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Episomal Viral cDNAs Identify a Reservoir That Fuels Viral Rebound after Treatment Interruption and That Contributes to Treatment Failure

机译:附加型病毒cDNA识别出储库该储库在治疗中断后为病毒反弹提供动力并导致治疗失败

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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.
机译:通过抗逆转录病毒疗法(ART)在感染HIV-1的个体中持续存在的病毒库是消除病毒的主要障碍。为了了解病毒的持久性并达到消灭病毒的目标,需要对ART患者的病毒库进行鉴定和定义。我们检查了对游离HIV-1基因组的分析是否提供了表征在ART期间持续存在的病毒的手段,以及它是否可以揭示导致ART患者治疗失败的病毒。对于六个个体,其中病毒复制被高度抑制了至少20个月,将在反弹之前出现的原病毒基因组和游离基因组与治疗中断后反弹病毒的RNA基因组进行了系统发育比较。游离包膜序列而非原病毒包膜序列与反弹病毒中的序列高度相似。由于附加体是近期感染的产物,因此系统发生关系支持以下结论:病毒反弹起源于隐性病毒库。为了评估通过游离序列分析揭示的储库是否具有临床意义,我们检查了游离序列是否定义了接受CCR5拮抗剂Vicriviroc的个体中导致病毒性衰竭的病毒种群。由于存在X4或D / M(双重/混合)病毒变体,处于基线或基线附近的附加型包膜序列可预测治疗失败。在没有携带X4或D / M病毒的患者中,Vicriviroc治疗失败的依据不确定。尽管这些样品是从病毒血症患者中获得的,但根据以前的研究,该测定方法仍适用于很大比例的非病毒血症患者。总而言之,这些结果支持使用游离型HIV-1作为传统检测方法的一种附加或替代方法,以表征长期抑制性ART期间维持的病毒。

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