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.

 产品说明：艾滋病毒感染与阿片类药物成瘾是一个新出现的日益严重的问题，部分原因是高效抗逆转录病毒疗法延长了预期寿命。尽管有效的抗逆转录病毒治疗（ART）和延长寿命，阿片类药物的使用加剧了艾滋病毒感染患者的神经异常。 我们的长期目标是改善或逆转尽管ART在吸毒成瘾的HIV感染者中出现的神经异常的发展。该R21/R33提案的目的是验证和确定血管周围巨噬细胞（PVM）对ART后SIV感染猕猴CNS中病毒储库的贡献，并测试阿片类药物成瘾是否改变免疫细胞亚群（包括PVM）的功能，以刺激病毒储库并加剧SIV感染的发病机制。我们的中心假设是，长寿命PVM不仅作为主要的SIV水库，但也影响建立病毒水库在其他细胞亚群的中枢神经系统，如小胶质细胞和星形胶质细胞在阿片类药物成瘾的猕猴。为了测试这一点，我们提出，在体内消耗的长寿PVM将减少或消除病毒水库，从而改善神经病理学和神经炎症的进展。我们的假设的基本原理是，（i）吗啡依赖性SIV感染的猕猴显示出在HIV感染和成瘾的人中平行观察到的神经异常的恶化，（ii）与HIV感染的人相比，在猕猴中可以更详细地和在更受控的实验条件下检查SIV的储库部位，以及（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储存库中的作用 和神经发病机制。我们在本申请的第一阶段（R21）提出了两个目标：目标1。确定吗啡对接受ART的SIV感染的猕猴中CNS病毒储库的大小和宿主细胞范围的影响。我们的工作假设是，在ART治疗开始时，吗啡治疗的SIV感染的猕猴将在PVM中产生更高的病毒储库水平和更高的单核细胞更新（指示疾病进展）。目标2.定义PVM对接受抑制性ART的阿片依赖性SIV感染猕猴的CNS病毒库的具体贡献。我们的工作假设是，体内PVM的消耗将减少或消除接受抑制性ART的吗啡治疗的SIV感染猕猴的脑病毒库。为了测试这一点，SIV感染猕猴将在达到病毒设定点后开始ART。然后，PVM将通过鞘内脂质体双膦酸盐（BP）治疗选择性耗尽，预期通过招募新鲜细胞诱导再增殖。这种方法还将揭示可能有助于SIV储库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处理的SIV感染恒河猴脑中SIV储库的细胞位点和大小。具体而言，这些结果将为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（R33）目标3的研究奠定基础，以证实感染后早期靶向PVM和ART是否会减少或改善吗啡治疗的SIV感染猕猴中CNS发病机制的恶化。目标3.确定是否在体内PVM的早期消耗，防止阿片类药物依赖性SIV感染的猕猴进行抑制性ART的神经病变进展。我们的工作假设是，PVM作为SIV水库和/或促进其他宿主细胞水库的发展。在此，我们将确定在开始ART后早期体内PVM的消除是否会控制或减少慢性吗啡治疗的SIV感染猕猴的CNS发病机制的进展。如果成功，这项研究将导致开发新的治疗策略，以有效地针对大脑的持续HIV感染和逆转HAND发育。