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

German G. Gornalusse, Srinivas Mummidi, Alvaro A. Gaitan, Fabio Jimenez, Veron Ramsuran, Anabela Picton, Kristen Rogers, Muthu Saravanan Manoharan, Nymisha Avadhanam, Krishna K. Murthy, Hernan Martinez, Angela Molano Murillo, Zoya A. Chykarenko, Richard Hutt, Demetre Daskalakis, Ludmila Shostakovich-Koretskaya, Salim Abdool Karim, Jeffrey N. Martin, Steven G. Deeks, Frederick Hecht & 10 others Elizabeth Sinclair, Robert A. Clark, Jason Okulicz, Fred T. Valentine, Neil Martinson, Caroline Tanya Tiemessen, Thumbi Ndung'U, Peter W. Hunt, Weijing He, Sunil K. Ahuja

Research output: Contribution to journalArticle

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 mm3) 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.

Original languageEnglish (US)
Pages (from-to)E4762-E4771
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number34
DOIs
StatePublished - Aug 25 2015

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CCR5 Receptors
Epigenomics
HIV-1
T-Lymphocytes
Nucleic Acid Regulatory Sequences
HIV
Methylation
Genotype
Haplotypes
Acquired Immunodeficiency Syndrome
Southern Africa

Keywords

  • CCR5
  • HIV
  • Methylation
  • Polymorphism
  • T-cell activation

ASJC Scopus subject areas

  • General

Cite this

Epigenetic mechanisms, T-cell activation, and CCR5 genetics interact to regulate T-cell expression of CCR5, the major HIV-1 coreceptor. / Gornalusse, German G.; Mummidi, Srinivas; Gaitan, Alvaro A.; Jimenez, Fabio; Ramsuran, Veron; Picton, Anabela; Rogers, Kristen; Manoharan, Muthu Saravanan; Avadhanam, Nymisha; Murthy, Krishna K.; Martinez, Hernan; Murillo, Angela Molano; Chykarenko, Zoya A.; Hutt, Richard; Daskalakis, Demetre; Shostakovich-Koretskaya, Ludmila; Karim, Salim Abdool; Martin, Jeffrey N.; Deeks, Steven G.; Hecht, Frederick; Sinclair, Elizabeth; Clark, Robert A.; Okulicz, Jason; Valentine, Fred T.; Martinson, Neil; Tiemessen, Caroline Tanya; Ndung'U, Thumbi; Hunt, Peter W.; He, Weijing; Ahuja, Sunil K.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 34, 25.08.2015, p. E4762-E4771.

Research output: Contribution to journalArticle

Gornalusse, GG, Mummidi, S, Gaitan, AA, Jimenez, F, Ramsuran, V, Picton, A, Rogers, K, Manoharan, MS, Avadhanam, N, Murthy, KK, Martinez, H, Murillo, AM, Chykarenko, ZA, Hutt, R, Daskalakis, D, Shostakovich-Koretskaya, L, Karim, SA, Martin, JN, Deeks, SG, Hecht, F, Sinclair, E, Clark, RA, Okulicz, J, Valentine, FT, Martinson, N, Tiemessen, CT, Ndung'U, T, Hunt, PW, He, W & Ahuja, SK 2015, 'Epigenetic mechanisms, T-cell activation, and CCR5 genetics interact to regulate T-cell expression of CCR5, the major HIV-1 coreceptor', Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 34, pp. E4762-E4771. https://doi.org/10.1073/pnas.1423228112
Gornalusse, German G. ; Mummidi, Srinivas ; Gaitan, Alvaro A. ; Jimenez, Fabio ; Ramsuran, Veron ; Picton, Anabela ; Rogers, Kristen ; Manoharan, Muthu Saravanan ; Avadhanam, Nymisha ; Murthy, Krishna K. ; Martinez, Hernan ; Murillo, Angela Molano ; Chykarenko, Zoya A. ; Hutt, Richard ; Daskalakis, Demetre ; Shostakovich-Koretskaya, Ludmila ; Karim, Salim Abdool ; Martin, Jeffrey N. ; Deeks, Steven G. ; Hecht, Frederick ; Sinclair, Elizabeth ; Clark, Robert A. ; Okulicz, Jason ; Valentine, Fred T. ; Martinson, Neil ; Tiemessen, Caroline Tanya ; Ndung'U, Thumbi ; Hunt, Peter W. ; He, Weijing ; Ahuja, Sunil K. / Epigenetic mechanisms, T-cell activation, and CCR5 genetics interact to regulate T-cell expression of CCR5, the major HIV-1 coreceptor. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 34. pp. E4762-E4771.
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T1 - Epigenetic mechanisms, T-cell activation, and CCR5 genetics interact to regulate T-cell expression of CCR5, the major HIV-1 coreceptor

AU - Gornalusse, German G.

AU - Mummidi, Srinivas

AU - Gaitan, Alvaro A.

AU - Jimenez, Fabio

AU - Ramsuran, Veron

AU - Picton, Anabela

AU - Rogers, Kristen

AU - Manoharan, Muthu Saravanan

AU - Avadhanam, Nymisha

AU - Murthy, Krishna K.

AU - Martinez, Hernan

AU - Murillo, Angela Molano

AU - Chykarenko, Zoya A.

AU - Hutt, Richard

AU - Daskalakis, Demetre

AU - Shostakovich-Koretskaya, Ludmila

AU - Karim, Salim Abdool

AU - Martin, Jeffrey N.

AU - Deeks, Steven G.

AU - Hecht, Frederick

AU - Sinclair, Elizabeth

AU - Clark, Robert A.

AU - Okulicz, Jason

AU - Valentine, Fred T.

AU - Martinson, Neil

AU - Tiemessen, Caroline Tanya

AU - Ndung'U, Thumbi

AU - Hunt, Peter W.

AU - He, Weijing

AU - Ahuja, Sunil K.

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N2 - 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 mm3) 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.

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KW - Methylation

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