Perinatal HIV-1 transmission: Fc gamma receptor variability associates with maternal infectiousness and infant susceptibility

Ria Lassaunière, Alfred Musekiwa, Glenda E. Gray, Louise Kuhn, Caroline T. Tiemessen

Accumulating data suggest that immune effector functions mediated through the Fc portion of HIV-1-specific immunoglobulin G (IgG) are a key component of HIV-1 protective immunity, affecting both disease progression and HIV-1 acquisition. Through studying Fc gamma receptor (FcγR) variants known to alter IgG Fc-mediated immune responses, we indirectly assessed the role of FcγR-mediated effector functions in modulating perinatal HIV-1 transmission risk. In this study, genotypic data from 79 HIV-1 infected mothers and 78 HIV-1 infected infants (transmitting cases) were compared to 234 HIV-1 infected mothers and 235 HIV-1 exposed-uninfected infants (non-transmitting controls). Associations, unadjusted and adjusted for multiple comparisons, were assessed for overall transmission and according to mode of transmission-intrapartum (n = 31), in utero (n = 20), in utero-enriched (n = 48). The maternal FcγRIIIa-158V allele that confers enhanced antibody binding affinity and antibody-dependent cellular cytotoxicity capacity significantly associated with reduced HIV-1 transmission [odds ratio (OR) 0.47, 95 % confidence interval (CI) 0.28-0.79, P = 0.004; PBonf > 0.05]. In particular, the FcγRIIIa-158V allele was underrepresented in the in utero transmitting group (P = 0.048; PBonf > 0.05) and in utero-enriched transmitting groups (P = 0.0001; PBonf < 0.01). In both mother and infant, possession of an FcγRIIIb-HNA1b allotype that reduces neutrophil-mediated effector functions associated with increased transmission (OR 1.87, 95 % CI 1.08-3.21, P = 0.025; PBonf > 0.05) and acquisition (OR 1.91, 95 % CI 1.11-3.30, P = 0.020; PBonf > 0.05), respectively. Conversely, the infant FcγRIIIb-HNA1a|1a genotype was significantly protective of perinatal HIV-1 acquisition (OR 0.42, 95 % CI 0.18-0.96, P = 0.040; PBonf > 0.05). The findings of this study suggest a potential role for FcγR-mediated effector functions in perinatal HIV-1 transmission. However, future studies are required to validate the findings of this study, in particular associations that did not retain significance after adjustment for multiple comparisons.