VRC01 Selects Rare HIV Escape Mutations After Acquisition in Antibody-Mediated Prevention Trials

Carolyn E. Williamson; Lyle Curry; Nonhlanhla N. Mkhize; Elena E. Giorgi; Craig A. Magaret; Bronwen E. Lambson; Sinethemba Bhebhe; Haajira Kaldine; Thandeka Moyo-Gwete; Morgane Rolland; Raabya Rossenkhan; Nina Marie G. Garcia; Chivonne Moodley; Anna Yssel; Yunda Huang; Alaine A. Marsden; Daniel B. Reeves; Bryan T. Mayer; Roger E. Bumgarner; Nicolas Beaume; Dylan H. Westfall; Michal Juraska; Allan C. deCamp; Hugh Murrell; Hongjun Bai; Wenjie Deng; Alec P. Pankow; Tanmoy Bhattacharya A; Talita York; Nonkululeko Ndabambi

doi:10.1101/2025.10.29.685411

MicrobiologybioRxivOct 29, 2025

Preprint

VRC01 Selects Rare HIV Escape Mutations After Acquisition in Antibody-Mediated Prevention Trials

Carolyn E. Williamson iD, Lyle Curry, Nonhlanhla N. Mkhize iD, Elena E. Giorgi iD, Craig A. Magaret iD, Bronwen E. Lambson iD, Sinethemba Bhebhe, Haajira Kaldine iD, Thandeka Moyo-Gwete iD, Morgane Rolland iD, Raabya Rossenkhan iD, Nina Marie G. Garcia iD, Chivonne Moodley iD, Anna Yssel iD, Yunda Huang iD, Alaine A. Marsden iD, Daniel B. Reeves iD, Bryan T. Mayer iD, Roger E. Bumgarner iD, Nicolas Beaume iD, Dylan H. Westfall iD, Michal Juraska iD, Allan C. deCamp iD, Hugh Murrell iD, Hongjun Bai iD, , James I. Mullins iD

Abstract

Broadly neutralizing antibodies (bnAbs) show promise in HIV prevention, yet viral escape remains a challenge. In the Antibody Mediated Prevention (AMP) trials, the CD4 binding site (CD4bs) bNAb VRC01 blocked acquisition by VRC01-sensitive strains. However, its influence on viral evolution post-acquisition is not fully understood. Here we analyzed >12,000 HIV env sequences from 47 participants from the AMP trials, identifying VRC01-mediated de novo escape mutations in 8 of 26 VRC01-treated participants but none in 21 placebo participants. These mutations were found at very low frequency (<1%) in global viruses. Escape mutations, primarily located in the Loop-D and {beta}23/V5 regions of Env, conferred cross-resistance to several CD4bs bnAbs, while more potent CD4bs bnAbs like N6 and 1-18 largely retained their activity. Our findings demonstrate that prophylactic VRC01 can select for viral escape after infection, underscoring the need for next-generation bnAbs with improved breadth and potency to enhance durability and efficacy of antibody-based HIV prevention.

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