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Proc Natl Acad Sci U S A. 2015 Aug 25;112(34):E4762-71. doi: 10.1073/pnas.1423228112. Epub 2015 Aug 11.

Epigenetic mechanisms, T-cell activation, and CCR5 genetics interact to regulate T-cell expression of CCR5, the major HIV-1 coreceptor.

Author information

1
Veterans Administration Research Center for AIDS and HIV-1 Infection, South Texas Veterans Health Care System, San Antonio, TX 78229; Center for Personalized Medicine, South Texas Veterans Health Care System, San Antonio, TX 78229; Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78229; Department of Microbiology, University of Texas Health Science Center, San Antonio, TX 78229;
2
Veterans Administration Research Center for AIDS and HIV-1 Infection, South Texas Veterans Health Care System, San Antonio, TX 78229; Center for Personalized Medicine, South Texas Veterans Health Care System, San Antonio, TX 78229; Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78229;
3
HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban 4013, South Africa; Centre for the AIDS Program of Research in South Africa (CAPRISA), Doris Duke Medical Research Institute, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban 4013, South Africa;
4
Centre for HIV and Sexually Transmitted Infections, National Institute for Communicable Diseases, Sandringham, Johannesburg 2131, South Africa; Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa;
5
Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, TX 78245;
6
Department of General Pediatrics and Pediatric Infectious Diseases, Dnepropetrovsk State Medical Academy, 49044 Dnepropetrovsk, Ukraine;
7
Department of Medicine, New York University School of Medicine, New York, NY 10016;
8
Centre for the AIDS Program of Research in South Africa (CAPRISA), Doris Duke Medical Research Institute, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban 4013, South Africa;
9
Department of Medicine, University of California, San Francisco, CA 94110; Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94110; San Francisco General Hospital, San Francisco, CA 94110;
10
San Antonio Military Medical Center, Fort Sam Houston, San Antonio, TX 78234;
11
Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa; Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg 2193, South Africa; Medical Research Council Soweto Matlosana Centre for HIV/AIDS and Tuberculosis, Johannesburg 2193, South Africa; Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
12
Centre for HIV and Sexually Transmitted Infections, National Institute for Communicable Diseases, Sandringham, Johannesburg 2131, South Africa; Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa; Medical Research Council Soweto Matlosana Centre for HIV/AIDS and Tuberculosis, Johannesburg 2193, South Africa;
13
Veterans Administration Research Center for AIDS and HIV-1 Infection, South Texas Veterans Health Care System, San Antonio, TX 78229; Center for Personalized Medicine, South Texas Veterans Health Care System, San Antonio, TX 78229; Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78229; Department of Microbiology, University of Texas Health Science Center, San Antonio, TX 78229; ahujas@uthscsa.edu.

Abstract

T-cell expression levels of CC chemokine receptor 5 (CCR5) are a critical determinant of HIV/AIDS susceptibility, and manifest wide variations (i) between T-cell subsets and among individuals and (ii) in T-cell activation-induced increases in expression levels. We demonstrate that a unifying mechanism for this variation is differences in constitutive and T-cell activation-induced DNA methylation status of CCR5 cis-regulatory regions (cis-regions). Commencing at an evolutionarily conserved CpG (CpG -41), CCR5 cis-regions manifest lower vs. higher methylation in T cells with higher vs. lower CCR5 levels (memory vs. naïve T cells) and in memory T cells with higher vs. lower CCR5 levels. HIV-related and in vitro induced T-cell activation is associated with demethylation of these cis-regions. CCR5 haplotypes associated with increased vs. decreased gene/surface expression levels and HIV/AIDS susceptibility magnify vs. dampen T-cell activation-associated demethylation. Methylation status of CCR5 intron 2 explains a larger proportion of the variation in CCR5 levels than genotype or T-cell activation. The ancestral, protective CCR5-HHA haplotype bears a polymorphism at CpG -41 that is (i) specific to southern Africa, (ii) abrogates binding of the transcription factor CREB1 to this cis-region, and (iii) exhibits a trend for overrepresentation in persons with reduced susceptibility to HIV and disease progression. Genotypes lacking the CCR5-Δ32 mutation but with hypermethylated cis-regions have CCR5 levels similar to genotypes heterozygous for CCR5-Δ32. In HIV-infected individuals, CCR5 cis-regions remain demethylated, despite restoration of CD4+ counts (≥800 cells per mm(3)) with antiretroviral therapy. Thus, methylation content of CCR5 cis-regions is a central epigenetic determinant of T-cell CCR5 levels, and possibly HIV-related outcomes.

KEYWORDS:

CCR5; HIV; T-cell activation; methylation; polymorphism

PMID:
26307764
PMCID:
PMC4553789
DOI:
10.1073/pnas.1423228112
[Indexed for MEDLINE]
Free PMC Article

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