Hosmane Nina N, Kwon Kyungyoon J, Bruner Katherine M, Capoferri Adam A, Beg Subul, Rosenbloom Daniel I S, Keele Brandon F, Ho Ya-Chi, Siliciano Janet D, Siliciano Robert F
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Department of Biomedical Informatics, Columbia University Medical Center, New York, NY 10032.
J Exp Med. 2017 Apr 3;214(4):959-972. doi: 10.1084/jem.20170193. Epub 2017 Mar 24.
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 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.
静息CD4 T淋巴细胞中存在的HIV-1潜伏储存库使得治愈变得不可能。储存库稳定性的潜在机制尚不清楚。最近的研究表明，体内受感染细胞存在出乎意料程度的增殖。T细胞活化会驱动增殖，但也会逆转潜伏期，导致产生有感染性的病毒，这通常会导致细胞死亡。在本研究中，我们表明潜伏感染的细胞可以在有丝分裂原刺激下增殖而不产生病毒，产生的子代细胞可以释放感染性病毒。因此，依赖一轮活化的检测方法会低估储存库的大小。对具有复制能力病毒的独立克隆分离株进行测序发现，57%的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序列一致性，这并非归因于有限的病毒多样性。系统发育和统计分析表明，相同序列源于受感染细胞的体内增殖，而非由优势病毒株感染多个细胞所致。储存库的很大一部分是由细胞增殖产生的这一可能性给治愈带来了挑战。
