Compartmentalized HIV rebound in the central nervous system after interruption of antiretroviral therapy
Compartmentalized HIV rebound in the central nervous system after interruption of antiretroviral therapy
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DOI：
10.1093/ve/vew020
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发表时间：
2016-07-01
期刊：
影响因子：
5.3
通讯作者：
Ellis, Ronald J.
中科院分区：
文献类型：
--
作者：
Gianella, Sara;Pond, Sergei L. Kosakovsky;Ellis, Ronald J.
为了设计有效的根除策略，可能有必要针对血液以外的解剖隔室中的HIV储库。本研究检测了中断抗逆转录病毒治疗（ART）后血液和脑脊液（CSF）中HIV RNA的反弹，以确定中枢神经系统（CNS）是否可能作为病毒复制恢复的独立来源。使用Roche 454 FLX Titanium平台对血液和CSF中的无细胞HIV RNA和细胞相关HIV DNA进行HIV env（C2-V3）、gag（p24）和pol（逆转录酶）测序。进行了全面的序列和系统发育分析，以寻找证据的独特或差异代表的病毒亚群出现在CSF上清液中相比，blood plasma.Using一个保守的定义划分的基础上四个不同的统计检验，9名参与者提出了一个划分的HIV RNA反弹后，中断抗逆转录病毒治疗的CSF内，即使在2周内从病毒反弹采样。病毒区室化的程度和持续时间在受试者之间和受试者内的时间点之间变化很大。在10例病例中，我们在ART中断后的第一个采样时间点鉴定了CSF上清液中的病毒群，这些病毒群在遗传学上与配对血浆中存在的病毒群不同，并且大多数病毒群随时间持续存在（当纵向时间点可用时）。我们的数据表明，HIV RNA的独立来源有助于治疗中断后CSF内的病毒反弹。区室化的HIV RNA最可能的来源是CNS储库，需要靶向该储库以实现完全的HIV根除。
To design effective eradication strategies, it may be necessary to target HIV reservoirs in anatomic compartments other than blood. This study examined HIV RNA rebound following interruption of antiretroviral therapy (ART) in blood and cerebrospinal fluid (CSF) to determine whether the central nervous system (CNS) might serve as an independent source of resurgent viral replication.Paired blood and CSF samples were collected longitudinally from 14 chronically HIV-infected individuals undergoing ART interruption. HIV env (C2-V3), gag (p24) and pol (reverse transcriptase) were sequenced from cell-free HIV RNA and cell-associated HIV DNA in blood and CSF using the Roche 454 FLX Titanium platform. Comprehensive sequence and phylogenetic analyses were performed to search for evidence of unique or differentially represented viral subpopulations emerging in CSF supernatant as compared with blood plasma.Using a conservative definition of compartmentalization based on four distinct statistical tests, nine participants presented a compartmentalized HIV RNA rebound within the CSF after interruption of ART, even when sampled within 2 weeks from viral rebound. The degree and duration of viral compartmentalization varied considerably between subjects and between time-points within a subject. In 10 cases, we identified viral populations within the CSF supernatant at the first sampled time-point after ART interruption, which were phylogenetically distinct from those present in the paired blood plasma and mostly persisted over time (when longitudinal time-points were available). Our data suggest that an independent source of HIV RNA contributes to viral rebound within the CSF after treatment interruption. The most likely source of compartmentalized HIV RNA is a CNS reservoir that would need to be targeted to achieve complete HIV eradication.