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Phylogenetic approach to recover integration dates of latent HIV sequences within-host [Medical Sciences]
Proceedings of the National Academy of Sciences of the United States of America ( IF 11.1 ) Pub Date : 2018-09-18 , DOI: 10.1073/pnas.1802028115
Bradley R. Jones 1 , Natalie N. Kinloch 2 , Joshua Horacsek 1 , Bruce Ganase 1 , Marianne Harris 1 , P. Richard Harrigan 3 , R. Brad Jones 4 , Mark A. Brockman 1, 2 , Jeffrey B. Joy 1, 3 , Art F. Y. Poon 5 , Zabrina L. Brumme 1, 2
Affiliation  

Given that HIV evolution and latent reservoir establishment occur continually within-host, and that latently infected cells can persist long-term, the HIV reservoir should comprise a genetically heterogeneous archive recapitulating within-host HIV evolution. However, this has yet to be conclusively demonstrated, in part due to the challenges of reconstructing within-host reservoir establishment dynamics over long timescales. We developed a phylogenetic framework to reconstruct the integration dates of individual latent HIV lineages. The framework first involves inference and rooting of a maximum-likelihood phylogeny relating plasma HIV RNA sequences serially sampled before the initiation of suppressive antiretroviral therapy, along with putative latent sequences sampled thereafter. A linear model relating root-to-tip distances of plasma HIV RNA sequences to their sampling dates is used to convert root-to-tip distances of putative latent lineages to their establishment (integration) dates. Reconstruction of the ages of putative latent sequences sampled from chronically HIV-infected individuals up to 10 y following initiation of suppressive therapy revealed a genetically heterogeneous reservoir that recapitulated HIV’s within-host evolutionary history. Reservoir sequences were interspersed throughout multiple within-host lineages, with the oldest dating to >20 y before sampling; historic genetic bottleneck events were also recorded therein. Notably, plasma HIV RNA sequences isolated from a viremia blip in an individual receiving otherwise suppressive therapy were highly genetically diverse and spanned a 20-y age range, suggestive of spontaneous in vivo HIV reactivation from a large latently infected cell pool. Our framework for reservoir dating provides a potentially powerful addition to the HIV persistence research toolkit.



中文翻译:

系统发育方法恢复宿主内潜在HIV序列的整合日期[医学]

鉴于艾滋病毒的进化和潜在宿主的建立是在宿主内持续发生的,并且潜在感染的细胞可以长期持续存在,因此艾滋病毒的宿主应该包括一个遗传多样性的档案库,概括宿主内的艾滋病毒的进化。但是,这还没有得到最终证实,部分原因是要在很长的时间范围内重建宿主内部储层建立动态的挑战。我们开发了一个系统进化框架,以重建各个潜在HIV谱系的整合日期。该框架首先涉及推断和生根,在抑制性抗逆转录病毒治疗开始之前,先对连续取样的血浆HIV RNA序列进行系统分析,然后再推定其潜在的潜在序列。将血浆HIV RNA序列的根尖距离与其采样日期相关联的线性模型可用于将假定的潜在谱系的根尖距离转换为其建立(整合)日期。在开始抑制治疗后长达10 y内,对从慢性HIV感染者中采集的假定潜伏序列的年龄进行了重建,结果揭示了遗传异质性宿主,概述了HIV在宿主体内的进化史。储层序列散布在多个宿主内部谱系中,最古老的可追溯到20 y之前。还记录了历史性的遗传瓶颈事件。值得注意的是,从接受其他方式抑制性治疗的人的病毒血症斑点中分离出的血浆HIV RNA序列具有高度的遗传多样性,跨越了20岁年龄段,提示从大量潜伏感染的细胞池中体内自发激活HIV。我们的水库测年框架为HIV持久性研究工具包提供了潜在强大的补充。

更新日期:2018-09-19
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