In:
Journal of the International AIDS Society, Wiley, Vol. 22, No. 9 ( 2019-09)
Abstract:
The chemokine receptor CCR 5 is the main co‐receptor for R5‐tropic HIV ‐1 variants. We have previously described a novel 24‐base pair deletion in the coding region of CCR 5 among individuals from Rwanda. Here, we investigated the prevalence of hCCR 5Δ24 in different cohorts and its impact on CCR 5 expression and HIV ‐1 infection in vitro . Methods We screened hCCR 5Δ24 in a total of 3232 individuals which were either HIV ‐1 uninfected, high‐risk HIV ‐1 seronegative and seropositive partners from serodiscordant couples, Long‐Term Survivors, or HIV ‐1 infected volunteers from Africa (Rwanda, Kenya, Guinea‐Conakry) and Luxembourg, using a real‐time PCR assay. The role of the 24‐base pair deletion on CCR 5 expression and HIV infection was assessed in cell lines and PBMC using mRNA quantification, confocal analysis, flow and imaging cytometry. Results and Discussion Among the 1661 patients from Rwanda, 12 individuals were heterozygous for hCCR 5Δ24 but none were homozygous. Although heterozygosity for this allele may not confer complete resistance to HIV ‐1 infection, the prevalence of the mutation was 2.41% (95% CI : 0.43; 8.37) in 83 Long‐Term Survivors ( LTS ) and 0.99% (95% CI : 0.45; 2.14) in 613 HIV ‐1 exposed seronegative members as compared with 0.35% (95% Cl: 0.06; 1.25) in 579 HIV ‐1 seropositive members. The prevalence of hCCR 5Δ24 was 0.55% (95% CI : 0.15; 1.69) in 547 infants from Kenya but the mutation was not detected in 224 infants from Guinea‐Conakry nor in 800 Caucasian individuals from Luxembourg. Expression of hCCR 5Δ24 in cell lines and PBMC showed that the hCCR 5Δ24 protein is stably expressed but is not transported to the plasma membrane due to a conformational change. Instead, the mutant receptor was retained intracellularly, colocalized with an endoplasmic reticulum marker and did not mediate HIV ‐1 infection. Co‐transfection of hCCR 5Δ24 and wt CCR 5 did not indicate a transdominant negative effect of CCR 5Δ24 on wtCCR5. Conclusions Our findings indicate that hCCR 5Δ24 is not expressed at the cell surface. This could explain the higher prevalence of the heterozygous hCCR 5Δ24 in LTS and HIV ‐1 exposed seronegative members from serodiscordant couples. Our data suggest an East‐African localization of this deletion, which needs to be confirmed in larger cohorts from African and non‐African countries.
Type of Medium:
Online Resource
ISSN:
1758-2652
,
1758-2652
Language:
English
Publisher:
Wiley
Publication Date:
2019
detail.hit.zdb_id:
2467110-1
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