Background:  Polymorphisms in CCR2 and CCR5, adjacent genes encoding chemokine receptors 2 and 5, respectively, influence occurrence of HIV-1 infection and disease progression in various settings, but little is known about the effect of these variants in HIV-1-discordant couples with a seropositive (index) and a seronegative (exposed) partner. We investigated the effect of CCR2-CCR5 haplotypes on HIV-1 viral load and heterosexual transmission in cohabiting discordant Zambian couples.

Methods:  Between 1995 and 2003, 337 initially discordant couples from Lusaka, Zambia, were enrolled for quarterly voluntary counseling and serologic testing to assess factors associated with change in serostatus. For HIV-1 acquired by the exposed partners, viral sequencing documented its phylogenetic linkage to the index virus. Polymerase chain reaction (PCR) -based genotyping at 8 polymorphic sites capable of resolving 9 previously recognized haplotypes was performed. To assess haplotypic effects on viral load among index partners, we used beta values from linear regression models. The risk of infection in exposed was assessed with Kaplan-Meier curves and Cox proportional hazard methods including multivariable analysis of genetic and non-genetic factors.

Results:  Of the 337 couples, serostatus and linkage of transmitted virus were unequivocal for 281 at the time of analysis. By December 2006, transmission had occurred within 157 of those 281 couples. The CCR2-CCR5 HHE haplotype (containing CCR2-64I) was associated with high viral load in the index (β = 0.26 log₁₀, p <0.01). In multivariable analyses of transmitting couples the HHE/HHD diplotype and the HHF*2 haplotype were associated with more rapid infection of the exposed (p ≤0.010), with a stronger association in females exposed to index males. After statistical adjustment for other known risk factors, including index partner viral load and genital ulcer/inflammation in either partner, adjusted hazard ratios for these genotypes ranged from 1.80 to 2.35 (p ≤0.016).

Conclusions:  At least 3 common CCR2-CCR5 haplotype variants (HHE, HHE/HHD, and HHF*2) appeared to modulate viral load in index partners or to alter the rate of acquisition of exposed partners among Zambian discordant couples. These findings indicate that patterns in which CCR2-CCR5 polymorphism alter the development and progression of HIV-1 infection are similar but not identical between populations of African and European ancestry.