Emory Vaccine Center, Emory University, Atlanta, Georgia, United States of America.
British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada.
PLoS Pathog. 2020 Jun 3;16(6):e1008378. doi: 10.1371/journal.ppat.1008378. eCollection 2020 Jun.
The HIV-1 reservoir consists of latently infected cells that persist despite antiretroviral therapy (ART). Elucidating the proviral genetic composition of the reservoir, particularly in the context of pre-therapy viral diversity, is therefore important to understanding reservoir formation and the persistence of latently infected cells. Here we investigate reservoir proviral variants from 13 Zambian acutely-infected individuals with additional pre-therapy sampling for a unique comparison to the ART-naïve quasispecies. We identified complete transmitted/founder (TF) viruses from seroconversion plasma samples, and additionally amplified and sequenced HIV-1 from plasma obtained one year post-infection and just prior to ART initiation. While the majority of proviral variants in the reservoir were most closely related to viral variants from the latest pre-therapy time point, we also identified reservoir proviral variants dating to or near the time of infection, and to intermediate time points between infection and treatment initiation. Reservoir proviral variants differing by five or fewer nucleotide changes from the TF virus persisted during treatment in five individuals, including proviral variants that exactly matched the TF in two individuals, one of whom had remained ART-naïve for more than six years. Proviral variants during treatment were significantly less divergent from the TF virus than plasma variants present at the last ART-naïve time point. These findings indicate that reservoir proviral variants are archived throughout infection, recapitulating much of the viral diversity that arises throughout untreated HIV-1 infection, and strategies to target and reduce the reservoir must therefore permit for the clearance of proviruses encompassing this extensive diversity.
HIV-1 储存库由潜伏感染细胞组成,尽管存在抗逆转录病毒治疗 (ART),但这些细胞仍能持续存在。因此,阐明储存库的前病毒遗传组成,特别是在治疗前病毒多样性的背景下,对于理解储存库的形成和潜伏感染细胞的持续存在非常重要。在这里,我们研究了来自 13 名赞比亚急性感染个体的储存库前病毒变异体,并进行了额外的治疗前采样,以便与未经 ART 治疗的准种进行独特比较。我们从血清转换血浆样本中鉴定出完整的传播/起始(TF)病毒,并额外扩增和测序了感染后一年和开始 ART 前获得的血浆中的 HIV-1。虽然储存库中的大多数前病毒变异体与最近治疗前时间点的病毒变异体最密切相关,但我们也鉴定出了储存库前病毒变异体,其时间可以追溯到感染时或接近感染时,以及在感染和治疗开始之间的中间时间点。在五名个体中,与 TF 病毒相差五个或更少核苷酸变化的储存库前病毒变异体在治疗期间持续存在,其中包括两名个体的前病毒变异体与 TF 完全匹配,其中一名个体在六年多的时间里一直未接受 ART 治疗。治疗期间的前病毒变异体与 TF 病毒的差异明显小于最后一次未经 ART 治疗时的血浆变异体。这些发现表明,储存库前病毒变异体在整个感染过程中被存档,重现了未经治疗的 HIV-1 感染过程中出现的大部分病毒多样性,因此,靶向和减少储存库的策略必须允许清除包含这种广泛多样性的前病毒。