Journal Article Ahead of print
PubMed: 41932899 DOI: 10.1038/s41467-026-70888-0
Influence of the broadly neutralizing antibody VRC01 on HIV breakthrough virus populations in antibody-mediated prevention trials.
Nat Commun
Authors: Carolyn Williamson, Chivonne Moodley, Craig A Magaret, Elena E Giorgi, Morgane Rolland, Dylan H Westfall, Anna Yssel, Wenjie Deng, Raabya Rossenkhan, Nonhlanhla N Mkhize, Lennie Chen, Hong Zhao, Tanmoy Bhattacharya, Alec Pankow, Ben Murrell, Talita York, Asanda Gwashu-Nyangiwe, Nonkululeko Ndabambi, Ruwayhida Thebus, Paula Cohen, Bronwen Lambson, Haajira Kaldine, Sinethemba Bhebhe, Michal Juraska, Hongjun Bai, Allan C deCamp, Maurine D Miner, James Ludwig, Cindy Molitor, Nicolas Beaume, David Matten, Yunda Huang, Lily Zhang, Daniel B Reeves, Bryan Mayer, Shelly T Karuna, John A Hural, Lynn Morris, David Montefiori, Roger E Bumgarner, Penny L Moore, Paul T Edlefsen, Srilatha Edupuganti, Nyaradzo Mgodi, M Juliana McElrath, Myron S Cohen, Lawrence Corey, Peter B Gilbert, James I Mullins
Affiliations
- Institute of Infectious Disease and Molecular Medicine, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
- Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu Natal, Durban, South Africa.
- National Health Laboratory Service, Cape Town, South Africa.
- Institute of Infectious Disease and Molecular Medicine, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
- U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
- Department of Microbiology, University of Washington, Seattle, WA, USA.
- National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa.
- SAMRC Antibody Immunity Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
- Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM, USA.
- Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Solna, Sweden.
- Department of Microbiology, The Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Department of Surgery, Duke University Medical Center, Durham, NC, USA.
- Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu Natal, Durban, South Africa.
- Department of Biostatistics, University of Washington, Seattle, WA, USA.
- Emory University, Atlanta, GA, USA.
- University of Zimbabwe College of Health Sciences Clinical Trials Research Centre, Harare, Zimbabwe.
- Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
- Department of Medicine, University of Washington, Seattle, WA, USA.
- Department of Microbiology, University of Washington, Seattle, WA, USA.
- Department of Medicine, University of Washington, Seattle, WA, USA.
- Department of Global Health, University of Washington, Seattle, WA, USA.
Abstract
In the antibody mediated prevention (AMP) trials, the broadly neutralizing antibody (bNAb) VRC01 demonstrated protective efficacy against susceptible HIV strains. To understand how VRC01 shaped breakthrough infections, deep sequencing was performed on 172 participants (>100,000 gag-Δpol and rev-env-Δnef sequences), at diagnosis and over time, in the placebo and treatment arms of the African (HVTN703/HPTN081; NCT02568215) and Americas/Europe (HVTN704/HPTN085; NCT02716675) cohorts. A high frequency of multilineage infections was detected (38%), including co-infection with both VRC01 sensitive and resistant viruses. This high frequency is largely accounted for by low-abundance lineages. Although VRC01 does not significantly affect the genetic transmission bottleneck compared to placebo, higher VRC01 doses trend towards greater VRC01 neutralization differences among co-infecting lineages. Two-thirds of multilineage infections showed evidence of recombination at the diagnostic timepoint. In the treatment group there is evidence of recombinant viruses preferentially inheriting resistance-associated mutations. This study provides critical insights into viral genetic and antigenic diversity that needs to be targeted to achieve protection, and highlights the role of recombination in facilitating escape.
MeSH
Recombination, Genetic, Broadly Neutralizing Antibodies, Antibodies, Neutralizing, Hiv, Viruses, Genes, Rev, Therapeutics, Infections