Eradicating Latent SIV from the CNS by CCR5 Inhibition

通过 CCR5 抑制消除 CNS 中潜在的 SIV

• 批准号: 9412921
• 负责人: JOSEPH L MANKOWSKI
• 金额: $ 74.09万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-15 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9412921
• 关键词: Acquired Immunodeficiency Syndrome; Animal Model; Animals; Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Astrocytes; Atazanavir; Blood; Brain; CCR5 gene; CD4 Positive T Lymphocytes; Cells; Cerebrospinal Fluid; Chemotaxis; Cognitive; DNA; Dementia; Development; Disease; Disease Progression; Effector Cell; Epidemic; Goals; HIV; HIV-associated neurocognitive disorder; Human; Impairment; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Integrase Inhibitors; Latent Virus; Leukocytes; Life; Lymphoid Tissue; Macaca; Macaca mulatta; Macaca nemestrina; Manuscripts; Mediating; Microglia; Modeling; Nervous system structure; Outcome; Patients; Penetrance; Peripheral; Pharmaceutical Preparations; Plasma; RNA; Recovery; Regimen; Residual state; Rest; SIV; Saquinavir; Signal Transduction; Sum; Synaptophysin; Tenofovir; Testing; Therapeutic; Tissues; Viral Load result; Viral reservoir; Virus; Virus Latency; Virus Replication; Withdrawal; analog; antiretroviral therapy; brain tissue; calmodulin-dependent protein kinase II; cellular targeting; drug candidate; immune activation; immunoregulation; inflammatory marker; inhibitor/antagonist; macrophage; monocyte; motor disorder; neurotoxicity; peripheral blood; pinacolyl methylphosphonic acid; prevent; public health relevance; reactivation from latency; recruit; response; viral DNA

DESCRIPTION (provided by applicant): Combined antiretroviral therapy (cART) has dramatically changed the HIV epidemic, delaying disease and prolonging life. With increasing emphasis on development of strategies to eradicate HIV from latent reservoirs including the CNS, it is critical to evaluate therapeutic approaches in established animal models of HIV latency. To do so, we developed and characterized a SIV model of cART that reduced viral load in peripheral blood and cerebrospinal fluid to undetectable levels. The value of this model is : 1) CD4+ T cells and monocyte/ macrophages are infected, 2) tissues including the brain harbor latent viral DNA, and 3) the number of latently infected resting CD4+ cells in the blood and lymphoid tissues is comparable to that in HIV-infected patients on cART. While SIV RNA in brain was dramatically reduced by cART, SIV DNA levels in brain were unchanged compared to untreated SIV-infected macaques and inflammatory markers remained elevated. In sum, our studies illustrate that cART that suppresses CSF and plasma viral load does not target the CNS latent DNA reservoir. CCR5 inhibitors are promising anti-HIV drug candidates with potential beneficial CNS effects. The CCR5 inhibitor maraviroc (MVC) has high CNS penetrance (CPE = 1.0) and minimal neurotoxicity in comparison with other classes of antiretrovirals. As R5-tropic HIV predominates in the CNS and intermittent HIV replication may persist in the brain despite cART, MVC treatment could block infection of additional cells in the CNS. MVC also may dampen immune activation of resident effector cells in the brain, including microglia and astrocytes, and decrease recruitment of leukocytes to the CNS. Provocative SIV studies by our group evaluated the impact of CCR5 inhibition on SIV-induced CNS damage. In SIV-infected rhesus macaques, maraviroc monotherapy significantly reduced CNS SIV DNA levels and lowered key CNS inflammatory responses in sharp contrast with animals treated with cART. Because of these findings, this proposal focuses on intensification of cART therapy in SIV-infected pigtailed macaques by adding maraviroc with the goal of virus eradication. Our hypothesis is that adding the CNS penetrant CCR5 inhibitor maraviroc to cART in SIV- infected macaques will be much more effective than cART alone in A) reducing viral DNA reservoirs in brain and B) delaying virus reactivation upon withdrawal of cART. These effects are attributable to MVC's ability to both block infection of new cellular targets in the CNS and inhibit pro-inflammatory signaling through CCR5. Aim 1 is to determine whether adding MVC to cART reduces viral DNA and impairs reactivation of latent virus in macrophages/ microglia and astrocytes in the CNS and resting CD4+ cells and monocyte/macrophages in peripheral tissues and blood of SIV-infected macaques. Aim 2 will compare the ability of cART+MVC versus cART alone regimens to prevent or delay reactivation of virus from the CNS reservoir in SIV-infected macaques after cessation of therapy. Aim 3 is to determine whether continuing MVC therapy after stopping cART suppresses reactivation of virus from the CNS reservoir or peripheral reservoirs.

描述（由申请人提供）：联合抗逆转录病毒疗法（cART）极大地改变了艾滋病毒的流行，延缓了疾病的发生，延长了生命。随着越来越重视从潜伏宿主（包括CNS）中根除HIV的策略的发展，在已建立的HIV潜伏期动物模型中评价治疗方法至关重要。为此，我们开发并表征了cART的SIV模型，该模型将外周血和脑脊液中的病毒载量降低至不可检测的水平。该模型的价值在于：1） CD 4 + T细胞和单核细胞/巨噬细胞被感染，2）包括脑在内的组织含有潜伏病毒DNA，3）血液和淋巴组织中潜伏感染的静息CD 4+细胞数量与接受cART的HIV感染患者相当。虽然脑中的SIV RNA通过cART显著降低，但与未经治疗的SIV感染的猕猴相比，脑中的SIV DNA水平没有变化，并且炎症标志物仍然升高。总之，我们的研究表明，抑制CSF和血浆病毒载量的cART不靶向CNS潜伏DNA库。CCR 5抑制剂是具有潜在有益CNS作用的有希望的抗HIV候选药物。与其他类型的抗逆转录病毒药物相比，CCR 5抑制剂马拉韦罗（MVC）具有较高的CNS抑制率（CPE = 1.0）和最小的神经毒性。由于R5嗜性HIV在CNS中占主导地位，尽管有cART，但间歇性HIV复制可能在脑中持续存在，因此MVC治疗可以阻断CNS中其他细胞的感染。MVC还可以抑制脑中常驻效应细胞（包括小胶质细胞和星形胶质细胞）的免疫活化，并减少白细胞向CNS的募集。本研究组的SIV研究评估了CCR 5抑制对SIV诱导的CNS损伤的影响。在SIV感染的恒河猴中，马拉韦罗单药治疗显著降低了CNS SIV DNA水平，并降低了关键的CNS炎症反应，与cART治疗的动物形成鲜明对比。由于这些发现，该提案的重点是通过添加马拉韦罗来加强SIV感染的猪尾猕猴的cART治疗，目的是根除病毒。我们的假设是在SIV感染的猕猴中将CNS渗透剂CCR 5抑制剂马拉韦罗加入cART中将比单独的cART在A）减少脑中的病毒DNA储库和B）延迟cART停药后的病毒再活化方面有效得多。这些作用归因于MVC阻断CNS中新细胞靶标感染和抑制通过CCR 5的促炎信号传导的能力。目的1是确定在cART中加入MVC是否减少病毒DNA并损害CNS中巨噬细胞/小胶质细胞和星形胶质细胞以及SIV感染猕猴外周组织和血液中静息CD 4+细胞和单核细胞/巨噬细胞中潜伏病毒的再活化。目的2将比较cART+MVC与单独cART方案在停止治疗后预防或延迟SIV感染猕猴CNS储库中病毒再活化的能力。目的3是确定在停止cART后继续MVC治疗是否抑制来自CNS储库或外周储库的病毒再活化。