CCR5AS lncRNA variation differentially regulates CCR5, influencing HIV disease outcome

被引：73

作者：

Kulkarni, Smita ^{[1
,2
,3
]}

Lied, Alexandra ^{[2
,3
]}

Kulkarni, Viraj ^{[2
,3
]}

Rucevic, Marijana ^{[2
,3
,4
]}

Martin, Maureen P. ^{[5
]}

Walker-Sperling, Victoria ^{[6
]}

Anderson, Stephen K. ^{[5
]}

Ewy, Rodger ^{[1
]}

Singh, Sukhvinder ^{[1
]}

Nguyen, Hoang ^{[1
]}

McLaren, Paul J. ^{[7
,8
]}

Viard, Mathias ^{[5
]}

Naranbhai, Vivek ^{[2
,3
]}

Zou, Chengcheng ^{[9
]}

Lin, Zhansong ^{[9
]}

Gatanaga, Hiroyuki ^{[9
,10
]}

Oka, Shinichi ^{[9
,10
]}

Takiguchi, Masafumi ^{[9
]}

Thio, Chloe L. ^{[11
]}

Margolick, Joseph ^{[12
]}

Kirk, Gregory D. ^{[13
]}

Goedert, James J. ^{[14
]}

Hoots, W. Keith ^{[15
]}

Deeks, Steven G. ^{[16
]}

Haas, David W. ^{[17
]}

Michael, Nelson ^{[18
]}

Walker, Bruce ^{[2
,3
,19
,20
]}

Le Gall, Sylvie ^{[2
,3
]}

Chowdhury, Fatema Z. ^{[2
,3
]}

Yu, Xu G. ^{[2
,3
]}

Carrington, Mary ^{[2
,3
,5
]}

机构：

[1] Texas Biomed Res Inst, San Antonio, TX 78227 USA

[2] MIT, Massachusetts Gen Hosp, Ragon Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[3] Harvard Univ, Cambridge, MA 02138 USA

[4] Olink Prote, Watertown, MA USA

[5] Frederick Natl Lab Canc Res, Basic Sci Program, Frederick, MD 21701 USA

[6] NCI, Canc & Inflammat Program, Ctr Canc Res, NIH, Frederick, MD 21701 USA

[7] Publ Hlth Agcy Canada, JC Wilt Infect Dis Res Ctr, Winnipeg, MB, Canada

[8] Univ Manitoba, Dept Med Microbiol & Infect Dis, Winnipeg, MB, Canada

[9] Kumamoto Univ, Ctr AIDS Res, Kumamoto, Japan

[10] Natl Ctr Global Hlth & Med, AIDS Clin Ctr, Tokyo, Japan

[11] Johns Hopkins Univ, Dept Med, Baltimore, MD USA

[12] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA

[13] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA

[14] NCI, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, Rockville, MD USA

[15] NHLBI, Div Blood Dis & Resources, NIH, Bldg 10, Bethesda, MD 20892 USA

[16] San Francisco Gen Hosp, Med Ctr, San Francisco, CA 94110 USA

[17] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA

[18] Walter Reed Army Inst Res, US Mil HIV Res Program, Silver Spring, MD USA

[19] Howard Hughes Med Inst, Chevy Chase, MD USA

[20] MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA

来源：

NATURE IMMUNOLOGY | 2019年 / 20卷 / 07期

关键词：

LONG NONCODING RNAS; HOST GENETIC-VARIATION; MESSENGER-RNA; VIRUS REPLICATION; EXPRESSION; INFECTION; PROGRESSION; CELLS; HEPATITIS; DENSITY;

D O I：

10.1038/s41590-019-0406-1

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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(+) Tcells. 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(+) Tcells 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.

引用

页码：824 / +

页数：13

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