Therapeutic Interventions during Acute Infection to Address the CNS Reservoir for

描述（由申请方提供）：HIV的中枢神经系统（CNS）感染在感染过程的早期建立，在急性HIV感染阶段（抗体血清转换前）进行干预为预防CNS中HIV储库的建立提供了最佳机会。在这里，我们利用一个既定的基础设施，在曼谷的一个独特的急性HIV感染受试者队列中进行密集的CNS研究，这些受试者是正在进行的美国军方资助的RV 254研究的一部分。我们提出了两种不同的随机干预策略，除了抗逆转录病毒治疗（ART）在急性HIV感染的最早阶段制定。第一项研究将采用立即预防性替米沙坦治疗（一种抗纤维化/抗炎血管紧张素II受体阻滞剂），以减少CNS中HIV相关炎症和储库建立。我们假设，在急性感染期间，替米沙坦联合ART治疗与单独ART治疗相比，将减少全身免疫激活以及活化和HIV感染细胞向CNS的运输，限制HIV CNS储库的建立和持续。第二项研究将评估用于激活和杀死全身潜伏性HIV感染细胞的延迟性罗米地辛（一种组蛋白去乙酰化酶抑制剂）治疗的CNS效应。我们假设，虽然罗米地辛具有激活潜伏HIV和清除全身储库的假定作用，但由于罗米地辛的CNS渗透性低，罗米地辛与ART相比安慰剂与ART对CNS储库的作用有限。最后，我们将评估HIV种类的早期CNS区室化以及在romidepsin研究中ART中断后CNS中检测到的HIV反弹的来源，使用超深度测序比较ART之前和ART中断之后的血液和脑脊液（CSF）变体。每项研究中的21例受试者将以2：1的比例随机分配至干预组和无干预组，并随访1.5年。将进行仔细的神经心理学测试，并收集血液，CSF样本和磁共振成像和光谱学，以询问脑功能和炎症。这些数据将大大促进我们对HIV在CNS中的持续存在和炎症的理解。所获得的知识将与全球4000万艾滋病毒感染者密切相关，为旨在根除艾滋病毒和预防中枢神经系统炎症的新策略提供信息。

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.