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

Alex C Stabell; Songhee Lee; Debby J Park; Christy L Lavine; Sebastian Mejia Espinosa; Viren A Baharani; Rachel Patejak; Michel C Nussenzweig; Marina Caskey; Michael S Seaman; Paul D Bieniasz; Theodora Hatziioannou

doi:10.1038/s41564-026-02347-x

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

Nat Microbiol. 2026 Jun;11(6):1573-1584. doi: 10.1038/s41564-026-02347-x. Epub 2026 May 11.

Authors

Alex C Stabell^{1

2}, Songhee Lee², Debby J Park², Christy L Lavine³, Sebastian Mejia Espinosa³, Viren A Baharani^{2

4}, Rachel Patejak², Michel C Nussenzweig^{4

5}, Marina Caskey⁴, Michael S Seaman³, Paul D Bieniasz^{6

7}, Theodora Hatziioannou⁸

Affiliations

¹ Weill Cornell, Department of Infectious Diseases, New York, NY, USA.
² Laboratory of Retrovirology, The Rockefeller University, New York, NY, USA.
³ Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
⁴ Laboratory of Molecular Immunology, The Rockefeller University, New York, NY, USA.
⁵ Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA.
⁶ Laboratory of Retrovirology, The Rockefeller University, New York, NY, USA. pbieniasz@rockefeller.edu.
⁷ Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA. pbieniasz@rockefeller.edu.
⁸ Laboratory of Retrovirology, The Rockefeller University, New York, NY, USA. thatziio@rockefeller.edu.

Abstract

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.

Abstract

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