Transmission of single HIV-1 genomes and dynamics of early immune escape revealed by ultra-deep sequencing.
Transmission of single HIV-1 genomes and dynamics of early immune escape revealed by ultra-deep sequencing.
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DOI：
10.1371/journal.pone.0012303
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发表时间：
2010-08-20
期刊：
影响因子：
3.7
通讯作者：
Korber BT
中科院分区：
文献类型：
--
作者：
Fischer W;Ganusov VV;Giorgi EE;Hraber PT;Keele BF;Leitner T;Han CS;Gleasner CD;Green L;Lo CC;Nag A;Wallstrom TC;Wang S;McMichael AJ;Haynes BF;Hahn BH;Perelson AS;Borrow P;Shaw GM;Bhattacharya T;Korber BT
我们使用超深度测序从来自三名急性感染受试者的纵向样本中的CD 8 + T淋巴细胞靶向区域获得了数万个HIV-1序列，并在感染的关键第一周期间模拟了病毒进化。以前的研究表明，一个单一的病毒建立了生产性感染，但这些结论是温和的，因为有限的采样;现在，我们已经大大增加了我们的信心，通过建模观察到的最早的样本多样性的基础上更广泛的采样。急性/早期感染的HIV-1的常规测序显示了不同表位的不同逃逸模式;我们详细研究了最早的逃逸。在3-6周的时间里，超深度测序显示，该病毒在逃避最早的CD 8 T淋巴细胞应答的过程中探索了一系列非凡的潜在逃逸途径-使用454测序，我们在早期免疫逃逸过程中鉴定了每个靶向表位的50多种变体形式，而通过常规测序在相同样品中仅检测到2-7种变体。与表位内观察到的多样性相反，非表位区域，包括包膜V3区域，其在每个受试者中作为对照进行测序，显示出非常低的变异水平。在早期感染中，在测序的区域中，共有形式没有足够大的适应性优势，以在没有免疫压力的情况下触发向共有氨基酸的逆转。在一个受试者中，观察到遗传瓶颈，在第二个时间点的广泛多样性在第三个时间点缩小到两种主要的逃逸形式，所有这些都在感染后两个月内。在最早的样本中观察到免疫逃逸的痕迹，表明免疫压力存在且比先前报道的更早有效;定量创始人病毒的损失率表明CD 8 T淋巴细胞应答在峰值病毒血症后的病毒遏制中的直接作用。在感染的第一周，表位变异频率的急剧变化揭示了病毒适应性和免疫逃逸之间复杂的相互作用。
We used ultra-deep sequencing to obtain tens of thousands of HIV-1 sequences from regions targeted by CD8+ T lymphocytes from longitudinal samples from three acutely infected subjects, and modeled viral evolution during the critical first weeks of infection. Previous studies suggested that a single virus established productive infection, but these conclusions were tempered because of limited sampling; now, we have greatly increased our confidence in this observation through modeling the observed earliest sample diversity based on vastly more extensive sampling. Conventional sequencing of HIV-1 from acute/early infection has shown different patterns of escape at different epitopes; we investigated the earliest escapes in exquisite detail. Over 3–6 weeks, ultradeep sequencing revealed that the virus explored an extraordinary array of potential escape routes in the process of evading the earliest CD8 T-lymphocyte responses – using 454 sequencing, we identified over 50 variant forms of each targeted epitope during early immune escape, while only 2–7 variants were detected in the same samples via conventional sequencing. In contrast to the diversity seen within epitopes, non-epitope regions, including the Envelope V3 region, which was sequenced as a control in each subject, displayed very low levels of variation. In early infection, in the regions sequenced, the consensus forms did not have a fitness advantage large enough to trigger reversion to consensus amino acids in the absence of immune pressure. In one subject, a genetic bottleneck was observed, with extensive diversity at the second time point narrowing to two dominant escape forms by the third time point, all within two months of infection. Traces of immune escape were observed in the earliest samples, suggesting that immune pressure is present and effective earlier than previously reported; quantifying the loss rate of the founder virus suggests a direct role for CD8 T-lymphocyte responses in viral containment after peak viremia. Dramatic shifts in the frequencies of epitope variants during the first weeks of infection revealed a complex interplay between viral fitness and immune escape.
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影响因子：
6.7
作者：
Brumme ZL;Brumme CJ;Heckerman D;Korber BT;Daniels M;Carlson J;Kadie C;Bhattacharya T;Chui C;Szinger J;Mo T;Hogg RS;Montaner JS;Frahm N;Brander C;Walker BD;Harrigan PR
通讯作者：
Harrigan PR
影响因子：
5.4
作者：
Bimber, Benjamin N.;Burwitz, Benjamin J.;O'Connor, David
通讯作者：
O'Connor, David
影响因子：
82.9
作者：
Fischer, Will;Perkins, Simon;Korber, Bette T.
通讯作者：
Korber, Bette T.
影响因子：
11.8
作者：
Lavreys, L;Baeten, JM;Overbaugh, J
通讯作者：
Overbaugh, J
影响因子：
5.4
作者：
KORBER, BTM;KUNSTMAN, KJ;WOLINSKY, SM
通讯作者：
WOLINSKY, SM