FCGR3A gene duplication, Fc gamma RIIb-232TT and Fc gamma RIIIb-HNA1a associate with an increased risk of vertical acquisition of HIV-1

Background Some mother-to-child transmission (MTCT) studies suggest that allelic variations of Fc gamma receptors (Fc gamma R) play a role in infant HIV-1 acquisition, but findings are inconsistent. To address the limitations of previous studies, the present study investigates the association between perinatal HIV-1 transmission and Fc gamma R variability in three cohorts of South African infants born to women living with HIV-1. Methods This nested case-control study combines FCGR genotypic data from three perinatal cohorts at two hospitals in Johannesburg, South Africa. Children with perinatally-acquired HIV-1 (cases, n = 395) were compared to HIV-1-exposed uninfected children (controls, n = 312). All study participants were black South Africans and received nevirapine for prevention of MTCT. Functional variants were genotyped using a multiplex ligation-dependent probe amplification assay, and their representation compared between groups using logistic regression analyses. Results FCGR3A gene duplication associated with HIV-1 acquisition (OR = 10.27; 95% CI 2.00-52.65; P= 0.005) as did the Fc gamma RIlb-232TT genotype even after adjusting for FCGR3A copy number and FCGR3B genotype (AOR = 1.72; 95%CI 1.07-2.76; P= 0.024). The association between Fc gamma RIIb-232TT genotype and HIV-1 acquisition was further strengthened (AOR = 2.28; 95%CI 1.11-4.69; P= 0.024) if adjusted separately for FCGR2Cc.134-96C>T. Homozygous Fc gamma RIIIb-HNA1a did not significantly associate with HIV-1 acquisition in a univariate model (OR = 1.42; 95%CI 0.94-2.16; P= 0.098) but attained significance after adjustment for FCGR3A copy number and FCGR2B genotype (AOR = 1.55; 95%CI 1.01-2.38; P= 0.044). Both Fc gamma RIIb-232TT (AOR = 1.83; 95%CI 1.13-2.97; P= 0.014) and homozygous Fc gamma RIIIb-HNA1a (AOR = 1.66; 95%CI 1.07-2.57; P= 0.025) retained significance when birthweight and breastfeeding were added to the model. The common FCGR2A and FCGR3A polymorphisms did not associate with HIV-1 acquisition. Conclusions Collectively, our findings suggest that the Fc gamma RIIb-232TT genotype exerts a controlling influence on infant susceptibility to HIV-1 infection. We also show a role for less studied variants-FCGR3A duplication and homozygous HNA1a. These findings provide additional insight into a role for Fc gamma Rs in HIV-1 infection in children.