CCR5AS lncRNA variation differentially regulates CCR5, influencing HIV disease outcome

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)824-834
Number of pages11
JournalNature Immunology
Volume20
Issue number7
DOIs
StatePublished - Jul 1 2019

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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