After determining the CCR2 genotypes of all WIHS participants, we stratified the 2047 HIV-1–seropositive and 559 HIV-1–seronegative women according to ethnicity and transmission risk. Among the 2606 women, 86.5% carried the homozygous wild-type genotype, 12.5% were V64I heterozygotes, and 1.0% were V64I homozygotes. The frequency of the CCR2-V64I allele in the cohort was also calculated as described in , and was 0.073 overall. Contrary to what has been observed in other studies [3
], the frequency of CCR2-V64I was only slightly less common among white subjects than among other ethnic groups (0.079 among African American subjects, 0.072 among Latino subjects, 0.055 among white subjects, and 0.069 among other groups).
Distribution of CCR2 genotypes among CCR5 wild-type participants in the Women’s Interagency HIV Study (WIHS).
Because CCR2-V64I is in complete negative linkage disequilibrium with CCR5-Δ32, a chemokine receptor mutation that affects HIV-1 transmission [1
], additional analyses included only those women who were homozygous for the wild-type CCR5 allele (1940 subjects were seropositive and 513 were seronegative). The CCR2 genotypes and CCR2-V64I allelic frequencies for these 2453 WIHS participants are shown in . Demographic characteristics and treatment histories of the women homozygous for the wild-type CCR5 allele are remarkably similar to those of the WIHS cohort as a whole [6
]. The frequency of the CCR2-V64I allele among these women was 0.074 overall and varied only marginally between the different ethnic groups.
We next determined whether the CCR2 polymorphisms influenced susceptibility to HIV-1 infection. HIV-1–infected and HIV-1–uninfected women were equally likely to have at least 1 copy of the CCR2-V64I allele (OR, 1.06; 95% CI, 0.79–1.41), indicating that the CCR2 genotype did not affect HIV-1 transmission (). Stratification by ethnicity or transmission risk also failed to show a statistically significant effect of the V64I allele on HIV-1 transmission ().
The influence of the CCR2 genotype on clinical HIV-1 disease progression was then examined in 1638 women, 80% of whom received ART during the study (see Methods). Because the CCR5Δ32 mutation also slows HIV-1 disease progression [1
], these analyses were restricted to women who were homozygous for the CCR5 wild-type allele. Univariate and multivariate models of disease progression failed to detect any protective effect, a finding seen both when individuals homozygous or heterozygous for CCR2-V64I were analyzed as 2 separate groups and when they were combined into 1 group. Compared with individuals homozygous for wild-type CCR2, patients carrying at least 1 copy of the V64I allele had an equivalent risk of developing AIDS (OR, 1.0; 95% CI, 0.8–1.3). Kaplan-Meier estimates also failed to show any significant effect of the CCR2-V64I allele on progression to AIDS (). These results were observed for the entire WIHS population and for subsets of patients stratified by ethnicity, treatment, and transmission risk.
Kaplan-Meier curves showing the proportion of Women’s Interagency HIV Study subjects who remained free of AIDS-defining illnesses over time.
We investigated the effect of the CCR2 genotype on response to ART in 901 women. No significant influence of CCR2 genotype on response to HAART was found by using any of the 4 methods defining response (P > .05; ).
Response to antiretroviral therapy, according to CCR2 genotype.