Miller Shannon M, Miles Brodie, Guo Kejun, Folkvord Joy, Meditz Amie L, McCarter Martin D, Levy David N, MaWhinney Samantha, Santiago Mario L, Connick Elizabeth
Department of Immunology and Microbiology, School of Medicine, Anschutz Medical Campus, University of Colorado Denver, Aurora, Colorado, USA.
Division of Infectious Diseases, Department of Medicine, Anschutz Medical Campus, University of Colorado Denver, Aurora, Colorado, USA.
J Virol. 2017 Aug 10;91(17). doi: 10.1128/JVI.00430-17. Print 2017 Sep 1.
Follicular regulatory T (TFR) cells are a subset of CD4 T cells in secondary lymphoid follicles. TFR cells were previously included in the follicular helper T (TFH) cell subset, which consists of cells that are highly permissive to HIV-1. The permissivity of TFR cells to HIV-1 is unknown. We find that TFR cells are more permissive than TFH cells to R5-tropic HIV-1 TFR cells expressed more CCR5 and CD4 and supported higher frequencies of viral fusion. Differences in Ki67 expression correlated with HIV-1 replication. Inhibiting cellular proliferation reduced Ki67 expression and HIV-1 replication. Lymph node cells from untreated HIV-infected individuals revealed that TFR cells harbored the highest concentrations of HIV-1 RNA and highest levels of Ki67 expression. These data demonstrate that TFR cells are highly permissive to R5-tropic HIV-1 both and This is likely related to elevated CCR5 levels combined with a heightened proliferative state and suggests that TFR cells contribute to persistent R5-tropic HIV-1 replication In chronic, untreated HIV-1 infection, viral replication is concentrated in secondary lymphoid follicles. Within secondary lymphoid follicles, follicular helper T (TFH) cells have previously been shown to be highly permissive to HIV-1. Recently, another subset of T cells in secondary lymphoid follicles was described, follicular regulatory T (TFR) cells. These cells share some phenotypic characteristics with TFH cells, and studies that showed that TFH cells are highly permissive to HIV-1 included TFR cells in their definition of TFH cells. The permissivity of TFR cells to HIV-1 has not previously been described. Here, we show that TFR cells are highly permissive to HIV-1 both and The expression of Ki67, a marker of proliferative capacity, is predictive of expression of viral proteins, and downregulating Ki67 leads to concurrent decreases in expression of viral proteins. Our study provides new insight into HIV-1 replication and a potential new cell type to target for future treatment.
滤泡调节性T（TFR）细胞是次级淋巴滤泡中CD4 T细胞的一个亚群。TFR细胞以前被归入滤泡辅助性T（TFH）细胞亚群，TFH细胞亚群由对HIV-1高度易感的细胞组成。TFR细胞对HIV-1的易感性尚不清楚。我们发现，TFR细胞比TFH细胞对R5嗜性HIV-1更易感。TFR细胞表达更多的CCR5和CD4，并支持更高频率的病毒融合。Ki67表达的差异与HIV-1复制相关。抑制细胞增殖可降低Ki67表达和HIV-1复制。来自未接受治疗的HIV感染个体的淋巴结细胞显示，TFR细胞中HIV-1 RNA浓度最高，Ki67表达水平也最高。这些数据表明，TFR细胞对R5嗜性HIV-1在体外和体内均高度易感。这可能与CCR5水平升高以及增殖状态增强有关，提示TFR细胞促成了R5嗜性HIV-1的持续复制。在慢性、未治疗的HIV-1感染中，病毒复制集中在次级淋巴滤泡。在次级淋巴滤泡内，滤泡辅助性T（TFH）细胞以前已被证明对HIV-1高度易感。最近，描述了次级淋巴滤泡中T细胞的另一个亚群，即滤泡调节性T（TFR）细胞。这些细胞与TFH细胞有一些表型特征相同，并且表明TFH细胞对HIV-1高度易感的研究在其TFH细胞定义中包括了TFR细胞。以前尚未描述TFR细胞对HIV-1的易感性。在这里，我们表明TFR细胞在体外和体内均对HIV-1高度易感。增殖能力标志物Ki67的表达可预测病毒蛋白的表达，下调Ki67会导致病毒蛋白表达同时降低。我们的研究为HIV-1复制提供了新见解，并为未来治疗提供了一种潜在的新的靶向细胞类型。
