Compartmentalized CSF viral escape and the CNS HIV reservoir

 描述（由申请人提供）：中枢神经系统（CNS）HIV储库对HIV治愈存在潜在障碍，尽管接受治疗，但可能在神经认知障碍进展中发挥作用，并且可能罕见地爆发为更严重的脑炎。这项建议的重点是这个水库和它的'释放'从抗逆转录病毒治疗（ART）诱导的复制抑制。使用在三种信息丰富的临床环境中获得的存档和前瞻性收集的样本，将通过包膜（env）和LTR调节基因的深度测序或单基因组扩增及其系统发育分析来表征脑脊液（CSF）和血液中的群体，并将评估这些基因对巨噬细胞和淋巴细胞嗜性以及巨噬细胞复制能力的功能影响。HIV感染的这些中心生物学特征将确定“逃逸的”CSF HIV与CNS储库的起源和关系，并追踪其释放、扩增和与源自全身感染的HIV混合。每个目标侧重于不同的受试者组：目标1针对停止ART的个体;目标2针对尽管ART控制了全身感染但仍患有HIV脑炎的患者;目标3针对队列研究中偶然发现的低水平无症状CSF HIV逃逸。总之，这些研究将提供一个水库及其释放的综合图片，并提供关键的洞察艾滋病毒的特征和细胞起源，坚持在中枢神经系统的ART设置和重新合并时，ART不再控制复制。这些结果将为预防、改善或清除CNS内这些储库的策略提供信息，从而最终实现无ART生存，而不会发生HIV相关的神经变性。

 DESCRIPTION (provided by applicant): The central nervous system (CNS) HIV reservoir presents a potential impediment to HIV cure, may play a role in progression of neurocognitive impairment despite treatment, and can uncommonly erupt into more severe encephalitis. This proposal focuses on this reservoir and its 'release' from antiretroviral therapy (ART)-induced inhibition of replication. Using archived and prospectively collected samples obtained in three informative clinical settings, populations in cerebrospinal fluid (CSF) and blood will be characterized by deep sequencing or single genome amplification of envelope (env) and LTR regulatory genes and their phylogenetic analysis, and the functional impact of these genes will be assessed with respect to macrophage and lymphocyte tropism and replication capacity in macrophages. These central biological features of HIV infection will define the origin and relationships of 'escaped' CSF HIV to the CNS reservoir and trace its release, expansion and intermingling with HIV derived from systemic infection. Each aim focuses on a different subject group: Aim 1 on individuals stopping ART; Aim 2 on patients with HIV encephalitis despite ART control of systemic infection; and Aim 3 on low-level asymptomatic CSF HIV escape found incidentally in cohort studies. Together these studies will provide a composite picture of the reservoir and its release, and provide critical insight into the characteristics and cellular origi of HIV that persists in the CNS in the setting of ART and remerges when ART no longer controls replication. The results will inform strategies to prevent, ameliorate or purge these reservoirs within the CNS, allowing eventual ART-free survival without HIV-related neurodegeneration.