Proliferation of latently infected CD4(+) T cells carrying replication-competent HIV-1: Potential role in latent reservoir dynamics.
Proliferation of latently infected CD4(+) T cells carrying replication-competent HIV-1: Potential role in latent reservoir dynamics.
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DOI：
10.1084/jem.20170193
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发表时间：
2017-04-03
期刊：
影响因子：
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通讯作者：
Siliciano RF
中科院分区：
文献类型：
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作者：
Hosmane NN;Kwon KJ;Bruner KM;Capoferri AA;Beg S;Rosenbloom DI;Keele BF;Ho YC;Siliciano JD;Siliciano RF
静息 CD4+ T 细胞中的 HIV-1 潜伏库阻碍了抗逆转录病毒治疗的治愈。霍斯曼等人。提供支持以下假设的证据：储存库中更大比例的细胞是由细胞增殖产生的，而不是由直接感染产生的。静息 CD4+ T 淋巴细胞中的 HIV-1 潜伏库阻碍了治愈。储层稳定性的机制尚不清楚。最近的研究表明受感染细胞在体内的增殖程度出人意料。 T 细胞激活可促进增殖，但也会逆转潜伏期，从而导致生产性感染，通常会导致细胞死亡。在这项研究中，我们表明，潜伏感染的细胞可以响应有丝分裂原而增殖，而不产生病毒，从而产生可以释放感染性病毒的子代细胞。因此，依赖一轮激活的测定低估了储库的大小。对具有复制能力的病毒的独立克隆分离株进行测序显示，57% 的病毒株的 env 序列与来自同一患者的其他分离株相同。通过全基因组测序证实了同一性，并且不归因于有限的病毒多样性。系统发育和统计分析表明，相同的序列来自受感染细胞的体内增殖，而不是由优势病毒种类感染多个细胞。大部分储存库可能是由细胞增殖产生的，这给治疗带来了挑战。
The latent reservoir for HIV-1 in resting CD4+ T cells prevents cure with antiretroviral therapy. Hosmane et al. provide evidence supporting the hypothesis that a larger fraction of cells in the reservoir is generated by cell proliferation than by direct infection. A latent reservoir for HIV-1 in resting CD4+ T lymphocytes precludes cure. Mechanisms underlying reservoir stability are unclear. Recent studies suggest an unexpected degree of infected cell proliferation in vivo. T cell activation drives proliferation but also reverses latency, resulting in productive infection that generally leads to cell death. In this study, we show that latently infected cells can proliferate in response to mitogens without producing virus, generating progeny cells that can release infectious virus. Thus, assays relying on one round of activation underestimate reservoir size. Sequencing of independent clonal isolates of replication-competent virus revealed that 57% had env sequences identical to other isolates from the same patient. Identity was confirmed by full-genome sequencing and was not attributable to limited viral diversity. Phylogenetic and statistical analysis suggested that identical sequences arose from in vivo proliferation of infected cells, rather than infection of multiple cells by a dominant viral species. The possibility that much of the reservoir arises by cell proliferation presents challenges to cure.