Publication Date:
2015-08-11
Description:
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 ofCCR5 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 thesecis-regions.CCR5haplotypes associated with increased vs. decreased gene/surface expression levels and HIV/AIDS susceptibility magnify vs. dampen T-cell activation-associated demethylation. Methylation status ofCCR5intron 2 explains a larger proportion of the variation in CCR5 levels than genotype or T-cell activation. The ancestral, protectiveCCR5-HHA haplotype bears a polymorphism at CpG −41 that is (i) specific to southern Africa, (ii) abrogates binding of the transcription factor CREB1 to thiscis-region, and (iii) exhibits a trend for overrepresentation in persons with reduced susceptibility to HIV and disease progression. Genotypes lacking theCCR5-Δ32 mutation but with hypermethylatedcis-regions have CCR5 levels similar to genotypes heterozygous forCCR5-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 ofCCR5 cis-regions is a central epigenetic determinant of T-cell CCR5 levels, and possibly HIV-related outcomes.
Print ISSN:
0027-8424
Electronic ISSN:
1091-6490
Topics:
Biology
,
Medicine
,
Natural Sciences in General
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