Background: HIV-1 is spreading in women worldwide.  The human gene for CCR5, a co-receptor for HIV-1, affects susceptibility to infection; people homozygous for a deleted form of the gene, D32, are unlikely to be infected.  Some studies of predominantly male cohorts found that D32 heterozygotes were not protected against transmission, but other studies involving both genders suggested that the heterozygous genotype conferred partial protection. We therefore investigated the D32 gene and HIV-1 transmission and disease progression in women.

Methods: We determined the CCR5 genotype of 2047 seropositive and 558 seronegative participants in the Women's Interagency HIV Study, a natural history cohort study of HIV-1 in U.S. women, and examined relationships of CCR5 genotypes to HIV-1 status, ethnicity, transmission risk, disease stage, and response to highly active antiretroviral therapy.

Results: Of 2605 women, 54.9% were African American, 24.6% Latina/Hispanic, 17.6% Caucasian, and 2.8% from other ethnic groups. The frequency of the CCR5 D32 allele was 0.029: 0.018 in African Americans, 0.024 in Latinas, 0.068 in Caucasians, and 0.041 for other groups. Although the D32 gene frequency was 0.040 for HIV-1-seronegative women, it was 0.026 for seropositives. Analysis of the relationship of HIV-1 infection to CCR5 genotype showed that D32 heterozygotes were significantly less likely to be infected, OR=0.63 (95% CI: 0.44-0.90). By contrast, we found no evidence of slowed disease progression or improved response to HAART in heterozygotes.

Conclusions: The CCR5 D32 heterozygous genotype may confer partial protection from HIV-1 infection in women. Such protection may reflect differences in routes and mechanisms of transmission to women as compared to men.  In addition, among our multiethnic, multiracial, geographically dispersed U.S. cohort, the D32 deletion was much more common in Caucasians  than in other groups. Because the protective D32 deletion is rare in Africans and Asians, it seems plausible that differential genetic susceptibility contributes to the rapid heterosexual spread of HIV-1 in Africa and Asia.