Host genetic variants regulates CCR5 expression on immune cells: a study in people living with HIV and healthy controls

dos Santos, J. C.; Zhang, Z.; van Eekeren, L. E.; Fok, E. T.; Vadaq, N.; van de Wijer, L.; van der Heijden, W.; Koeken, V. A.; Koenen, H. J.; Mhlanga, M.; Netea, M.; van der Ven, A. J.; Li, Y.

doi:10.1101/2022.06.19.496757

bioRxiv · 10.1101/2022.06.19.496757

Host genetic variants regulates CCR5 expression on immune cells: a study in people living with HIV and healthy controls

dos Santos, J. C.·Zhang, Z.·van Eekeren, L. E.·Fok, E. T.·Vadaq, N.·van de Wijer, L.·van der Heijden, W.·Koeken, V. A.·Koenen, H. J.·Mhlanga, M.·Netea, M.·van der Ven, A. J.·Li, Y.

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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 lymphocyte-derived 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. Author SummaryCCR5 plays a important role in the acquisition of HIV and it is associated to immune activation in people living with HIV (PLHIV). Using samples of cohorts composed of healthy individuals and PLHIV, we sought to map genomic regions that influence CCR5 expression on monocytes and subsets of CD4+ and CD8+ cells. We identified distinct genetic variants that are associated with CCR5 cell proportions or mean fluorescence intensity in subpopulations of T cells with memory functions in both healthy and PLHIV. The genetic variants also influenced the expression of other nearby chemokine receptors and the production of inflammatory mediators. Thus, we demonstrated that the genetic regulation of CCR5 expression is cell-type specific and may impact HIV susceptibility and disease progression.

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dos Santos, J. C., Zhang, Z., van Eekeren, L. E., Fok, E. T., Vadaq, N., van de Wijer, L., van der Heijden, W., Koeken, V. A., Koenen, H. J., Mhlanga, M., Netea, M., van der Ven, A. J., Li, Y.. 2022-06-20. Host genetic variants regulates CCR5 expression on immune cells: a study in people living with HIV and healthy controls. https://doi.org/10.1101/2022.06.19.496757

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