Integration in oncogenes plays only a minor role in determining the in vivo distribution of HIV integration sites before or during suppressive antiretroviral therapy.
Integration in oncogenes plays only a minor role in determining the in vivo distribution of HIV integration sites before or during suppressive antiretroviral therapy.
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DOI：
10.1371/journal.ppat.1009141
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发表时间：
2021-04
期刊：
影响因子：
6.7
通讯作者：
Hughes SH
中科院分区：
文献类型：
--
作者：
Coffin JM;Bale MJ;Wells D;Guo S;Luke B;Zerbato JM;Sobolewski MD;Sia T;Shao W;Wu X;Maldarelli F;Kearney MF;Mellors JW;Hughes SH
HIV在抗逆转录病毒治疗(ART)期间持续存在，因为在ART开始之前，从感染的一小部分CD4+T细胞下来的细胞中存在整合的前病毒。为了更好地了解是什么控制了HIV的持久性和整合位点(IS)的分布，我们比较了大约15,000和54,000来自ART前和ART上的个体，以及大约395,000来自体外感染的PBMC。IS在体内的分布与在PBMC中的分布非常相似，但通过对表达基因中前病毒的选择、对整合到7个特定基因之一的前病毒的选择和克隆扩增而改变。原病毒整合到癌基因中有助于细胞存活的克隆只占坚持使用ART的克隆的一小部分。不涉及前病毒或其在宿主基因组中位置的机制在决定哪些克隆扩展和持续存在方面更重要。在感染艾滋病毒的个体中，一小部分感染细胞持续存在并分裂。这个蓄水池在完全抑制ART期间持续存在，如果ART停止，可能会重新引发感染。由于HIV DNA整合的可能位置非常多，每个受感染的细胞及其所有后代都可以通过整合前病毒的位置(IS)来识别。为了了解决定体内感染细胞命运的选择性力量，我们比较了新感染细胞中HIV IS的分布与ART前和ART期间采集的HIV感染捐赠者的细胞。我们发现，正如之前报道的那样，整合有利于高表达的基因。然而，随着时间的推移，整合到高表达基因中的前病毒细胞的比例会减少，这意味着它们生长得不太好。这种广泛的负面选择也有例外。当前病毒整合在七个基因中的一个特定区域时，前病毒会影响目标基因的表达，促进细胞的生长和/或存活。尽管这种影响是惊人的，但它只是ART期间促进受感染细胞数量增长和存活的力量中的一小部分。
HIV persists during antiretroviral therapy (ART) as integrated proviruses in cells descended from a small fraction of the CD4+ T cells infected prior to the initiation of ART. To better understand what controls HIV persistence and the distribution of integration sites (IS), we compared about 15,000 and 54,000 IS from individuals pre-ART and on ART, respectively, with approximately 395,000 IS from PBMC infected in vitro. The distribution of IS in vivo is quite similar to the distribution in PBMC, but modified by selection against proviruses in expressed genes, by selection for proviruses integrated into one of 7 specific genes, and by clonal expansion. Clones in which a provirus integrated in an oncogene contributed to cell survival comprised only a small fraction of the clones persisting in on ART. Mechanisms that do not involve the provirus, or its location in the host genome, are more important in determining which clones expand and persist. In HIV-infected individuals, a small fraction of the infected cells persist and divide. This reservoir persists during fully suppressive ART and can rekindle the infection if ART is discontinued. Because the number of possible sites of HIV DNA integration is very large, each infected cell, and all of its descendants, can be identified by the site where the provirus is integrated (IS). To understand the selective forces that determine the fates of infected cells in vivo, we compared the distribution of HIV IS in freshly-infected cells to cells from HIV-infected donors sampled both before and during ART. We found that, as previously reported, integration favors highly-expressed genes. However, over time, the fraction of cells with proviruses integrated in highly-expressed genes decreases, implying that they grow less well. There are exceptions to this broad negative selection. When a provirus is integrated in a specific region in one of seven genes, the proviruses affect the expression of the target gene, promoting growth and/or survival of the cell. Although this effect is striking, it is only a minor component of the forces that promote the growth and survival of the population of infected cells during ART.
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影响因子：
16.6
作者：
Cesana D;Santoni de Sio FR;Rudilosso L;Gallina P;Calabria A;Beretta S;Merelli I;Bruzzesi E;Passerini L;Nozza S;Vicenzi E;Poli G;Gregori S;Tambussi G;Montini E
通讯作者：
Montini E
影响因子：
56.9
作者：
COFFIN, JM
通讯作者：
COFFIN, JM
影响因子：
8
作者：
Coffin, John M.;Wells, David W.;Hughes, Stephen H.
通讯作者：
Hughes, Stephen H.
DOI：
10.1073/pnas.1609057113
发表时间：
2016-08-02
影响因子：
11.1
作者：
Imamichi, Hiromi;Dewar, Robin L.;Lane, H. Clifford
通讯作者：
Lane, H. Clifford
影响因子：
6.4
作者：
Crooks, Amanda M.;Bateson, Rosalie;Archin, Nancie M.
通讯作者：
Archin, Nancie M.