Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, 19104, PA, USA.
Department of Molecular Biosciences, Northwestern University, Evanston, 60201, IL, USA.
Nat Commun. 2019 Feb 13;10(1):728. doi: 10.1038/s41467-019-08431-7.
After initiating antiretroviral therapy (ART), a rapid decline in HIV viral load is followed by a long period of undetectable viremia. Viral outgrowth assay suggests the reservoir continues to decline slowly. Here, we use full-length sequencing to longitudinally study the proviral landscape of four subjects on ART to investigate the selective pressures influencing the dynamics of the treatment-resistant HIV reservoir. We find intact and defective proviruses that contain genetic elements favoring efficient protein expression decrease over time. Moreover, proviruses that lack these genetic elements, yet contain strong donor splice sequences, increase relatively to other defective proviruses, especially among clones. Our work suggests that HIV expression occurs to a significant extent during ART and results in HIV clearance, but this is obscured by the expansion of proviral clones. Paradoxically, clonal expansion may also be enhanced by HIV expression that leads to splicing between HIV donor splice sites and downstream human exons.
启动抗逆转录病毒疗法（ART）后，HIV 病毒载量会迅速下降，随后是很长一段时间的不可检测到的病毒血症。病毒生长测定表明，储存库仍在缓慢下降。在这里，我们使用全长测序技术对接受 ART 的四位受试者的前病毒景观进行纵向研究，以调查影响治疗耐药性 HIV 储存库动态的选择压力。我们发现，随着时间的推移，有利于高效蛋白表达的完整和缺陷前病毒逐渐减少。此外，缺乏这些遗传元件但含有强供体位点拼接序列的前病毒相对其他缺陷前病毒增加，尤其是在克隆中。我们的工作表明，在 ART 期间 HIV 表达发生的程度很大，导致 HIV 清除，但这被前病毒克隆的扩增所掩盖。矛盾的是，HIV 表达也可能通过导致 HIV 供体位点和下游人类外显子之间的拼接来增强克隆扩增。
