Texas Biomedical Research Institute, San Antonio, TX, USA.
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA.
Nat Immunol. 2019 Jul;20(7):824-834. doi: 10.1038/s41590-019-0406-1. Epub 2019 Jun 17.
Multiple genome-wide studies have identified associations between outcome of human immunodeficiency virus (HIV) infection and polymorphisms in and around the gene encoding the HIV co-receptor CCR5, but the functional basis for the strongest of these associations, rs1015164A/G, is unknown. We found that rs1015164 marks variation in an activating transcription factor 1 binding site that controls expression of the antisense long noncoding RNA (lncRNA) CCR5AS. Knockdown or enhancement of CCR5AS expression resulted in a corresponding change in CCR5 expression on CD4 T cells. CCR5AS interfered with interactions between the RNA-binding protein Raly and the CCR5 3' untranslated region, protecting CCR5 messenger RNA from Raly-mediated degradation. Reduction in CCR5 expression through inhibition of CCR5AS diminished infection of CD4 T cells with CCR5-tropic HIV in vitro. These data represent a rare determination of the functional importance of a genome-wide disease association where expression of a lncRNA affects HIV infection and disease progression.
多项全基因组研究已经确定了人类免疫缺陷病毒（HIV）感染结果与编码 HIV 辅助受体 CCR5 的基因及其周围基因多态性之间的关联，但这些关联中最强的关联 rs1015164A/G 的功能基础尚不清楚。我们发现 rs1015164 标记了激活转录因子 1 结合位点的变异，该位点控制着反义长非编码 RNA（lncRNA）CCR5AS 的表达。CCR5AS 的表达敲低或增强导致 CD4 T 细胞上 CCR5 表达相应变化。CCR5AS 干扰 RNA 结合蛋白 Raly 与 CCR5 3'非翻译区之间的相互作用，从而保护 CCR5 信使 RNA 免受 Raly 介导的降解。通过抑制 CCR5AS 降低 CCR5 表达可减少体外 CD4 T 细胞中 CCR5 嗜性 HIV 的感染。这些数据代表了全基因组疾病关联中罕见的功能重要性的确定，其中 lncRNA 的表达影响 HIV 感染和疾病进展。
