Genetic Diversity, Compartmentalization, and Age of HIV Proviruses Persisting in CD4+ T Cell Subsets during Long-Term Combination Antiretroviral Therapy
Genetic Diversity, Compartmentalization, and Age of HIV Proviruses Persisting in CD4+ T Cell Subsets during Long-Term Combination Antiretroviral Therapy
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DOI：
10.1128/jvi.01786-19
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发表时间：
2020-03-01
影响因子：
5.4
通讯作者：
Brumme, Zabrina L.
中科院分区：
文献类型：
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作者：
Jones, Bradley R.;Miller, Rachel L.;Brumme, Zabrina L.
HIV储存库包括整合到感染者基因组中的多种前病毒，主要是CD4(+) T细胞，是开发有效的HIV治愈方法的主要障碍。然而，我们对在不同CD4(+) T细胞亚群中持续存在的前病毒的遗传学和动力学的理解仍然不完整。利用单基因组扩增技术，研究人员对5名接受长期联合抗逆转录病毒治疗（cART）的HIV感染者的初始、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）进行了表征，并将这些序列与从cART开始前收集的存档血浆中纵向分离的HIV RNA序列进行了比较，得出了每个参与者平均跨越19.5年（范围10至20年）的HIV数据集。我们推断了每个参与者宿主内系统发育的分布，从中我们表征了前病毒年龄、系统发育多样性和CD4(+) T细胞亚群之间的遗传区隔化。虽然5名参与者中有3名在CD4(+) T细胞亚群之间表现出一定程度的前区隔性，但综合分析显示，没有证据表明任何特定的CD4(+) T细胞亚群拥有持续时间最长、遗传多样性最高和/或遗传独特性最高的HIV库。在一名参与者中，保存在幼稚T细胞中的多种前病毒明显比记忆亚群中的年轻，而在另外三名参与者中，我们观察到亚群之间的前病毒年龄没有显著差异。在一名参与者中，从所有亚群中恢复了“旧”原病毒，包括一个序列，估计有21.5年历史，占主导地位（bb0 93%）他们的效应记忆子集。根除艾滋病毒的战略将需要克服宿主内部和宿主之间的遗传复杂性，可能通过个性化的方法。HIV治愈的主要障碍是整合到受感染CD4(+) T细胞基因组中的遗传多样性原病毒库的持续能力，尽管长期抑制性联合抗逆转录病毒治疗（cART）。然而，CD4(+) T细胞由于其在发育连续体中的成熟，构成了一个异质群体，并且其中潜伏前病毒的遗传“景观”仍未完全了解。我们应用系统发育技术（很大程度上是HIV持久性研究的新技术）来重建宿主内HIV进化史，并表征长期cART的5个个体中CD4(+) T细胞亚群的前病毒多样性。参与者在CD4(+) T细胞亚群之间的原病毒负担、遗传多样性和年龄分布方面差异很大，这表明个体之间和个体内感染细胞类型之间的原病毒景观可能不同。我们的研究结果揭示了每个宿主内潜伏库在其遗传复杂性方面是独特的，并支持个性化的艾滋病毒根除策略。
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.