Genetic signatures in the highly virulent subtype B HIV-1 conferring immune escape to V1/V2 and V3 broadly neutralizing antibodies

HIV-1 is considered to become less susceptible to existing neutralizing antibodies over time. Our study on the virulent B (VB) HIV-1 identified genetic signatures responsible for immune escape from broadly neutralizing antibodies (bNAbs) targeting V1/V2 and V3 glycan epitopes. We found that the absence of N295 and N332 glycans in the high mannose patch, which are crucial for neutralization by V3 glycan bNAbs and are typically conserved in subtype B HIV-1, is a notable feature in more than half of the VB variants. Neutralization assays confirmed that the loss of these two glycans in VB HIV-1 leads to escape from V3 glycan bNAbs. Additionally, all VB variants we investigated have an insertion in V2, contributing to immune escape from V1/V2 bNAbs PG9 and PG16. These findings suggest potential co-evolution of HIV-1 virulence and antigenicity, underscoring the need to monitor both the pathogenicity and neutralization susceptibility of newly emerged HIV-1 strains.