학술논문
CCR5AS lncRNA variation differentially regulates CCR5, influencing HIV disease outcome
Document Type
article
Author
Kulkarni, Smita; Lied, Alexandra; Kulkarni, Viraj; Rucevic, Marijana; Martin, Maureen P; Walker-Sperling, Victoria; Anderson, Stephen K; Ewy, Rodger; Singh, Sukhvinder; Nguyen, Hoang; McLaren, Paul J; Viard, Mathias; Naranbhai, Vivek; Zou, Chengcheng; Lin, Zhansong; Gatanaga, Hiroyuki; Oka, Shinichi; Takiguchi, Masafumi; Thio, Chloe L; Margolick, Joseph; Kirk, Gregory D; Goedert, James J; Hoots, W Keith; Deeks, Steven G; Haas, David W; Michael, Nelson; Walker, Bruce; Le Gall, Sylvie; Chowdhury, Fatema Z; Yu, Xu G; Carrington, Mary
Source
Nature Immunology. 20(7)
Subject
Language
Abstract
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.