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Genetic Diversity, Compartmentalization, and Age of HIV Proviruses Persisting in CD4+ T Cell Subsets during Long-Term Combination Antiretroviral Therapy.
Journal of Virology ( IF 5.4 ) Pub Date : 2020-02-14 , DOI: 10.1128/jvi.01786-19
Bradley R Jones 1, 2 , Rachel L Miller 3 , Natalie N Kinloch 1, 3 , Olivia Tsai 3 , Hawley Rigsby 4 , Hanwei Sudderuddin 1, 3 , Aniqa Shahid 1, 3 , Bruce Ganase 1 , Chanson J Brumme 1, 5 , Marianne Harris 1 , Art F Y Poon 6 , Mark A Brockman 1, 3 , Rémi Fromentin 4 , Nicolas Chomont 4, 7 , Jeffrey B Joy 1, 2, 5 , Zabrina L Brumme 3, 8
Affiliation  

The HIV reservoir, which comprises diverse proviruses integrated into the genomes of infected, primarily CD4+ T cells, is the main barrier to developing an effective HIV cure. Our understanding of the genetics and dynamics of proviruses persisting within distinct CD4+ T cell subsets, however, remains incomplete. Using single-genome amplification, we characterized subgenomic proviral sequences (nef region) from naive, central memory, transitional memory, and effector memory CD4+ T cells from five HIV-infected individuals on long-term combination antiretroviral therapy (cART) and compared these to HIV RNA sequences isolated longitudinally from archived plasma collected prior to cART initiation, yielding HIV data sets spanning a median of 19.5 years (range, 10 to 20 years) per participant. We inferred a distribution of within-host phylogenies for each participant, from which we characterized proviral ages, phylogenetic diversity, and genetic compartmentalization between CD4+ T cell subsets. While three of five participants exhibited some degree of proviral compartmentalization between CD4+ T cell subsets, combined analyses revealed no evidence that any particular CD4+ T cell subset harbored the longest persisting, most genetically diverse, and/or most genetically distinctive HIV reservoir. In one participant, diverse proviruses archived within naive T cells were significantly younger than those in memory subsets, while for three other participants we observed no significant differences in proviral ages between subsets. In one participant, "old" proviruses were recovered from all subsets, and included one sequence, estimated to be 21.5 years old, that dominated (>93%) their effector memory subset. HIV eradication strategies will need to overcome within- and between-host genetic complexity of proviral landscapes, possibly via personalized approaches.IMPORTANCE The main barrier to HIV cure is the ability of a genetically diverse pool of proviruses, integrated into the genomes of infected CD4+ T cells, to persist despite long-term suppressive combination antiretroviral therapy (cART). CD4+ T cells, however, constitute a heterogeneous population due to their maturation across a developmental continuum, and the genetic "landscapes" of latent proviruses archived within them remains incompletely understood. We applied phylogenetic techniques, largely novel to HIV persistence research, to reconstruct within-host HIV evolutionary history and characterize proviral diversity in CD4+ T cell subsets in five individuals on long-term cART. Participants varied widely in terms of proviral burden, genetic diversity, and age distribution between CD4+ T cell subsets, revealing that proviral landscapes can differ between individuals and between infected cell types within an individual. Our findings expose each within-host latent reservoir as unique in its genetic complexity and support personalized strategies for HIV eradication.

中文翻译:

在长期联合抗逆转录病毒疗法期间,CD4 + T细胞亚群中存在的HIV原病毒的遗传多样性,分区和年龄。

HIV储库是整合到受感染的主要是CD4 + T细胞基因组中的各种原病毒,是开发有效的HIV治愈方法的主要障碍。然而,我们对前病毒的遗传学和动力学的理解仍然存在于不同的CD4 + T细胞亚群中。使用单基因组扩增,我们通过长期联合抗逆转录病毒疗法(cART)对来自5个HIV感染者的幼稚,中枢记忆,过渡记忆和效应记忆CD4 + T细胞的亚基因组前病毒序列(nef区域)进行了表征,并将其与从cART启动之前从收集的血浆中纵向分离出HIV RNA序列,得出每个参与者平均19.5年(范围为10至20年)的HIV数据集。我们推断出每个参与者的宿主内部系统发育分布,从中我们表征了前病毒时代,系统发育多样性和CD4 + T细胞亚群之间的遗传区室化。虽然五分之三的参与者在CD4 + T细胞亚群之间表现出一定程度的前病毒区隔,但联合分析显示没有证据表明任何特定的CD4 + T细胞亚群具有最长的持续存在,遗传上最多样化和/或遗传上最独特的HIV贮藏库。在一名参与者中,原始T细胞中存档的多种原病毒明显比记忆亚群中的幼小,而对于其他三名参与者,我们观察到亚群之间的前病毒年龄没有显着差异。在一名参与者中,从所有亚组中回收了“旧”原病毒,并包括一个序列,估计为21.5岁,主导了效应记忆子集(> 93%)。HIV根除策略将需要克服宿主病毒内部和宿主之间遗传的复杂性,可能需要通过个性化方法。重要信息治愈HIV的主要障碍是遗传多样性的前病毒库整合到感染的CD4 + T基因组中的能力。尽管进行了长期抑制性联合抗逆转录病毒治疗(cART),但细胞仍然存在。然而,由于CD4 + T细胞在整个发育连续体中的成熟,它们构成了一个异质群体,并且对保存在其中的潜在前病毒的遗传“景观”还没有完全了解。我们应用了系统发育技术,这在HIV持久性研究中大都是新颖的,重建宿主内HIV进化史,并在长期cART上表征5个人中CD4 + T细胞亚群的前病毒多样性。参与者在CD4 + T细胞亚群之间的前病毒负担,遗传多样性和年龄分布方面差异很大,这表明前病毒景观在个体之间以及个体内感染细胞类型之间可能有所不同。我们的研究结果揭示了每个宿主内部潜伏性贮藏库在遗传复杂性方面的独特性,并支持根除艾滋病毒的个性化策略。揭示了个体之间以及个体内感染细胞类型之间的前病毒景观可能会有所不同。我们的研究结果揭示了每个宿主内部潜伏性贮藏库在遗传复杂性方面的独特性,并支持根除艾滋病毒的个性化策略。揭示了个体之间以及个体内感染细胞类型之间的前病毒景观可能会有所不同。我们的研究结果揭示了每个宿主内部潜伏性贮藏库在遗传复杂性方面的独特性,并支持个性化的消除HIV策略。
更新日期:2019-11-01
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