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: 9243331
• 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 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9243331
• 关键词: Acquired Immunodeficiency Syndrome; Animal Model; Animals; Anti-HIV Agents; Anti-Retroviral 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; 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; Recruitment Activity; Regimen; Residual state; Rest; SIV; Saquinavir; Signal Transduction; Sum; Synaptophysin; Tenofovir; Testing; Therapeutic; Tissues; Viral; 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; 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）：抗逆转录病毒疗法（CART）的合并已大大改变了HIV流行，延迟了疾病和延长寿命。随着越来越重视从包括中枢神经系统在内的潜在储层中消除艾滋病毒的策略的发展，评估艾滋病毒潜伏期既定动物模型的治疗方法至关重要。为此，我们开发并表征了一种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无法检测到的水平。该模型的价值是：1） CD4+ T细胞和单核细胞/巨噬细胞被感染，2）包括脑部潜伏病毒DNA在内的组织，以及3）血液和淋巴组织中潜在感染的静息CD4+细胞的数量与CART上HIV感染的患者相当。尽管与未处理的SIV感染的猕猴相比，大脑中的SIV RNA大大降低了，但脑中的SIV DNA水平没有变化，炎症标记仍升高。总而言之，我们的研究表明，抑制CSF和血浆病毒载荷的CART并不针对CNS潜在DNA储量。 CCR5抑制剂是具有潜在有益CNS效应的抗HIV药物候选者。与其他类别的抗逆转录病毒相比，CCR5抑制剂MARAVIROC（MVC）具有高CNS渗透率（CPE = 1.0）和最小的神经毒性。尽管CNS中的R5效率HIV占主导地位，并且尽管CART进行了间歇性HIV复制，但MVC治疗仍可能持续在大脑中，因此MVC治疗可能阻止中枢神经系统中其他细胞的感染。 MVC还可能抑制大脑中常驻效应细胞的免疫激活，包括小胶质细胞和星形胶质细胞，并降低白细胞募集到中枢神经系统。我们小组的挑衅性SIV研究评估了CCR5抑制对SIV诱导的CNS损伤的影响。在感染SIV的恒河猕猴中，Maraviroc单一疗法显着降低了中枢神经系统SIV DNA水平，并降低了与用购物车治疗的动物形成鲜明对比的密钥中枢神经系统炎症反应。由于这些发现，该提案的重点是通过添加Maraviroc以消除病毒的目标来加强CART疗法的锯齿状猕猴。我们的假设是，在SIV感染的猕猴中添加CNS渗透剂CCR5抑制剂maraviroc将比单独单独添加到a）在大脑中减少病毒DNA储层的效率要多得多，而b）延迟撤回购物车后病毒重新激活。这些作用归因于MVC能够阻止中枢神经系统中新细胞靶标的感染并通过CCR5抑制促炎信号传导的能力。目的1是确定在巨噬细胞/小胶质细胞和静止的CD4+细胞中添加MVC是否会减少病毒DNA并损害潜在病毒的重新激活，以及静止的CD4+细胞，以及单核细胞/巨噬细胞中的单核细胞/巨噬细胞，以及siv感染的麦克风的血液。 AIM 2将比较CART+MVC与单独的CART方案的能力，以防止或延迟在停止治疗后，在SIV感染的猕猴中从中枢神经系统储层中延迟病毒的重新激活。 AIM 3是确定停止CART抑制CNS储层或外围储层中病毒重新激活的MVC治疗是否继续进行。