Global distribution of the CCR2-64I/CCR5-59653T HIV-1 disease-protective haplotype

Objectives: Several natural polymorphisms in the genes for the human CC-chemokine receptors CCR5 and CCR2 are associated with HIV-1 disease. The CCR2-64I genetic variant [a G to A substitution resulting in a valine (V) to isoleucine (I) change at position 64] is in strong linkage disequilibrium with a mutation within the CCR5 regulatory region (CCR5-59653T). Individuals with two CCR2-64I alleles are not resistant to sexual transmission of HIV-1, but progress significantly more slowly to HIV-1 disease. It is therefore important to determine the global distributions of CCR264I and CCR5-59653T genetic variants and define the degree of linkage between them. Design and methods: We have developed molecular beacon-based, real-time PCR allele discrimination assays for all three chemokine receptor mutations, and used these spectral genotyping assays to genotype 3923 individuals from a globally distributed set of 53 populations. Results: CCR2-64I and CCR5-59653T genetic variants are found in almost all populations studied: their allele frequencies are greatest (35%) in Africa and Asia but decrease in Northern Europe. We confirm that CCR2-64I is in strong linkage disequilibrium with CCR5-59653T (96.92% of individuals had the same genotype for both CCR2-64I and CCR5-59653T polymorphisms). Conclusions: The greater geographical distribution of the CCR2-64I/CCR5-59653T haplotype compared with that of CCR5-˜32 suggests that it is a much older mutation whose origin predates the dispersal of modern humans.