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CCR5AS lncRNA variation differentially regulates CCR5, influencing HIV disease outcome
- 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
Published Web Location
https://doi.org/10.1038/s41590-019-0406-1Abstract
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.
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