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: 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, 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
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 112 Issue 34 Pg. E4762-71 (Aug 25 2015) ISSN: 1091-6490 [Electronic] United States
• PMID: 26307764 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• CCR5 protein, human
• Receptors, CCR5
• Receptors, Virus

Topics

• DNA Methylation
• Epigenesis, Genetic
• HIV-1 (metabolism)
• Humans
• Lymphocyte Activation
• Receptors, CCR5 (genetics, metabolism)
• Receptors, Virus (metabolism)
• T-Lymphocytes (immunology)