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

Williamson, C.; Curry, L.; Mkhize, N. N.; Giorgi, E. E.; Magaret, C. A.; Lambson, B. E.; Bhebhe, S.; Kaldine, H.; Moyo-Gwete, T.; Rolland, M.; Rossenkhan, R.; Garcia, N. M. G.; Moodley, C.; Yssel, A.; Huang, Y.; Marsden, A. A.; Reeves, D. B.; Mayer, B. T.; Bumgarner, R. E.; Beaume, N.; Westfall, D. H.; Juraska, M.; DeCamp, A. C.; Murrell, H. G.; Bai, H.; Deng, W.; Pankow, A.; Bhattacharya, T.; York, T.; Ndabambi, N.; Chen, L.; Zhao, H.; Gwashu-Nyangiri, A.; Thebus, R.; Cohen, P.; Murrell, B.; Karuna, S.; Hural, J.; Mgodi, N.; Edupuganti, S.; Morris, L.; Montefiori, D.; McElrath, M. J.; Cohen,

doi:10.1101/2025.10.29.685411

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bioRxiv · 10.1101/2025.10.29.685411

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

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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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Williamson, C., Curry, L., Mkhize, N. N., Giorgi, E. E., Magaret, C. A., Lambson, B. E., Bhebhe, S., Kaldine, H., Moyo-Gwete, T., Rolland, M., Rossenkhan, R., Garcia, N. M. G., Moodley, C., Yssel, A., Huang, Y., Marsden, A. A., Reeves, D. B., Mayer, B. T., Bumgarner, R. E., Beaume, N., Westfall, D. H., Juraska, M., DeCamp, A. C., Murrell, H. G., Bai, H., Deng, W., Pankow, A., Bhattacharya, T., York, T., Ndabambi, N., Chen, L., Zhao, H., Gwashu-Nyangiri, A., Thebus, R., Cohen, P., Murrell, B., Karuna, S., Hural, J., Mgodi, N., Edupuganti, S., Morris, L., Montefiori, D., McElrath, M. J., Cohen,. 2025-10-29. VRC01 Selects Rare HIV Escape Mutations After Acquisition in Antibody-Mediated Prevention Trials. https://doi.org/10.1101/2025.10.29.685411

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