title: Epigenetic mechanisms, T-cell activation, and CCR5 genetics interact to regulate T-cell expression of CCR5, the major HIV-1 coreceptor.
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.
authors: 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;
authors: German G
authors: GG
authors: Gornalusse
authors: 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;
authors: Srinivas
authors: S
authors: Mummidi
authors: 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;
authors: Alvaro A
authors: AA
authors: Gaitan
authors: 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;
authors: Fabio
authors: F
authors: Jimenez
authors: 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;
authors: Veron
authors: V
authors: Ramsuran
authors: 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;
authors: Anabela
authors: A
authors: Picton
authors: 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;
authors: Kristen
authors: K
authors: Rogers
authors: 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;
authors: Muthu Saravanan
authors: MS
authors: Manoharan
authors: 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;
authors: Nymisha
authors: N
authors: Avadhanam
authors: Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, TX 78245;
authors: Krishna K
authors: KK
authors: Murthy
authors: 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;
authors: Hernan
authors: H
authors: Martinez
authors: 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;
authors: Angela
authors: A
authors: Molano Murillo
authors: Department of General Pediatrics and Pediatric Infectious Diseases, Dnepropetrovsk State Medical Academy, 49044 Dnepropetrovsk, Ukraine;
authors: Zoya A
authors: ZA
authors: Chykarenko
authors: Department of Medicine, New York University School of Medicine, New York, NY 10016;
authors: Richard
authors: R
authors: Hutt
authors: Department of Medicine, New York University School of Medicine, New York, NY 10016;
authors: Demetre
authors: D
authors: Daskalakis
authors: Department of General Pediatrics and Pediatric Infectious Diseases, Dnepropetrovsk State Medical Academy, 49044 Dnepropetrovsk, Ukraine;
authors: Ludmila
authors: L
authors: Shostakovich-Koretskaya
authors: 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;
authors: Salim
authors: S
authors: Abdool Karim
authors: 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;
authors: Jeffrey N
authors: JN
authors: Martin
authors: 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;
authors: Steven G
authors: SG
authors: Deeks
authors: 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;
authors: Frederick
authors: F
authors: Hecht
authors: 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;
authors: Elizabeth
authors: E
authors: Sinclair
authors: 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;
authors: Robert A
authors: RA
authors: Clark
authors: San Antonio Military Medical Center, Fort Sam Houston, San Antonio, TX 78234;
authors: Jason
authors: J
authors: Okulicz
authors: Department of Medicine, New York University School of Medicine, New York, NY 10016;
authors: Fred T
authors: FT
authors: Valentine
authors: 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.
authors: Neil
authors: N
authors: Martinson
authors: 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;
authors: Caroline Tanya
authors: CT
authors: Tiemessen
authors: 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;
authors: Thumbi
authors: T
authors: Ndung'u
authors: 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;
authors: Peter W
authors: PW
authors: Hunt
authors: 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;
authors: Weijing
authors: W
authors: He
authors: 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.
authors: Sunil K
authors: SK
authors: Ahuja
mesh_terms: D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D008213:Lymphocyte Activation; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism*; D011991:Receptors, Virus / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: C584933:CCR5 protein, human; D019713:Receptors, CCR5; D011991:Receptors, Virus
keywords: CCR5; HIV; T-cell activation; methylation; polymorphism