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

Autor:	Gornalusse GG; 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;, Mummidi S; 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;, Gaitan AA; 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;, Jimenez F; 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;, Ramsuran V; 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;, Picton A; 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;, Rogers K; 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;, Manoharan MS; 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;, Avadhanam N; 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;, Murthy KK; Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, TX 78245;, Martinez H; 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;, Molano Murillo A; 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;, Chykarenko ZA; Department of General Pediatrics and Pediatric Infectious Diseases, Dnepropetrovsk State Medical Academy, 49044 Dnepropetrovsk, Ukraine;, Hutt R; Department of Medicine, New York University School of Medicine, New York, NY 10016;, Daskalakis D; Department of Medicine, New York University School of Medicine, New York, NY 10016;, Shostakovich-Koretskaya L; Department of General Pediatrics and Pediatric Infectious Diseases, Dnepropetrovsk State Medical Academy, 49044 Dnepropetrovsk, Ukraine;, Abdool Karim S; 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;, Martin JN; 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;, Deeks SG; 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;, Hecht F; 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;, Sinclair E; 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;, Clark RA; 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;, Okulicz J; San Antonio Military Medical Center, Fort Sam Houston, San Antonio, TX 78234;, Valentine FT; Department of Medicine, New York University School of Medicine, New York, NY 10016;, Martinson N; 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., Tiemessen CT; 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;, Ndung'u T; 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;, Hunt PW; 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;, He W; 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;, Ahuja SK; 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.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2015 Aug 25; Vol. 112 (34), pp. E4762-71. Date of Electronic Publication: 2015 Aug 11.
DOI:	10.1073/pnas.1423228112
Abstrakt:	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.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu