HIV-1-mediated insertional activation of STAT5B and BACH2 trigger viral reservoir in T regulatory cells.
HIV-1-mediated insertional activation of STAT5B and BACH2 trigger viral reservoir in T regulatory cells.
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DOI：
10.1038/s41467-017-00609-1
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发表时间：
2017-09-08
影响因子：
16.6
通讯作者：
Montini E
中科院分区：
文献类型：
--
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
靶向BACH 2或MLK 2的HIV-1插入物在接受联合抗逆转录病毒治疗的患者的造血细胞中富集并持续数十年。然而，目前还不清楚这些插入如何为感染的细胞克隆提供这种选择性优势。在这里，我们发现，在30/87（34%）的联合抗逆转录病毒治疗的患者中，BACH 2和STAT 5 B被插入激活，触发形成含有病毒序列的mRNA，通过剪接融合到其第一个蛋白编码外显子。这些嵌合的mRNA，预测表达全长蛋白质，是丰富的T调节和T中央记忆细胞，但不是在其他T淋巴细胞亚群或单核细胞。原代调节性T细胞中BACH 2或STAT 5 B的过表达增加了它们的增殖和存活，而不损害它们的功能。因此，我们提供的证据表明，HIV-1介导的BACH 2和STAT 5 B的插入激活有利于联合抗逆转录病毒治疗患者T调节细胞中病毒库的持久性。造血细胞中的HIV插入富含BACH 2或MLK 2基因，但所赋予的选择性优势尚不清楚。在这里，作者表明BACH 2和另外的STAT 5 B被病毒插入激活，产生特异性富集在T调节细胞中的嵌合mRNA，有利于它们的持久性。
HIV-1 insertions targeting BACH2 or MLK2 are enriched and persist for decades in hematopoietic cells from patients under combination antiretroviral therapy. However, it is unclear how these insertions provide such selective advantage to infected cell clones. Here, we show that in 30/87 (34%) patients under combination antiretroviral therapy, BACH2, and STAT5B are activated by insertions triggering the formation of mRNAs that contain viral sequences fused by splicing to their first protein-coding exon. These chimeric mRNAs, predicted to express full-length proteins, are enriched in T regulatory and T central memory cells, but not in other T lymphocyte subsets or monocytes. Overexpression of BACH2 or STAT5B in primary T regulatory cells increases their proliferation and survival without compromising their function. Hence, we provide evidence that HIV-1-mediated insertional activation of BACH2 and STAT5B favor the persistence of a viral reservoir in T regulatory cells in patients under combination antiretroviral therapy. HIV insertions in hematopoietic cells are enriched in BACH2 or MLK2 genes, but the selective advantages conferred are unknown. Here, the authors show that BACH2 and additionally STAT5B are activated by viral insertions, generating chimeric mRNAs specifically enriched in T regulatory cells favoring their persistence.
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影响因子：
3.7
作者：
Abel U;Deichmann A;Nowrouzi A;Gabriel R;Bartholomae CC;Glimm H;von Kalle C;Schmidt M
通讯作者：
Schmidt M
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通讯作者：
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