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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.
Affiliation
  • Kulkarni S; Texas Biomedical Research Institute, San Antonio, TX, USA. skulkarni@txbiomed.org.
  • Lied A; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. skulkarni@txbiomed.org.
  • Kulkarni V; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA.
  • Rucevic M; Texas Biomedical Research Institute, San Antonio, TX, USA.
  • Martin MP; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA.
  • Walker-Sperling V; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA.
  • Anderson SK; Olink Proteomic, Watertown, MA, USA.
  • Ewy R; Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
  • Singh S; Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
  • Nguyen H; Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
  • McLaren PJ; Texas Biomedical Research Institute, San Antonio, TX, USA.
  • Viard M; Texas Biomedical Research Institute, San Antonio, TX, USA.
  • Naranbhai V; Texas Biomedical Research Institute, San Antonio, TX, USA.
  • Zou C; J.C. Wilt Infectious Disease Research Centre, Public Health Agency of Canada, Winnipeg, MB, Canada.
  • Lin Z; Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada.
  • Gatanaga H; Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
  • Oka S; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA.
  • Takiguchi M; Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
  • Thio CL; Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
  • Margolick J; Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
  • Kirk GD; AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan.
  • Goedert JJ; Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
  • Hoots WK; AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan.
  • Deeks SG; Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
  • Haas DW; Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
  • Michael N; Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
  • Walker B; Department of Epidemiology, Johns Hopkins University, Baltimore, MD, USA.
  • Le Gall S; Epidemiology and Biostatistics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
  • Chowdhury FZ; Division of Blood Diseases and Resources, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
  • Yu XG; San Francisco General Hospital Medical Center, San Francisco, CA, USA.
  • Carrington M; Vanderbilt University School of Medicine, Nashville, TN, USA.
Nat Immunol ; 20(7): 824-834, 2019 07.
Article in En | MEDLINE | ID: mdl-31209403
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Genetic Variation / HIV Infections / Gene Expression Regulation / RNA, Antisense / HIV-1 / Receptors, CCR5 / RNA, Long Noncoding Type of study: Prognostic_studies Limits: Humans Language: En Journal: Nat Immunol Journal subject: ALERGIA E IMUNOLOGIA Year: 2019 Type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Genetic Variation / HIV Infections / Gene Expression Regulation / RNA, Antisense / HIV-1 / Receptors, CCR5 / RNA, Long Noncoding Type of study: Prognostic_studies Limits: Humans Language: En Journal: Nat Immunol Journal subject: ALERGIA E IMUNOLOGIA Year: 2019 Type: Article Affiliation country: United States