Compartmentalized CSF viral escape and the CNS HIV reservoir

 描述(申请人提供)：中枢神经系统(CNS)HIV病毒宿主是HIV治愈的潜在障碍，尽管接受治疗，但可能在神经认知障碍的进展中发挥作用，并可罕见地爆发为更严重的脑炎。这项提议的重点是这个储存库及其从抗逆转录病毒疗法(ART)诱导的复制抑制中的“释放”。利用在三个信息丰富的临床环境中获得的存档和预期收集的样本，脑脊液(CSF)和血液中的种群将通过深度测序或单基因组扩增包膜(Env)和LTR调节基因及其系统发育分析来表征，并将从巨噬细胞和淋巴细胞的趋向性和巨噬细胞的复制能力方面评估这些基因的功能影响。艾滋病毒感染的这些主要生物学特征将确定“逃脱”的脑脊液艾滋病毒与中枢神经系统储存的艾滋病毒的来源和关系，并追踪其释放、扩展和与系统感染产生的艾滋病毒的混合。每个目标侧重于不同的受试组：目标1针对停止抗逆转录病毒疗法的个人；目标2针对尽管抗逆转录病毒治疗控制了全身感染的艾滋病毒脑炎患者；以及目标3关于队列研究中偶然发现的低水平无症状脑脊液艾滋病毒逃逸。这些研究将共同提供宿主及其释放的综合图景，并提供关键的洞察力，了解艾滋病毒的特征和细胞来源，它在ART的背景下持续存在于中枢神经系统，并在ART不再控制复制时重新融合。这一结果将为预防、改善或清除中枢神经系统内的这些储存库提供策略，最终实现无ART生存，而不会出现艾滋病毒相关的神经退化。

 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.