Broadly neutralising monoclonal antibodies display heterogeneous neutralisation activity against HIV-1 subtype C transmitter/founder viruses from infants.

Abstract

Introduction: Vertical transmission of HIV-1 remains a global health challenge, especially in resource-limited settings due to drug resistance and mothers’ non-adherence to antiretroviral therapy. The aim of the study was to determine the characteristics of HIV-1 subtype C envelope in infants and their mothers, determine their sensitivity to broadly neutralizing antibodies (bNAbs) and coreceptor usage. Methods: We characterized 21 transmitted/founder (TF) pseudoviruses produced from infants and a subset of mothers and evaluated their susceptibility to clinically relevant broadly neutralizing antibodies (bNAbs). We also analysed amino acid signatures within bNAb epitopes to identify bNAb resistance mechanisms. Bioinformatics tools and tissue culture methods were used to determine the coreceptor usage in infants and mothers. This was followed by comparing the neutralizasion sensitivity and coreceptor usage between mother-infant pairs. Results: VRC07-523LS, 10-1074, and 10E8 demonstrated the highest neutralisation coverage in infants, while resistance was frequently observed against CAP256-VRC26, PGDM1400, and PGT151. Key escape mutations were identified in various epitope regions, particularly in the CD4 binding site, V3 glycan and V2-apex regions. In addition, 71% of infants isolates utilised CCR5, while 29% used CXCR4 or both CCR5/CXCR4, representing a higher frequency of CXCR4 usage than previously reported in subtype C infections. Analysis of mother-infant pairs showed predominantly concordant coreceptor usage, though notable exceptions were observed. Mother-infant pairs revealed distinct patterns in neutralizasion sensitivity, infants isolates showing enhanced sensitivity to CD4 binding site antibodies but increased resistance to antibodies targeting the V2 apex-targeting and gp120-gp41 interface. Sequence analysis of the V3 loop identified specific determinants of coreceptor tropism, including the N-linked glycosylation patterns, loop length, and crown motif substitutions. Conclusion: These findings suggest either the transmission of minor maternal viral populations or rapid post-transmission adaptation. Structural analysis identified variations in variable loop lengths and glycosylation patterns between maternal and infant isolates, suggesting complex selective pressures during transmission events. Prevention of vertical HIV transmission may require the combination of broadly neutralizing antibodies that target different epitopes, and potentially with entry inhibitors. The higher frequency of CXCR4-using viruses in this population suggests prevention strategies must be tailored to local viral characteristics, highlighting the need for multi-target approaches in effective HIV prevention.