PDF(Pubmed)
Abstract：
The rebound competent viral reservoir (RCVR)-virus that persists during antiretroviral treatment (ART) and can reignite systemic infection when treatment is stopped-is the primary barrier to eradicating HIV. We used time to initiation of ART during primary infection of rhesus macaques (RMs) after intravenous challenge with barcoded SIVmac239 as a means to elucidate the dynamics of RCVR establishment in groups of RMs by creating a multi-log range of pre-ART viral loads and then assessed viral time-to-rebound and reactivation rates resulting from the discontinuation of ART after one year. RMs started on ART on days 3, 4, 5, 6, 7, 9 or 12 post-infection showed a nearly 10-fold difference in pre-ART viral measurements for successive ART-initiation timepoints. Only 1 of 8 RMs initiating ART on days 3 and 4 rebounded after ART interruption despite measurable pre-ART plasma viremia. Rebounding plasma from the 1 rebounding RM contained only a single barcode lineage detected at day 50 post-ART. All RMs starting ART on days 5 and 6 rebounded between 14- and 50-days post-ART with 1-2 rebounding variants each. RMs starting ART on days 7, 9, and 12 had similar time-to-measurable plasma rebound kinetics despite multiple log differences in pre-ART plasma viral load (pVL), with all RMs rebounding between 7- and 16-days post-ART with 3-28 rebounding lineages. Calculated reactivation rates per pre-ART pVL were highest for RMs starting ART on days 5, 6, and 7 after which the rate of accumulation of the RCVR markedly decreased for RMs treated on days 9 and 12, consistent with multiphasic establishment and near saturation of the RCVR within 2 weeks post infection. Taken together, these data highlight the heterogeneity of the RCVR between RMs, the stochastic establishment of the very early RCVR, and the saturability of the RCVR prior to peak viral infection.
摘要：
反弹型病毒库(RCVR)-在抗逆转录病毒治疗(ART)期间持续存在并且在治疗停止时可以重新引发全身感染-是根除HIV的主要障碍。我们使用条形码SIVmac239静脉攻击后的恒河猴（RM）初次感染期间开始ART的时间，通过创建多对数范围的ART前病毒载量来阐明RM组中RCVR建立的动态，然后评估一年后因ART停药而导致的病毒反弹时间和再激活率。在感染后第3、4、5、6、7、9或12天开始于ART的RM在连续ART起始时间点的ART前病毒测量中显示近10倍差异。尽管可测量的ART前血浆病毒血症，但在ART中断后第3天和第4天开始ART的8个RM中只有1个反弹。来自1个反弹RM的反弹血浆仅含有在ART后第50天检测到的单个条形码谱系。在第5天和第6天开始ART的所有RM在ART后14天和50天之间反弹，每个反弹变体为1-2。尽管ART前血浆病毒载量（pVL）存在多个对数差异，但在第7、9和12天开始ART的RM具有相似的可测量血浆反弹动力学时间。所有RM在ART后7至16天之间反弹，反弹谱系为3-28。在第5、6和7天开始ART的RM计算的每个ART前pVL的再激活率最高，之后在第9和12天治疗的RM的RCVR积累率明显下降，这与多相建立和接近饱和一致感染后2周内RCVR。一起来看,这些数据凸显了RM之间RCVR的异质性，早期RCVR的随机建立，和RCVR在病毒感染高峰之前的饱和度。
