ArticleProceedings of the National Academy of Sciences of the United States of America2015
Epigenetic mechanisms, T-cell activation, and CCR5 genetics interact to regulate T-cell expression of CCR5, the major HIV-1 coreceptor.
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Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers, 1 of them a synthesis that pooled it.
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43citing papers in PubMed, 1 pooled it
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Who cites it
43 citing papers in PubMed, 1 synthesis or guideline pooled it, 62 citations in OpenAlex.
- Pooled it
- Quantification and localization of integrated HIV-1 in memory and naïve CD4+ T cells from adolescents and young adults with perinatally-acquired HIV-1.PLoS pathogens · 2026Article
- Mechanisms of transcriptional regulation of CCR5, which is the co-receptor for R5-tropic HIV and is also involved in other disease processes.Biochemical Society transactions · 2026Review
- Host genetics influences HIV reservoir persistence, treatment outcomes and CCR5 expression in patients on long-term antiretroviral therapy in Ghana.Frontiers in immunology · 2026Article
- Uncovering Cellular Interactome Drivers of Immune Checkpoint Inhibitor Response in Advanced Melanoma Patients.Cellular and molecular bioengineering · 2025Article
- mRNA Isoforms and Variants in Health and Disease.International journal of molecular sciences · 2025Review
- CCR5 + T cells as a potential biomarker for primary Sjögren's disease based on bioinformatics analysis.Clinical rheumatology · 2025Article
- Human models that inform antiretroviral therapy-free remission with perinatally acquired HIV infection.Current opinion in HIV and AIDS · 2025Review
- Promoter Methylation of HIV Coreceptor-Related Genes CCR5 and CXCR4: Original Research.Viruses · 2025Article
- Article
- Special Issue "Molecular and Genetic Aspects of SARS-CoV-2 Infection and COVID-19 Disease".International journal of molecular sciences · 2024Article
- Low prevalence of HIV in the northern Cameroon: contribution of some AIDS restriction genes and potential implications for gene therapy.Frontiers in genetics · 2024Article
- Distinct mucosal and systemic immunological characteristics in transgender women potentially relating to HIV acquisition.JCI insight · 2023Article
- CCR5∆32 and SDF1 3'A: Gene Variants, Expression and Influence on Biological Markers for the Clinical Progression to AIDS among HIV-1 Virus Controllers in a Mixed Population of the Amazon Region of Brazil.International journal of molecular sciences · 2023Article
- The Influence BetweenAIDS research and human retroviruses · 2023Review
- MiRNA-103 downmodulates CCR5 expression reducing human immunodeficiency virus type-1 entry and impacting latency establishment in CD4iScience · 2022Article
- People with HIV have higher percentages of circulating CCR5+ CD8+ T cells and lower percentages of CCR5+ regulatory T cells.Scientific reports · 2022Article
- So Pathogenic or So What?-A Brief Overview of SIV Pathogenesis with an Emphasis on Cure Research.Viruses · 2022Review
- Regulatory Noncoding and Predicted Pathogenic Coding Variants ofInternational journal of molecular sciences · 2021Article
- Epigenetic Regulation ofFrontiers in immunology · 2021Article
Corrections and comments
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Authors and funding
30 authors at 13 institutions in 3 countries.
German G GornalusseVeterans 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;
Srinivas MummidiVeterans 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;
Alvaro A GaitanVeterans 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;
Fabio JimenezVeterans 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;
Veron RamsuranHIV 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;
Anabela PictonCentre 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;
Kristen RogersVeterans 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;
Muthu Saravanan ManoharanVeterans 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;
Nymisha AvadhanamVeterans 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;
Krishna K MurthyDepartment of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, TX 78245;
Hernan MartinezVeterans 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;
Angela Molano MurilloVeterans 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;
Zoya A ChykarenkoDepartment of General Pediatrics and Pediatric Infectious Diseases, Dnepropetrovsk State Medical Academy, 49044 Dnepropetrovsk, Ukraine;
Richard HuttDepartment of Medicine, New York University School of Medicine, New York, NY 10016;
Demetre DaskalakisDepartment of Medicine, New York University School of Medicine, New York, NY 10016;
Ludmila Shostakovich-KoretskayaDepartment of General Pediatrics and Pediatric Infectious Diseases, Dnepropetrovsk State Medical Academy, 49044 Dnepropetrovsk, Ukraine;
Salim Abdool KarimCentre 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;
Jeffrey N MartinDepartment 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;
Steven G DeeksDepartment 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;
Frederick HechtDepartment 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;
Elizabeth SinclairDepartment 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;
Robert A ClarkVeterans 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;
Jason OkuliczSan Antonio Military Medical Center, Fort Sam Houston, San Antonio, TX 78234;
Fred T ValentineDepartment of Medicine, New York University School of Medicine, New York, NY 10016;
Neil MartinsonFaculty 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.
