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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2015-08, Vol.112 (34), p.E4762-E4771
• Main Authors: 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, Molano Murillo, Angela, Chykarenko, Zoya A, Hutt, Richard, Daskalakis, Demetre, Shostakovich-Koretskaya, Ludmila, Abdool Karim, Salim, 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
• Format: Article
• Language: English
• Subjects: Biological Sciences; DNA Methylation; Epigenesis, Genetic; Epigenetics; Haplotypes; HIV; HIV-1 - metabolism; Human immunodeficiency virus; Human immunodeficiency virus 1; Humans; Lymphocyte Activation; Mutation; PNAS Plus; Polymorphism; Receptors, CCR5 - genetics; Receptors, CCR5 - metabolism; Receptors, Virus - metabolism; T cell receptors; T-Lymphocytes - immunology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1423228112

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.