Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
PLoS Pathog. 2011 Feb;7(2):e1001303. doi: 10.1371/journal.ppat.1001303. Epub 2011 Feb 24.
Viral reservoirs that persist in HIV-1 infected individuals on antiretroviral therapy (ART) are the major obstacle to viral eradication. The identification and definition of viral reservoirs in patients on ART is needed in order to understand viral persistence and achieve the goal of viral eradication. We examined whether analysis of episomal HIV-1 genomes provided the means to characterize virus that persists during ART and whether it could reveal the virus that contributes to treatment failure in patients on ART. For six individuals in which virus replication was highly suppressed for at least 20 months, proviral and episomal genomes present just prior to rebound were phylogenetically compared to RNA genomes of rebounding virus after therapy interruption. Episomal envelope sequences, but not proviral envelope sequences, were highly similar to sequences in rebounding virus. Since episomes are products of recent infections, the phylogenetic relationships support the conclusion that viral rebound originated from a cryptic viral reservoir. To evaluate whether the reservoir revealed by episomal sequence analysis was of clinical relevance, we examined whether episomal sequences define a viral population that contributes to virologic failure in individuals receiving the CCR5 antagonist, Vicriviroc. Episomal envelope sequences at or near baseline predicted treatment failure due to the presence of X4 or D/M (dual/mixed) viral variants. In patients that did not harbor X4 or D/M viruses, the basis for Vicriviroc treatment failure was indeterminate. Although these samples were obtained from viremic patients, the assay would be applicable to a large percentage of aviremic patients, based on previous studies. Summarily, the results support the use of episomal HIV-1 as an additional or alternative approach to traditional assays to characterize virus that is maintained during long-term, suppressive ART.
在抗逆转录病毒疗法（ART）下，持续性病毒库是 HIV-1 感染者病毒无法被彻底清除的主要障碍。为了理解病毒的持续性并实现清除病毒的目标，我们需要确定和定义接受 ART 的患者中的病毒库。我们研究了分析游离 HIV-1 基因组是否可以用来描述 ART 期间持续存在的病毒，以及它是否可以揭示导致接受 ART 的患者治疗失败的病毒。对于 6 名患者，他们的病毒复制在至少 20 个月内得到了高度抑制，在治疗中断后病毒反弹之前，我们对前病毒和游离基因组与反弹后病毒的 RNA 基因组进行了系统发育比较。游离包膜序列，但不是前病毒包膜序列，与反弹病毒的序列高度相似。由于游离体是最近感染的产物，系统发育关系支持这样的结论，即病毒反弹源自隐匿的病毒库。为了评估通过游离序列分析揭示的储库是否具有临床相关性，我们研究了游离序列是否定义了一个导致接受 CCR5 拮抗剂 Vicriviroc 治疗的个体病毒学失败的病毒群体。在基线时或接近基线时存在的游离包膜序列可以预测 X4 或 D/M（双重/混合）病毒变异体的存在会导致治疗失败。在未携带 X4 或 D/M 病毒的患者中，Vicriviroc 治疗失败的基础尚不确定。尽管这些样本取自病毒血症患者，但根据之前的研究，该检测方法适用于很大一部分无病毒血症患者。总之，这些结果支持使用游离 HIV-1 作为传统检测方法的补充或替代方法，以描述在长期抑制性 ART 期间维持的病毒。
