Abstract
BackgroundPolymorphisms in chemokine (C-C motif) receptors 2 and 5 genes (CCR2 and CCR5) have been associated with HIV-1 infection and disease progression. We investigated the impact of CCR2-CCR5 haplotypes on HIV-1 viral load (VL) and heterosexual transmission in an African cohort. Between 1995 and 2006, cohabiting Zambian couples discordant for HIV-1 (index seropositive and HIV-1 exposed seronegative {HESN}) were monitored prospectively to determine the role of host genetic factors in HIV-1 control and heterosexual transmission. Genotyping for eight CCR2 and CCR5 variants resolved nine previously recognized haplotypes. By regression and survival analytic techniques, controlling for non-genetic factors, we estimated the effects of these haplotypic variants on a) index partner VL, b) seroconverter VL, c) HIV-1 transmission by index partners, d) HIV-1 acquisition by HESN partners.ResultsAmong 567 couples, 240 virologically linked transmission events had occurred through 2006. HHF*2 homozygosity was associated with significantly lower VL in seroconverters (mean beta = -0.58, log10 P = 0.027) and the HHD/HHE diplotype was associated with significantly higher VL in the seroconverters (mean beta = 0.54, log10 P = 0.014) adjusted for age and gender in multivariable model. HHD/HHE was associated with more rapid acquisition of infection by the HESNs (HR = 2.0, 95% CI = 1.20-3.43, P = 0.008), after adjustments for index partner VL and the presence of genital ulcer or inflammation in either partner in Cox multivariable models. The HHD/HHE effect was stronger in exposed females (HR = 2.1, 95% CI = 1.14-3.95, P = 0.018).ConclusionsAmong Zambian discordant couples, HIV-1 coreceptor gene haplotypes and diplotypes appear to modulate HIV-1 VL in seroconverters and alter the rate of HIV-1 acquisition by HESNs. These associations replicate or resemble findings reported in other African and European populations.
Highlights
Polymorphisms in chemokine (C-C motif) receptors 2 and 5 genes (CCR2 and chemokine receptor 5 gene (CCR5)) have been associated with HIV-1 infection and disease progression
General characteristics of Zambian couples with linked HIV-1 viruses During the study period 567 couples were eligible for analysis
Certain non-genetic characteristics of the partners were independently associated with increased transmission: genital ulcers or genital inflammation in any partner (HR = 3.62, 95% confidence interval (CI): 2.65-4.93, P < 0.0001) and high viral load (VL) in the index partner (HR = 1.59, 95% CI: 1.32-1.91, P < 0.0001)
Summary
Polymorphisms in chemokine (C-C motif) receptors 2 and 5 genes (CCR2 and CCR5) have been associated with HIV-1 infection and disease progression. Between 1995 and 2006, cohabiting Zambian couples discordant for HIV-1 (index seropositive and HIV-1 exposed seronegative {HESN}) were monitored prospectively to determine the role of host genetic factors in HIV-1 control and heterosexual transmission. In southern Africa, unusual biological features of the predominant C subtype of HIV-1 [5] and absence of the human CC chemokine receptor 5 gene (CCR5) 32-bp deletion (Δ32) as a resistance factor may contribute to relatively high transmission rate. Research on the association of these variants with transmission has been largely crosssectional or retrospective; the few prospective studies have focused on vertical (mother-to-child) transmission [13] and on HIV-1 exposed seronegatives (HESNs), in part because of the difficulty in enrolling and following HIV-1-discordant couples
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