸盐（BP）治疗选择性地耗尽，该处理有望通过募集新鲜细胞来诱导重生。这种方法还将揭示可能导致SIV储层的其他细胞类型的大小，例如小胶质细胞和星形胶质细胞。这些结果将证明细胞部位和SIV储存量的大脑中的细胞位点和大脑中的SIV感染的恒河猕猴。具体而言，结果将为PVM的体内耗竭及其对病毒储层的贡献提供概念证明 导致测试针对PVM的治疗策略，以减少疾病进展。如果在感染和ART后较早针对PVM靶向PVM，这将为核对II阶段的AIM 3奠定基础。目标3。确定PVM的体内耗竭早期是否可以防止阿片类药物依赖性SIV感染的猕猴的神经病变的进展。我们的工作假设是PVM充当SIV储层和/或促进其他宿主细胞中储层的发展。在这里，我们将确定启动ART后早期消除PVM是否会控制或重新减少通过慢性吗啡治疗的SIV感染猕猴中CNS发病机理的进展。如果成功，这项研究将导致开发新型的治疗策略，以有效地靶向大脑的持续性HIV感染并反向手部发育。