FCGR3A gene duplication, FcγRIIb-232TT and FcγRIIIb-HNA1a associate with an increased risk of vertical acquisition of HIV-1

PLoS One. 2022 Sep 9;17(9):e0273933. doi: 10.1371/journal.pone.0273933. eCollection 2022.

Abstract

Background: Some mother-to-child transmission (MTCT) studies suggest that allelic variations of Fc gamma receptors (FcγR) 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 FcγR 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 FcγRIIb-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 FcγRIIb-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 FCGR2C c.134-96C>T. Homozygous FcγRIIIb-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 FcγRIIb-232TT (AOR = 1.83; 95%CI 1.13-2.97; P = 0.014) and homozygous FcγRIIIb-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 FcγRIIb-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 FcγRs in HIV-1 infection in children.

MeSH terms

  • Case-Control Studies
  • Female
  • Gene Duplication
  • HIV Infections* / genetics
  • HIV Seropositivity* / genetics
  • HIV-1* / physiology
  • Humans
  • Infant
  • Infectious Disease Transmission, Vertical
  • Pregnancy
  • Receptors, IgG / genetics
  • South Africa

Substances

  • FCGR3A protein, human
  • Receptors, IgG

Grants and funding

This study is supported in part by grants from the National Institutes of Child Health and Human Development (HD 42402, HD 47177, HD 57784, HD 073977 and HD 073952), Secure the Future Foundation, the South African Medical Research Council, and the South African Research Chairs Initiative of the Department of Science and Innovation and National Research Foundation (84177). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.