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CCR5 promoter haplotypes differentially influence CCR5 expression on natural killer and T cell subsets in ethnically divergent HIV-1 uninfected South African populations

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Abstract

CCR5 plays a critical and central role in HIV-1 infection and, to date, a number of genetic mutations and haplotypes within the gene have been found to positively or negatively influence an individual’s susceptibility and rate of disease progression. In this study, we have evaluated the influence of CCR5 haplotypes, HHA, HHC, HHD, and HHE, on CCR5 expression in healthy HIV-1 uninfected individuals from two populations, South African Africans (SAA, n = 22) and South African Caucasians (SAC, n = 31). CCR5 haplotypes were determined through sequencing and real time polymerase chain reaction. Flow cytometry was used to quantitate CCR5 surface expression, as both CCR5 density and percentage of CCR5-expressing cells, on B, T, natural killer (NK) cells and monocytes. SAA individuals positive for the HHA haplotype had significantly lower percentages of CCR5-expressing CD8+ T cells in comparison to individuals without HHA (P = 0.001). HHC+ SAC individuals had significantly higher CCR5 molecules per cell (density) on NK (CD56+) and CD16+ CD56+ NK cell subsets (P = 0.030 and P = 0.024, respectively) compared to HHC− SAC individuals. Haplotypes HHD and HHE had no impact on CCR5 expression. Overall, our data highlight that the protective effect of the HHC haplotype in Caucasians might be explained by higher density of CCR5 expression on NK cells that is not evident in HHC+ SAA individuals. Findings raise the question as to the role of CCR5-expressing cells other than CD4+ T cells in protection from HIV-1 acquisition and disease progression.

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Acknowledgments

This study was supported by grants from the Poliomyelitis Research Foundation (PRF) and the Technology Innovation Agency [South African HIV/AIDS Research (and Innovation) Platform (SHARP)]. We would like to thank all our volunteer participants in this study and Dr Sharon Shalekoff for assistance with flow cytometry.

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  1. Centre for HIV and STIs, National Institute for Communicable Diseases, Private Bag X4, Sandringham, Johannesburg, 2131, South Africa

    Anabela C. P. Picton, Maria Paximadis & Caroline T. Tiemessen

  2. Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

    Anabela C. P. Picton, Maria Paximadis & Caroline T. Tiemessen

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  1. Anabela C. P. Picton
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  2. Maria Paximadis
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Correspondence to Caroline T. Tiemessen.

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Supplementary Fig. 1

Influence of the HHC haplotype on the percentage of CCR5-expressing cells on natural killer cell subsets, NK (i) and CD16+CD56+ NK (ii), within the SAC population (a), the SAC population with the exclusion of individuals with the CCR5Δ32 allele (b) and the SAA population (c). Individuals with or without an HHC allele are indicated as HHC+ and HHC−, respectively. The HHC homozygous individuals are indicated with (empty diamond). P values and the number of individuals in each group are indicated (JPEG 69 kb)

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Picton, A.C.P., Paximadis, M. & Tiemessen, C.T. CCR5 promoter haplotypes differentially influence CCR5 expression on natural killer and T cell subsets in ethnically divergent HIV-1 uninfected South African populations. Immunogenetics 64, 795–806 (2012). https://doi.org/10.1007/s00251-012-0642-0

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