Identification of a potent V3 glycan site broadly neutralizing antibody targeting an N332gp120 glycan-independent epitope
Broadly neutralizing antibodies (bNAbs) against HIV-1 can suppress viremia in vivo and inform vaccine development. Here we characterized 007, a V3 glycan site bNAb exhibiting high levels of antiviral activity against multiclade pseudovirus panels. 007 targets an N332<sub>gp120</sub> glycan-independent V3 epitope, a site of the HIV-1 envelope protein (Env) vulnerability to which only weakly neutralizing antibodies had previously been identified. Functional analyses demonstrated distinct binding and neutralization profiles compared to classical V3 glycan site bNAbs. A 007 Fab-Env cryogenic electron microscopy structure revealed contacts with the V3 <sup>324</sup>GD/NIR<sup>327</sup> motif and interactions with N156<sub>gp120</sub> and N301<sub>gp120</sub> glycans. In contrast to classical V3 bNAbs, 007 binding to Env does not depend on the N332<sub>gp120</sub> glycan, rendering it resistant to common escape mutations. Structures of 007 IgG-Env trimer complexes showed two Env trimers crosslinked by three bivalent IgGs. Bivalent 007 IgG was more potent than monovalent 007 IgG heterodimer, suggesting a role for avidity in potent neutralization. Finally, in HIV-1<sub>ADA</sub>-infected humanized mice, 007 caused transient decline of viremia and overcame classical V3 escape mutations, highlighting 007's potential for HIV-1 prevention, therapy, functional cure and vaccine design.
Authors
- Colin Havenar‐Daughton (ORCID: https://orcid.org/0000-0002-2880-3927)
- Lucas Maganga (ORCID: https://orcid.org/0000-0001-7519-0628)
- Henning Gruell (ORCID: https://orcid.org/0000-0002-0725-7138)
- Andrew T. DeLaitsch (ORCID: https://orcid.org/0000-0002-3458-3449)
- Sharvari Deshpande
- Matthew B. Renfrow (ORCID: https://orcid.org/0000-0002-4193-7305)
- Elvin Ahmadov
- Jacqueline Knüfer
- Christoph Kreer (ORCID: https://orcid.org/0000-0002-9140-9850)
- Judith A. Burger (ORCID: https://orcid.org/0000-0002-7311-9921)
- Harry B. Gristick (ORCID: https://orcid.org/0000-0002-1957-2821)
- Caelan E. Radford
- Wiston William (ORCID: https://orcid.org/0000-0003-4094-4201)
- Federico Giovannoni (ORCID: https://orcid.org/0000-0003-1443-5040)
- Johanna Worczinski
- Anthony P. West (ORCID: https://orcid.org/0000-0003-4213-5184)
- Meryem S. Ercanoglu (ORCID: https://orcid.org/0000-0001-8026-8565)
- Jan Novák (ORCID: https://orcid.org/0000-0001-6288-5025)
- Florian Klein (ORCID: https://orcid.org/0000-0002-7082-0317)
- Marit van Gils
- Arne Kroidl
- Lutz Gieselmann
- Malena Rohde
- Christof Geldmacher
- Ivelin S. Georgiev
- Jesse D. Bloom
- Michael Hoelscher
- Anna Ashurov
- Todd J. Green
- Zhengrong Yang
- Ricarda Stumpf
- Davide Corti
- Nyanda E. Ntinginya
- Qing Wei
Institutions
- California Institute of Technology (US)
- Beth Israel Deaconess Medical Center (US)
- Howard Hughes Medical Institute (US)
- University of Cologne (DE)
- Vanderbilt University (US)
- Helmholtz Zentrum München (DE)
- University of Alabama at Birmingham (US)
- Fred Hutch Cancer Center (US)
- Netherlands Center for Occupational Diseases (NL)
- Vir Biotechnology (Switzerland) (CH)
- Fraunhofer Institute for Translational Medicine and Pharmacology (DE)
- Amsterdam Neuroscience (NL)
- German Center for Infection Research (DE)
- VIR Biotechnology (United States) (US)
- Amsterdam University Medical Centers (NL)
- University Hospital Cologne (DE)
- National Institute for Medical Research (TZ)
- Ludwig-Maximilians-Universität München (DE)
- Vanderbilt University Medical Center (US)
Publication Details
- Journal
- Nature Immunology
- Published
- 2026-02-03
- DOI
- https://doi.org/10.1038/s41590-025-02385-3
- Citations
- 2
- Primary Topic
- HIV Research and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 54.40