The influence of CCR2-CCR5 genetic variants on HIV-2 disease progression in West Africa
Alberta Davis1, Weijing He2, Miriam Wautho1, Alfred Amambua Ngwa1, Sunil K Ahuja2, Assan Jaye1
1MRC Unit Gambia at London School of Hygiene and Tropical Medicine; 2University of Texas Health San Antonio
The host genetic factors that determine susceptibility to HIV/AIDS in contrasting HIV-2 infections remains largely unknown. Here, we assessed the effect of variations in 2 adjacent genes that encode products critical to HIV pathogenesis and disease progression: CCR2 and CCR5 . 157 HIV-2 infected patients sample from Gambia and Guinea Bissau where categorised into low (<100), medium (101 - 10,000) and high (>10,000) viral load (copies/ml). We genotyped 6 SNPs in CCR5 cis-regulatory regions, the CCR5-32 mutation, and the SNP CCR2-V64I, which together form the chemokine receptor 5 (CCR5) human haplotype groups (HHA - HHG). These were tested for their association with plasma viral load and CD4 percentage alongside their frequency distributions. The frequency of HHA was higher in the low (32.8%) and medium (32.3%) groups compared to the high group (25%). In contrast both HHD and HHE were more frequent in the high viral load group (39.6% and 17.7%, respectively) compared to the other two groups. In a multivariable regression model, possession of HHA or HHC haplotypes were associated with 59% (95% CI = 21% - 79%; p = 0.007) or 76% (95% CI = 29% - 92%; p = 0.010) lower odds of having higher viral loads, respectively. We found that the homozygous mutant allele 303A, from which HHE haplotype is derived, was significantly associated with lower CD4 percentage (p = 0.0096). Further analysis showed that CD4 percentage among individuals possessing the HHE haplotype was significantly lower compared to those without HHE (p = 0.0317). These data suggest that HHA and HHC haplotypes have a protective effect on HIV-2 infections in this study population as observed by their association with lower viral load levels, thereby contributing to delayed disease progression. In contrast, HHE showed trends consistent with worse disease outcomes such as lower CD4 percentage. These findings contribute to a better understanding of the human genetics of HIV-2 disease progression.
1. Gornalusse, G.G., et al., Epigenetic mechanisms, T-cell activation, and CCR5 genetics interact to regulate T-cell expression of CCR5, the major HIV-1 coreceptor. Proc Natl Acad Sci U S A, 2015. 112(34): p. E4762-71.