Caroline Tanya TiemessenCentre 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;
Thumbi Ndung'uHIV 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;
Peter W HuntDepartment 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;
Weijing HeVeterans 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;
Sunil K AhujaVeterans 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.
South Texas Veterans Health Care System · USThe University of Texas Health Science Center at San Antonio · USNew York University · USSan Francisco General Hospital · USUniversity of KwaZulu-Natal · ZADnipropetrovsk State Medical Academy · UAUnited States Department of Veterans Affairs · USUniversity of California, San Francisco · USJohns Hopkins University · USNational Institute for Communicable DiseasesSan Antonio Military Medical Center · USTexas Biomedical Research Institute · USUniversity of the Witwatersrand · ZA
Funding
The Southwest National Primate Research Center Supplement- Infrastructure improvements of ABSL2 holding areasP51OD011133 · OD · TEXAS BIOMEDICAL RESEARCH INSTITUTE · PI Larry S. Schlesinger · 2012 to 2026
$129.7MUCSF CLINICAL AND TRANSLATIONAL SCIENCE INSTITUTEUL1RR024131 · NCRR · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI JOHNSTON, S. CLAIBORNE · 2006 to 2011
$111.2MUnsolicited R24 for the CFAR-Network of Integrated Clinical Sciences, CNICSR24AI067039 · NIAID · UNIVERSITY OF ALABAMA AT BIRMINGHAM · PI Michael S. Saag · 2006 to 2026
$99.4MVirology CoreP30AI027763 · NIAID · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI STEVEN Grant DEEKS · 1988 to 2026
$93.6MTISSUE CULTURE---COREP30CA054174 · NCI · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · PI Lei Zheng · 1991 to 2026
$59.1MUjima Mentoring ProgramP30MH062246 · NIMH · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Sheri Ann Lippman · 2001 to 2026
$57.4MINSTITUTE FOR INTEGRATION OF MEDICINE & SCIENCE: A PARTNERSHIP TO IMPROVE HEALTHUL1RR025767 · NCRR · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · PI CLARK, ROBERT A · 2008 to 2011
$23.8MThe Viral Set Point in HIV-1 Subtype C InfectionU19AI051794 · NIAID · UNIVERSITY OF KWAZULU-NATAL · PI ABDOOL KARIM, SALIM S · 2002 to 2007
$22.5MVIROLOGY COREP30AI027742 · NIAID · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI GORNY, MIROSLAW K · 1989 to 2010
$19.4MInstitute for Integration of Medicine & Science: A Partnership to Improve HealthUL1TR001120 · NCATS · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · PI CLARK, ROBERT A, HARGREAVES, KENNETH M · 2013 to 2017
$16.5MThymic output, lymphocyte activation and turnoverP01AI057127 · NIAID · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI VALENTINE, FRED T · 2004 to 2009
$9.0MHost Genetic Determinants of HIV PathogenesisR37AI046326 · NIAID · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · PI AHUJA, SUNIL K · 2005 to 2014
$7.8MBLRD VA I01 BX000975CSRD VA IP1 CX000875NCATS NIH HHS UL1 TR001120NCI NIH HHS NIH-NCI P30CA54174NCRR NIH HHS UL1 RR024131NCRR NIH HHS UL1RR025767NHLBI NIH HHS R01HL090312NIAID NIH HHS NIH P01AI057127NIAID NIH HHS P01 AI057127NIAID NIH HHS P30 AI027742NIAID NIH HHS P30AI027742NIAID NIH HHS P30 AI027763NIAID NIH HHS R01 AI043279NIAID NIH HHS R01-AI043279NIAID NIH HHS R24 AI067039NIAID NIH HHS R37 AI046326NIAID NIH HHS R37-AI046326NIAID NIH HHS U19 AI 51794NIH HHS P51 OD011133NIMH NIH HHS P30 MH62246
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.
Indexed as
Epigenesis, GeneticLymphocyte ActivationDNA MethylationHIV-1HumansReceptors, CCR5Receptors, VirusT-LymphocytesCCR5 protein, humanReceptors, CCR5Receptors, VirusCCR5HIVmethylationpolymorphismT-cell activation
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