Recurrent HIV-1 integration at the BACH2 locus in resting CD4+ T cell populations during effective highly active antiretroviral therapy
Recurrent HIV-1 integration at the BACH2 locus in resting CD4+ T cell populations during effective highly active antiretroviral therapy
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DOI：
10.1086/510915
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发表时间：
2007-03-01
影响因子：
6.4
通讯作者：
Matsushita, Shuzo
中科院分区：
文献类型：
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作者：
Ikeda, Terumasa;Shibata, Junji;Matsushita, Shuzo
潜伏的人类免疫缺陷病毒1型（HIV-1）的持续存在被认为是在接受成功的抗逆转录病毒疗法的受感染个体中根除病毒的主要障碍之一。为了确定整合位点对临床环境中病毒潜伏期的贡献，使用反向聚合酶链反应方法分析显示长期检测不到血浆病毒RNA的患者的CD 4（+）T细胞中的整合位点。在7例患者中发现的457个位点中，几乎所有（96%）都位于转录单位内，通常位于人类基因组的内含子中。对HIV-1整合的18个基因的研究发现，它们在静息CD 4（+）T细胞中活跃表达。另一方面，在一些患者中也发现了α卫星区域的整合位点，尽管频率较低。特别令人感兴趣的是，在对来自3名患者的样品的纵向分析中检测到具有多个相同整合位点的HIV-1感染细胞，这表明这些细胞持续很长时间并且可能发生克隆扩增。此外，在2名患者中观察到BACH 2基因中的强整合簇（患者1中31%，患者3中5%）。我们的研究结果不仅提高了有偏见的靶点整合的可能性，而且还提供了对HIV-1长期持续存在的机制性见解。
The persistence of latent human immunodeficiency virus type 1 ( HIV-1) has been considered one of the major obstacles for eradication of the virus in infected individuals receiving successful antiretroviral therapy. To determine the contribution of integration sites to viral latency within clinical settings, an inverse polymerase chain reaction method was used to analyze integration sites in CD4(+) T cells from patients showing long-term undetectable plasma viral RNA. Of 457 sites identified in 7 patients, almost all ( 96%) resided within transcriptional units, usually in introns of the human genome. Studies of 18 genes in which HIV-1 integrates found them to be actively expressed in resting CD4(+) T cells. On the other hand, integration sites in the a satellite region was also identified in some patients, albeit at low frequency. Of particular interest, HIV-1 infected cells with multiple identical integration sites were detected in longitudinal analysis of samples from 3 patients, suggesting that these cells persist for long periods and that clonal expansion may occur. Furthermore, strong integration clusters in the BACH2 gene were observed in 2 patients ( 31% in patient 1 and 5% in patient 3). Our findings not only raise the possibility of biased target-site integration but also provide mechanistic insights into the long-term persistence of HIV-1.