CCR5AS lncRNA variation differentially regulates CCR5, influencing HIV disease outcome

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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Alleles
  • Biomarkers
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / virology
  • Cell Membrane / metabolism
  • Gene Expression Regulation*
  • Genes, Reporter
  • Genetic Variation*
  • Genotype
  • HIV Infections / genetics*
  • HIV Infections / metabolism
  • HIV Infections / virology*
  • HIV-1*
  • Humans
  • Linkage Disequilibrium
  • Polymorphism, Single Nucleotide
  • Population Groups / genetics
  • Prognosis
  • RNA Stability
  • RNA, Antisense / genetics*
  • RNA, Long Noncoding / genetics*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, CCR5 / genetics*
  • Receptors, CCR5 / metabolism
  • Viral Load


  • 3' Untranslated Regions
  • Biomarkers
  • RNA, Antisense
  • RNA, Long Noncoding
  • RNA, Messenger
  • Receptors, CCR5