Background:  Chemokines, chemokine receptors, and their genetic variants have been shown to affect HIV-1-infection and disease progression. However, there is little information on role of such host genetic variants on HIV-1 mother-to-child transmission (MTCT).

Methods:  CX₃CR1-V/I249, -T/M280, CCR5-59029-G/A, CCR5-59353-T/C, and CCR5-59356-C/T polymorphisms were detected by real-time PCR in 980 children born to ART-naïve HIV-1-infected mothers from Malawi (n = 322) and South Africa (n = 300); both cohorts involved in vitamin A intervention trials to reduce MTCT of HIV-1; and from Uganda (HIVNET-012, n = 358) where intrapartum and neonatal single-dose nevirapine (NVP) was compared with zidovudine (ZDV) for preventing MTCT. Data were assessed by Cochran-Mantel-Haenszel test and logistic regression analyses.

Results:  Overall 210 of 980 children (21%) were HIV-1-infected (20% in Malawi cohort, 25% in South Africa cohort and 20% in Uganda cohort). There was a marginal association of HIV-1 infection with CCR5-59356 polymorphism: the percentages of HIV-1-infected infants were 23%, 17%, and 19% for the CCR5-59356-C/C, -C/T and –T/T genotypes, respectively (p = 0.065) and among infants with T allele, 17% were infected compared with 23% with C/C homozygotes (OR: 0.66, 95% CI 0.47 to 0.94; p =0.02). These effects persisted in analyses adjusted for maternal HIV-1 RNA, CD4⁺ cell count and study (p = 0.05). Furthermore, an association of HIV-1 infection with CX₃CR1-249 polymorphism was observed: the percentages of HIV-1-infected infants were 0% (0 of 9), 28% (42 of 150), and 20% (166 of 816) for the CX3CR1-249-I/I, -V/I, and -V/V genotypes, respectively (p = 0.035).  Because 0 of 9 infants having 249-I/I genotype was infected, we compared the risk of infection between the V/I and V/V genotypes. V/I genotype was associated with higher risks of infection when adjusted for maternal CD4⁺ cell count (OR = 1.56, 95% CI 1.04 to 2.35, p = 0.033) and HIV-1 RNA level (OR = 1.60, 95% CI 0.99 to 2.58, p = 0.053) or both (OR = 1.68, 95% CI 1.03 to 2.73, p = 0.036).

Conclusions:  These data suggest that CX₃CR1 V/I249 and CCR5-59356-C/C genotypes are associated with risk of MTCT of HIV-1 in African infants. The mechanisms through which CCR5-59356 and CX₃CR1-249 polymorphisms alter MTCT are unknown, but may involve alteration in co-receptor usage of HIV-1 and inefficient recruitment of immunomodulatory cells for the control of HIV-1 at the maternal-fetal interface, respectively.

Keywords: CCR5 CX3CR1 polymorphism; HIV-1; perinatal transmission