Journal Article

CCR5AS lncRNA variation differentially regulates CCR5, influencing HIV disease outcome

Martin, Maureen P., Naranbhai, Vivek, Nguyen, Hoang, Le Gall, Sylvie, Lin, Zhansong, Anderson, Stephen K., Viard, Mathias, Zou, Chengcheng, Walker, Bruce, Walker-Sperling, Victoria, Singh, Sukhvinder, Yu, Xu G., Margolick, Joseph, Michael, Nelson, Haas, David W., Deeks, Steven G., Chowdhury, Fatema Z., McLaren, Paul J., Lied, Alexandra, Kulkarni, Smita, Gatanaga, Hiroyuki, Thio, Chloe L., Rucevic, Marijana, Carrington, Mary, Kirk, Gregory D., Goedert, James J., Oka, Shinichi, Takiguchi, Masafumi, Kulkarni, Viraj, Ewy, Rodger, Hoots, W. Keith

2019

Overview

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. Multiple genetic variants have been identified that influence the outcome of HIV infection. Carrington and colleagues investigate the mechanism of one of the strongest variants, rs1015164, and show that it influences expression of a lncRNA controlling CCR5 expression.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 3' Untranslated Regions / 631/250/2502 / 692/699/255/1901 / Activating transcription factor 1 / Alleles / Analysis / Antisense RNA / Binding sites / Biomarkers / Biomedical and Life Sciences / Biomedicine / Care and treatment / CCR5 protein / CD4 antigen / CD4-Positive T-Lymphocytes - immunology / CD4-Positive T-Lymphocytes - metabolism / CD4-Positive T-Lymphocytes - virology / Cell Membrane - metabolism / Gene Expression Regulation / Genes, Reporter / Genetic aspects / Genetic diversity / Genetic variance / Genetic Variation / Genome-wide association studies / Genomes / Genotype / HIV / HIV infection / HIV Infections - genetics / HIV Infections - metabolism / HIV Infections - virology / HIV-1 / Human immunodeficiency virus / Humans / Immunology / Infections / Infectious Diseases / Linkage Disequilibrium / Lymphocytes T / mRNA / Polymorphism, Single Nucleotide / Population Groups - genetics / Prognosis / Receptors, CCR5 - genetics / Receptors, CCR5 - metabolism / RNA Stability / RNA, Antisense - genetics / RNA, Long Noncoding - genetics / RNA, Messenger - genetics / RNA, Messenger - metabolism / RNA-binding protein / Single nucleotide polymorphisms / Viral Load