1. CCR5AS lncRNA variation differentially regulates CCR5, influencing HIV disease outcome
- Author
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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, and Carrington, Mary
- Subjects
Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Sexually Transmitted Infections ,Genetics ,Human Genome ,Infectious Diseases ,HIV/AIDS ,2.1 Biological and endogenous factors ,Infection ,Good Health and Well Being ,3' Untranslated Regions ,Alleles ,Biomarkers ,CD4-Positive T-Lymphocytes ,Cell Membrane ,Gene Expression Regulation ,Genes ,Reporter ,Genetic Variation ,Genotype ,HIV Infections ,HIV-1 ,Humans ,Linkage Disequilibrium ,Polymorphism ,Single Nucleotide ,Population Groups ,Prognosis ,RNA Stability ,RNA ,Antisense ,RNA ,Long Noncoding ,RNA ,Messenger ,Receptors ,CCR5 ,Viral Load ,Biochemistry and cell biology - 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.
- Published
- 2019