Compartmentalized Replication of R5 T Cell-Tropic HIV-1 in the Central Nervous System Early in the Course of Infection

Compartmentalized HIV-1 replication within the central nervous system (CNS) likely provides a foundation for neurocognitive impairment and a potentially important tissue reservoir. The timing of emergence and character of this local CNS replication has not been defined in a population of subjects. We examined the frequency of elevated cerebrospinal fluid (CSF) HIV-1 RNA concentration, the nature of CSF viral populations compared to the blood, and the presence of a cellular inflammatory response (with the potential to bring infected cells into the CNS) using paired CSF and blood samples obtained over the first two years of infection from 72 ART-naïve subjects. Using single genome amplification (SGA) and phylodynamics analysis of full-length env sequences, we compared CSF and blood viral populations in 33 of the 72 subjects. Independent HIV-1 replication in the CNS (compartmentalization) was detected in 20% of sample pairs analyzed by SGA, or 7% of all sample pairs, and was exclusively observed after four months of infection. In subjects with longitudinal sampling, 30% showed evidence of CNS viral replication or pleocytosis/inflammation in at least one time point, and in approximately 16% of subjects we observed evolving CSF/CNS compartmentalized viral replication and/or a marked CSF inflammatory response at multiple time points suggesting an ongoing or recurrent impact of the infection in the CNS. Two subjects had one of two transmitted lineages (or their recombinant) largely sequestered within the CNS shortly after transmission, indicating an additional mechanism for establishing early CNS replication. Transmitted variants were R5 T cell-tropic. Overall, examination of the relationships between CSF viral populations, blood and CSF HIV-1 RNA concentrations, and inflammatory responses suggested four distinct states of viral population dynamics, with associated mechanisms of local viral replication and the early influx of virus into the CNS. This study considerably enhances the generalizability of our results and greatly expands our knowledge of the early interactions of HIV-1 in the CNS.人类免疫缺陷病毒1型（HIV-1）在中枢神经系统（CNS）内的区域化复制，可能是神经认知功能障碍的发病基础，同时也是一处具有重要研究价值的组织病毒储存库。目前学界尚未在受试者队列中明确该中枢神经系统局部复制的出现时机与特征。本研究纳入72例未接受抗逆转录病毒治疗（ART）的受试者，采集其感染最初两年内的配对脑脊液（CSF）与血液样本，以此分析脑脊液中HIV-1 RNA浓度升高的发生频率、脑脊液病毒群体与血液病毒群体的差异特征，以及细胞炎症反应（该反应可能促使受感染细胞迁移至中枢神经系统）的存在情况。本研究针对72例受试者中的33例，采用单基因组扩增（SGA）技术与全长env基因序列系统动力学分析方法，对比其脑脊液与血液的病毒群体特征。经单基因组扩增分析的样本对中，有20%可检测到中枢神经系统内独立的HIV-1复制（即区域化），占全部样本对的7%，且该现象仅在感染4个月后被观察到。在接受纵向采样的受试者中，30%至少在一个时间点出现中枢神经系统病毒复制或脑脊液细胞增多/炎症反应的证据；约16%的受试者在多个时间点观察到脑脊液/中枢神经系统区域化病毒复制的动态变化，以及显著的脑脊液炎症反应，提示感染对中枢神经系统存在持续或复发性影响。有2例受试者在感染早期即存在两种传播谱系（或其重组体）之一大量隔离于中枢神经系统内的情况，这提示了早期中枢神经系统复制建立的另一潜在机制。传播的病毒变体均为R5嗜T细胞型。综合而言，通过对脑脊液病毒群体、血液与脑脊液HIV-1 RNA浓度及炎症反应之间关联的分析，本研究揭示了病毒群体动态变化的四种不同状态，并阐明了局部病毒复制与病毒早期侵入中枢神经系统的相关机制。本研究大幅提升了研究结果的外推性，极大拓展了我们对HIV-1在中枢神经系统内早期相互作用的认知。