Diverse paths to broadly neutralizing antibody escape among HIV-1 strains

Broadly neutralizing antibodies (bnAbs) are promising agents for HIV-1 treatment and prevention. However, the genetic barriers and mutational pathways to viral resistance, which can limit therapeutic antibody utility, remain poorly defined. Here we developed a medium-to-high throughput approach to determine the mutations that confer resistance to neutralization by the bnAbs 3BNC117 and 10-1074 currently in clinical development. We performed 7,776 parallel selection experiments to identify bnAb resistance mutations in 15 primary isolates that span global HIV-1 genetic diversity. There was substantial variability among HIV-1 isolates in the identity of mutations that conferred bnAb resistance. For 12 of 15 HIV-1 isolates, single amino acid changes could increase bnAb IC₈₀ to >10 μg ml^-1. Some 3BNC117 resistance mutations conferred resistance to additional bnAbs targeting the same or different epitopes, and unconventional escape mechanisms were occasionally encountered. These data provide a rationale for selecting bnAb combinations that are most likely to achieve treatment success.