HIV Proviral Burden, Genetic Diversity, and Dynamics in Viremic Controllers Who Subsequently Initiated Suppressive Antiretroviral Therapy.
HIV Proviral Burden, Genetic Diversity, and Dynamics in Viremic Controllers Who Subsequently Initiated Suppressive Antiretroviral Therapy.
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DOI：
10.1128/mbio.02490-21
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发表时间：
2021-12-21
期刊：
影响因子：
6.4
通讯作者：
Brumme ZL
中科院分区：
文献类型：
--
作者：
Omondi FH;Sudderuddin H;Shahid A;Kinloch NN;Jones BR;Miller RL;Tsai O;MacMillan D;Trocha A;Brockman MA;Brumme CJ;Joy JB;Liang R;Walker BD;Brumme ZL
治愈艾滋病毒需要消除尽管接受抗逆转录病毒治疗（ART）但仍持续存在的整合的、具有复制能力的前病毒库。了解负担，遗传多样性和持久的前病毒在不同的艾滋病毒感染者的寿命是这一目标的关键，但这些特征仍然在一些群体研究不足。其中包括病毒血症患者，他们自然地将HIV抑制到低水平，但仍然建议对其进行治疗。我们重建了宿主内的HIV进化史，从纵向单基因组扩增的病毒序列在四个病毒血症控制者谁最终启动ART，并使用这些信息来表征的年龄和多样性的前病毒持续治疗。我们进一步利用这些宿主内前病毒年龄分布来估计ART前前病毒周转率。这是一个重要但尚未充分研究的指标，因为ART前病毒周转决定了ART启动时（及其后）的储库组成，这是治疗性干预措施一旦开发出来，将被管理的时候。尽管自然病毒血症控制，所有参与者显示出显着的宿主内HIV进化pretherapy，其中整体上ART前病毒的负担和多样性广泛反映了病毒复制和多样性pre-ART的程度。与最近的研究noncontrollers一致，前病毒池的两名参与者倾向于序列，整合近ART启动，表明动态前病毒营业额在未经治疗的感染。相比之下，从其他两名参与者中回收的前病毒可追溯到整个感染过程中更均匀分布的时间点，表明沉积后前病毒衰减缓慢或可忽略不计。HIV治疗策略需要克服宿主内前病毒的多样性，即使是在治疗前自然控制HIV复制的个体中。
Curing HIV will require eliminating the reservoir of integrated, replication-competent proviruses that persist despite antiretroviral therapy (ART). Understanding the burden, genetic diversity, and longevity of persisting proviruses in diverse individuals with HIV is critical to this goal, but these characteristics remain understudied in some groups. Among them are viremic controllers—individuals who naturally suppress HIV to low levels but for whom therapy is nevertheless recommended. We reconstructed within-host HIV evolutionary histories from longitudinal single-genome amplified viral sequences in four viremic controllers who eventually initiated ART and used this information to characterize the age and diversity of proviruses persisting on therapy. We further leveraged these within-host proviral age distributions to estimate rates of proviral turnover prior to ART. This is an important yet understudied metric, since pre-ART proviral turnover dictates reservoir composition at ART initiation (and thereafter), which is when curative interventions, once developed, would be administered. Despite natural viremic control, all participants displayed significant within-host HIV evolution pretherapy, where overall on-ART proviral burden and diversity broadly reflected the extent of viral replication and diversity pre-ART. Consistent with recent studies of noncontrollers, the proviral pools of two participants were skewed toward sequences that integrated near ART initiation, suggesting dynamic proviral turnover during untreated infection. In contrast, proviruses recovered from the other two participants dated to time points that were more evenly spread throughout infection, suggesting slow or negligible proviral decay following deposition. HIV cure strategies will need to overcome within-host proviral diversity, even in individuals who naturally controlled HIV replication before therapy.