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

作者：Carolyn 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 Pankow, Tanmoy Bhattacharya, Talita York, Nonkululeko Ndabambi, Lennie Chen, Hong Zhao, Asanda Gwashu-Nyangiri, Ruwayhida Thebus, Paula Marantz Cohen, Ben Murrell, Shelly Karuna, John Hural, Nyaradzo Mgodi, Srilatha Edupuganti, Lynn Morris, David C. Montefiori, M. Juliana McElrath, Myron S. Cohen, Lawrence Corey, Paul T. Edlefsen, Peter B. Gilbert, Penny L. Moore, James I. Mullins · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2025 · DOI：10.1101/2025.10.29.685411 · 被引用次数：1 · 研究领域：HIV Research and Treatment、Monoclonal and Polyclonal Antibodies Research、T-cell and B-cell Immunology

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 β23/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.