T-cell expression of CC chemokine receptor 5 (CCR5), the major HIV-1 coreceptor, is a key determinant of AIDS susceptibility.
Researchers found that the DNA methylation status of noncoding DNA regions, such as promoters and introns, within CCR5 called cis-regulatory regions (cis-regions) was inversely correlated with T-cell CCR5 levels.
As a result, constitutive differences in cis-region DNA methylation content between different types of T cells or between individual T cells were associated with differences in CCR5 levels between different T cell types or between individual T cells, respectively. Relatively small differences in methylation content were associated with large effects on T-cell CCR5 levels.
HIV-associated or in vitro-induced activation of T cells resulted in demethylation of CCR5 cis-regions. Genetic variations in the CCR5 cis-regions that are associated with high or low AIDS susceptibility were associated with increased or decreased sensitivity to activation-induced demethylation, respectively.
The findings uncover an epigenetic mechanism that influences CCR5 expression on T cells. Genetically determined differences in sensitivity to HIV-associated demethylation of CCR5 cis-regions may serve as a mechanism for the wide interindividual variation in AIDS susceptibility and disease outcomes, according to the authors.