Genetic signatures in the highly virulent subtype B human immunodeficiency virus-1 conferring resistance to broadly neutralizing antibodies.

HIV-1 is considered to become less sensitive to existing neutralizing antibodies over time. Our study on virulent B (VB) HIV-1 identified genetic signatures responsible for immune escape from broadly neutralizing antibodies (bNAbs) targeting V1/V2 and V3 epitopes. We found that the absence of the 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 have an insertion in V2, contributing to escape from V1/V2 bNAbs PG9 and PG16. These findings demonstrate that the VB strains have unique genetic and neutralization characteristics compared to other subtype B strains. The evolutionary origin of these distinctive features remains to be determined.