Phylogenetic approach to recover integration dates of latent HIV sequences within-host.
Phylogenetic approach to recover integration dates of latent HIV sequences within-host.
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DOI：
10.1073/pnas.1802028115
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发表时间：
2018-09-18
影响因子：
11.1
通讯作者：
Brumme ZL
中科院分区：
文献类型：
--
作者：
Jones BR;Kinloch NN;Horacsek J;Ganase B;Harris M;Harrigan PR;Jones RB;Brockman MA;Joy JB;Poon AFY;Brumme ZL
表征宿主内潜伏HIV序列多样性的研究已经深入了解了储层动态和持久性。然而，我们对这些过程的理解，可以进一步提高，如果水库的多样性解释的背景下，艾滋病毒的宿主内的进化历史。推断原始机构的方法（即，在这方面，个体宿主内潜伏HIV谱系的整合）日期将特别有用。我们描述了一个系统发育框架来推断潜伏的HIV年龄从病毒序列信息，并将其应用于潜伏的HIV序列采样长达10年的抑制治疗，以深入了解HIV水库动态。从序列信息推断宿主内潜伏HIV年龄的能力具有广泛的潜在应用，可能会推动我们走向HIV治愈。考虑到HIV进化和潜伏库建立在宿主内持续发生，并且潜伏感染的细胞可以长期存在，HIV库应该包括一个遗传异质性档案，重现宿主内HIV进化。然而，这一点尚未得到最终证明，部分原因是在很长一段时间内重建宿主体内水库建立动态的挑战。我们开发了一个系统发育框架来重建个体潜伏HIV谱系的整合日期。该框架首先涉及推断和生根的最大似然同源性相关的血浆HIV RNA序列的抑制性抗逆转录病毒治疗开始前连续采样，沿着与假定的潜伏序列采样后。血浆HIV RNA序列的根-尖距离与其采样日期相关的线性模型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。重建推定的潜伏序列的年龄从慢性HIV感染者的样本长达10年后开始抑制治疗揭示了一个遗传异质性水库，概括了HIV的宿主内进化史。储库序列散布在多个宿主内谱系中，最古老的可追溯到采样前>20年;其中还记录了历史遗传瓶颈事件。值得注意的是，从接受其他抑制性治疗的个体中的病毒血症斑点中分离的血浆HIV RNA序列具有高度遗传多样性，并且跨越20岁的年龄范围，这表明来自大的潜伏感染细胞池的自发体内HIV再活化。我们的水库测年框架提供了一个潜在的强大的除了艾滋病毒持久性研究工具包。
Studies characterizing within-host latent HIV sequence diversity have yielded insight into reservoir dynamics and persistence. Our understanding of these processes, however, can be further enhanced if reservoir diversity is interpreted in context of HIV’s within-host evolutionary history. Approaches to infer the original establishment (i.e., integration) dates of individual within-host latent HIV lineages would be particularly useful in this regard. We describe a phylogenetic framework to infer latent HIV ages from viral sequence information and apply it to latent HIV sequences sampled up to 10 y on suppressive therapy to yield insights into HIV reservoir dynamics. The ability to infer within-host latent HIV ages from sequence information has broad potential applications that may advance us toward an HIV cure. 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.
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影响因子：
3.3
作者：
Alizon S;Fraser C
通讯作者：
Fraser C
影响因子：
6.7
作者：
Evering TH;Mehandru S;Racz P;Tenner-Racz K;Poles MA;Figueroa A;Mohri H;Markowitz M
通讯作者：
Markowitz M
DOI：
10.1073/pnas.94.24.13193
发表时间：
1997-11-25
影响因子：
11.1
作者：
Chun, TW;Stuyver, L;Fauci, AS
通讯作者：
Fauci, AS
DOI：
10.1111/j.1096-0031.1996.tb00196.x
发表时间：
1994-09-01
期刊：
CLADISTICS-THE INTERNATIONAL JOURNAL OF THE WILLI HENNIG SOCIETY
影响因子：
--
作者：
FARRIS, JS;KALLERSJO, M;BULT, C
通讯作者：
BULT, C
影响因子：
16.8
作者：
Durand CM;Blankson JN;Siliciano RF
通讯作者：
Siliciano RF