Abstract
C-C chemokine receptor 5 (CCR5) is the main HIV co-receptor affecting susceptibility and disease course. Quantitative trait loci (QTL) mapping analysis was performed to assess genetic variants associated with CCR5 expression on circulating immune cells in 209 PLHIV using ART and 304 healthy controls, all of Western European ancestry. The proportions of CCR5 positive cells and CCR5 mean fluorescence intensity (MFI) were assessed by flow cytometry in monocytes and CD4+ and CD8+ T cell subsets using flow cytometry. We identified the rs60939770, which is an intergenic variant in cis-region to CCR5 gene not in linkage disequilibrium with CCR5d32, related to the proportion of CCR5+ memory T regulatory cells, both in PLHIV and healthy controls. Two genome-wide significant loci, in linkage equilibrium with CCR5d32, were found to be associated with CCR5 MFI of multiple subsets of mostly differentiated memory T cells in both groups. The expression of nearby chemokines receptors (CCR1, CCR2, CCR3, CCRL2), existing in the same the same topologically associating domain, were also influenced by these genetic variants. Furthermore, we show the genetic variants which modulate CCR5 surface expression affect the production of other inflammatory mediators, including monocyte- and lymphocytederived cytokines as well as CCL4 and IL-8. Our data indicate that the genetic regulation of CCR5 expression is cell-specific and affects the production of various inflammatory mediators.
Competing Interest Statement
The authors have declared no competing interest.
