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 Margolick; Gregory 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

doi:10.1038/s41590-019-0406-1

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 journal › Article › peer-review

30 Scopus citations

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 language	English (US)
Pages (from-to)	824-834
Number of pages	11
Journal	Nature Immunology
Volume	20
Issue number	7
DOIs	https://doi.org/10.1038/s41590-019-0406-1
State	Published - Jul 1 2019

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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Kulkarni, S., Lied, A., Kulkarni, V., Rucevic, M., Martin, M. P., Walker-Sperling, V., Anderson, S. K., Ewy, R., Singh, S., Nguyen, H., McLaren, P. J., Viard, M., Naranbhai, V., Zou, C., Lin, Z., Gatanaga, H., Oka, S., Takiguchi, M., Thio, C. L., ... Carrington, M. (2019). CCR5AS lncRNA variation differentially regulates CCR5, influencing HIV disease outcome. Nature Immunology, 20(7), 824-834. https://doi.org/10.1038/s41590-019-0406-1

Kulkarni, S, Lied, A, Kulkarni, V, Rucevic, M, Martin, MP, Walker-Sperling, V, Anderson, SK, Ewy, R, Singh, S, Nguyen, H, McLaren, PJ, Viard, M, Naranbhai, V, Zou, C, Lin, Z, Gatanaga, H, Oka, S, Takiguchi, M, Thio, CL , Margolick, J , Kirk, GD, Goedert, JJ, Hoots, WK, Deeks, SG, Haas, DW, Michael, N, Walker, B, Le Gall, S, Chowdhury, FZ, Yu, XG & Carrington, M 2019, 'CCR5AS lncRNA variation differentially regulates CCR5, influencing HIV disease outcome', Nature Immunology, vol. 20, no. 7, pp. 824-834. https://doi.org/10.1038/s41590-019-0406-1

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title = "CCR5AS lncRNA variation differentially regulates CCR5, influencing HIV disease outcome",

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.",

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

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doi = "10.1038/s41590-019-0406-1",

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AU - Kulkarni, Smita

AU - Lied, Alexandra

AU - Kulkarni, Viraj

AU - Rucevic, Marijana

AU - Martin, Maureen P.

AU - Walker-Sperling, Victoria

AU - Anderson, Stephen K.

AU - Ewy, Rodger

AU - Singh, Sukhvinder

AU - Nguyen, Hoang

AU - McLaren, Paul J.

AU - Viard, Mathias

AU - Naranbhai, Vivek

AU - Zou, Chengcheng

AU - Lin, Zhansong

AU - Gatanaga, Hiroyuki

AU - Oka, Shinichi

AU - Takiguchi, Masafumi

AU - Thio, Chloe L.

AU - Margolick, Joseph

AU - Kirk, Gregory D.

AU - Goedert, James J.

AU - Hoots, W. Keith

AU - Deeks, Steven G.

AU - Haas, David W.

AU - Michael, Nelson

AU - Walker, Bruce

AU - Le Gall, Sylvie

AU - Chowdhury, Fatema Z.

AU - Yu, Xu G.

AU - Carrington, Mary

PY - 2019/7/1

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N2 - 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.

AB - 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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CCR5AS lncRNA variation differentially regulates CCR5, influencing HIV disease outcome

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