Prophylactic treatment with broadly neutralizing antibody VRC01 selects for escape mutants after infection in Antibody-Mediated Prevention trials

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 analysed 11,730 HIV envelope sequences generated during the AMP trials from 47 participants, 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 frequencies (<1%) in globally circulating viruses, suggesting that they may confer fitness costs. Escape mutations, primarily located in the Loop-D and β23/V5 regions of Env, conferred cross-resistance to several CD4bs bnAbs; however, more potent CD4bs bnAbs such as 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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Publication Details

Journal
Nature Microbiology
Published
2026-09-28
DOI
https://doi.org/10.1038/s41564-026-02467-4
Primary Topic
HIV Research and Treatment
Type
article
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article

Prophylactic treatment with broadly neutralizing antibody VRC01 selects for escape mutants after infection in Antibody-Mediated Prevention trials

David C. Montefiori, Michal Juraska, Lennie Chen, Lyle Curry et al.
Nature Microbiology
HIV Research and Treatment
article

Prophylactic treatment with broadly neutralizing antibody VRC01 selects for escape mutants after infection in Antibody-Mediated Prevention trials

David C. Montefiori, Michal Juraska, Lennie Chen, Lyle Curry, Yunda Huang, Bronwen E. Lambson, Roger E. Bumgarner, Srilatha Edupuganti, Raabya Rossenkhan, Nonkululeko Ndabambi, Talita York, Dylan H. Westfall, James I. Mullins, Penny L. Moore, Paul T. Edlefsen, Allan C. deCamp, Craig A. Magaret, Ben Murrell, Nonhlanhla N. Mkhize, Chivonne Moodley, Carolyn E. Williamson, Tanmoy Bhattacharya A, Nina Marie G. Garcia, Hugh Murrell, Nicolas Beaume, Thandeka Moyo-Gwete, Lawrence Corey, Alec P. Pankow, Shelly Karuna, Bryan T. Mayer, Morgane Rolland, Ruwayhida Thebus, Haajira Kaldine, M. Juliana McElrath, Peter B. Gilbert, Daniel B. Reeves, Hongjun Bai, Lynn Morris, Alaine A. Marsden, Sinethemba Bhebhe, John Hural, Anna Yssel, Hong Zhao, Elena E. Giorgi, Paula Cohen, Nyaradzo Mgodi, Myron S. Cohen, Asanda Gwashu-Nyangiri, Wenjie Deng
article en

Abstract

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 analysed 11,730 HIV envelope sequences generated during the AMP trials from 47 participants, 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 frequencies (<1%) in globally circulating viruses, suggesting that they may confer fitness costs. Escape mutations, primarily located in the Loop-D and β23/V5 regions of Env, conferred cross-resistance to several CD4bs bnAbs; however, more potent CD4bs bnAbs such as 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.

Nature Microbiology
National Health Laboratory Service (ZA), University of North Carolina at Chapel Hill (US), Henry M. Jackson Foundation (US), Santa Fe Institute (US), Los Alamos National Laboratory (US), Emory University (US), University of Zimbabwe (ZW), University of Cape Town (ZA), University of the Witwatersrand (ZA), University of Washington (US), Centre for the AIDS Programme of Research in South Africa (ZA), Karolinska Institutet (SE), Fred Hutch Cancer Center (US), Duke Medical Center (US), Wellcome Centre for Infectious Diseases Research in Africa (ZA), National Institute for Communicable Diseases, Institute of Infectious Disease and Molecular Medicine (ZA), Walter Reed Army Institute of Research (US), University of KwaZulu-Natal (ZA)
Good health and well-being
Openalex Percentile: Top 13%
HIV Research and Treatment
DOIOpen Access PDFOpenAlex
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