Therapeutic Interventions during Acute Infection to Address the CNS Reservoir for

描述(申请人提供)：艾滋病毒的中枢神经系统(CNS)感染是在感染过程的早期建立的，在急性艾滋病毒感染阶段(抗体血清转换之前)进行干预提供了防止艾滋病毒在中枢神经系统建立的最佳机会。在这里，我们利用已建立的基础设施，在曼谷的一个独特的急性艾滋病毒感染受试者队列中进行密集的中枢神经系统研究，作为正在进行的美国军方资助的RV254研究的一部分。我们提出了两种不同的随机干预策略，除了在急性HIV感染的早期阶段建立的抗逆转录病毒治疗(ART)之外。第一项研究将采用即刻辅助替米沙坦疗法(一种抗纤维化/抗炎的血管紧张素II受体阻滞剂)，以减少HIV相关的炎症和中枢神经系统储存库的建立。我们假设，在急性感染期间，与单独使用ART相比，替米沙坦治疗将减少全身免疫激活以及活化和HIV感染细胞向中枢神经系统的运输，限制了中枢神经系统艾滋病毒储备库的建立和持续。第二项研究将评估延迟辅助性罗米非辛(一种组蛋白去乙酰化酶抑制剂)治疗对激活和杀死全身潜伏的HIV感染细胞的中枢神经系统的影响。我们推测，虽然罗米非辛具有激活潜伏的HIV和清除全身储存库的假定作用，但由于罗米地平对中枢神经系统的渗透率较低，罗米地平与ART的安慰剂相比，对中枢神经系统储存库的影响有限。最后，我们将评估早期中枢神经系统对艾滋病毒种类的划分，以及在罗米非辛研究中使用超深测序比较ART之前和ART中断后血液和脑脊液(CSF)变体后在中枢神经系统中检测到的反弹HIV的来源。每项研究中的21名受试者将以2：1的比例随机分为干预组和非干预组，并跟踪观察1.5年。将进行仔细的神经心理测试，并收集血液、脑脊液样本以及磁共振成像和光谱分析，以询问大脑功能和炎症情况。这些数据将极大地促进我们对艾滋病毒在中枢神经系统的持久性和炎症的理解。所获得的知识将对全世界4000万艾滋病毒携带者至关重要，为旨在根除艾滋病毒和预防中枢神经系统炎症的新战略提供信息。

DESCRIPTION (provided by applicant): Central nervous system (CNS) infection of HIV is established early in the course of infection and intervention during the phase of acute HIV infection (prior to antibody seroconversion) provides the best opportunity to prevent the establishment of HIV reservoirs in the CNS. Here we capitalize on an established infrastructure for intensive CNS studies in a unique cohort of acute HIV infection subjects in Bangkok enrolled as part of the ongoing US Military-funded RV254 study. We propose two distinct randomized intervention strategies given in addition to antiretroviral therapy (ART) instituted during the earliest stages of acute HIV infection. The first study will employ immediate adjunctive telmisartan therapy (an antifibrotic/anti-inflammatory angiotensin II receptor blocker) to reduce HIV-associated inflammation and reservoir establishment in the CNS. We hypothesize that telmisartan therapy with ART versus ART alone during acute infection will reduce systemic immune activation and trafficking of activated and HIV-infected cells to the CNS, limiting establishment and persistence of the CNS reservoir of HIV. The second study will assess the CNS effect of delayed adjunctive romidepsin (a histone deacetylase inhibitor) therapy given to activate and kill systemic latently HIV-infected cells. We hypothesize that while romidepsin has a postulated effect of activating latent HIV and purging systemic reservoirs, due to low CNS penetration of romidepsin, romidepsin with ART versus placebo with ART will have limited effect on the CNS reservoir. Finally, we will assess early CNS compartmentalization of HIV species as well as the source of rebound HIV detected in the CNS after interruption of ART in the romidepsin study using ultra-deep sequencing to compare blood and cerebrospinal fluid (CSF) variants prior to ART and after ART interruption. Twenty-one subjects in each study will be randomized 2:1 to intervention versus no intervention and followed for 1.5 years. Careful neuropsychological testing will be performed, and blood, CSF samples and magnetic resonance imaging and spectroscopy will be collected to interrogate brain function and inflammation. These data will significantly advance our understanding of HIV persistence and inflammation in the CNS. The knowledge gained will be critically relevant to the 40 million people worldwide living with HIV, informing novel strategies aimed at viral eradication of HIV and prevention of inflammation in the CNS.