Li Ming, Tucker Lynne D, Asara John M, Cheruiyot Collins K, Lu Huafei, Wu Zhijin J, Newstein Michael C, Dooner Mark S, Friedman Jennifer, Lally Michelle A, Ramratnam Bharat
J Clin Invest. 2016 Aug 1;126(8):3117-29. doi: 10.1172/JCI82360. Epub 2016 Jul 25.
A rare subset of HIV-1-infected individuals is able to maintain plasma viral load (VL) at low levels without antiretroviral treatment. Identifying the mechanisms underlying this atypical response to infection may lead to therapeutic advances for treating HIV-1. Here, we developed a proteomic analysis to compare peripheral blood cell proteomes in 20 HIV-1-infected individuals who maintained either high or low VL with the aim of identifying host factors that impact HIV-1 replication. We determined that the levels of multiple histone proteins were markedly decreased in cohorts of individuals with high VL. This reduction was correlated with lower levels of stem-loop binding protein (SLBP), which is known to control histone metabolism. Depletion of cellular SLBP increased promoter engagement with the chromatin structures of the host gene high mobility group protein A1 (HMGA1) and viral long terminal repeat (LTR), which led to higher levels of HIV-1 genomic integration and proviral transcription. Further, we determined that TNF-α regulates expression of SLBP and observed that plasma TNF-α levels in HIV-1-infected individuals correlated directly with VL levels and inversely with cellular SLBP levels. Our findings identify SLBP as a potentially important cellular regulator of HIV-1, thereby establishing a link between histone metabolism, inflammation, and HIV-1 infection.
一小部分罕见的HIV-1感染者在未接受抗逆转录病毒治疗的情况下能够将血浆病毒载量（VL）维持在低水平。确定这种对感染的非典型反应背后的机制可能会推动HIV-1治疗取得进展。在此，我们开展了一项蛋白质组学分析，以比较20名HIV-1感染者的外周血细胞蛋白质组，这些感染者的VL水平有高有低，目的是确定影响HIV-1复制的宿主因子。我们发现，在VL水平高的感染者队列中，多种组蛋白的水平显著降低。这种降低与茎环结合蛋白（SLBP）水平较低有关，已知SLBP可控制组蛋白代谢。细胞SLBP的缺失增加了启动子与宿主基因高迁移率族蛋白A1（HMGA1）和病毒长末端重复序列（LTR）的染色质结构的结合，这导致HIV-1基因组整合和前病毒转录水平升高。此外，我们确定肿瘤坏死因子-α（TNF-α）调节SLBP的表达，并观察到HIV-1感染者的血浆TNF-α水平与VL水平直接相关，与细胞SLBP水平呈负相关。我们的研究结果确定SLBP是HIV-1潜在的重要细胞调节因子，从而在组蛋白代谢、炎症和HIV-1感染之间建立了联系。
