Rapid elicitation of neutralizing Asn332-glycan-independent antibodies to the V3-glycan epitope of HIV-1 Env in nonhuman primates

Ignacio Relano-Rodriguez; Jianqiu Du; Zi Jie Lin; Margaret Kerwin; Marta Tarquis-Medina; Eduardo Urbano; Jiayan Cui; Meagan Watkins; Christy L Lavine; Peng Zhao; Rumi Habib; Colby Agostino; Sukanya Ghosh; Joyce Park; Caroline Boroughs; Agnes A Walsh; Mariane B Melo; Niharika Shukla; George M Shaw; Beatrice H Hahn; Darrell J Irvine; Lance Wells; David B Weiner; Michael S Seaman; Daniel W Kulp; Ronald S Veazey; Jesper Pallesen; Amelia Escolano

doi:10.1038/s41590-025-02408-z

Rapid elicitation of neutralizing Asn332-glycan-independent antibodies to the V3-glycan epitope of HIV-1 Env in nonhuman primates

Nat Immunol. 2026 Feb 3. doi: 10.1038/s41590-025-02408-z. Online ahead of print.

Authors

Ignacio Relano-Rodriguez^#¹, Jianqiu Du^#^{1

2}, Zi Jie Lin^{1

3}, Margaret Kerwin¹, Marta Tarquis-Medina¹, Eduardo Urbano¹, Jiayan Cui^{1

4}, Meagan Watkins⁵, Christy L Lavine⁶, Peng Zhao⁷, Rumi Habib^{1

8

9}, Colby Agostino^{1

10}, Sukanya Ghosh¹, Joyce Park¹, Caroline Boroughs¹, Agnes A Walsh¹¹, Mariane B Melo¹¹, Niharika Shukla¹, George M Shaw^{8

9}, Beatrice H Hahn^{8

9}, Darrell J Irvine^{11

12}, Lance Wells⁷, David B Weiner¹, Michael S Seaman⁶, Daniel W Kulp¹, Ronald S Veazey⁵, Jesper Pallesen¹, Amelia Escolano^{13

14}

Affiliations

¹ Vaccine & Immunotherapy Center, The Wistar Institute, Philadelphia, PA, USA.
² Department of Molecular and Cellular Biochemistry, Indiana University Bloomington, Bloomington, IN, USA.
³ Department of Chemistry, Indiana University Bloomington, Bloomington, IN, USA.
⁴ Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
⁵ Division of Comparative Pathology, Tulane National Primate Research Center, Covington, LA, USA.
⁶ Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA, USA.
⁷ Complex Carbohydrate Research Center, University of Georgia, Athens, GA, USA.
⁸ Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁹ Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA.
¹⁰ Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹¹ Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, CA, USA.
¹² Howard Hughes Medical Institute, Chevy Chase, MD, USA.
¹³ Vaccine & Immunotherapy Center, The Wistar Institute, Philadelphia, PA, USA. aescolano@wistar.org.
¹⁴ Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA. aescolano@wistar.org.

^# Contributed equally.

PMID: 41634485
DOI: 10.1038/s41590-025-02408-z

Abstract

Sequential immunization is a promising approach to elicit broadly neutralizing antibodies (bNAbs) against the HIV-1 Envelope (Env). However, available protocols are inefficient and involve multiple immunizations over long periods of time. Here, we present WIN332, a new engineered Env immunogen that induces a new class of Asn332-glycan-independent antibodies to the conserved V3-glycan epitope of Env with low inhibitory activity indicative of a neutralization activity after a single bolus immunization in nonhuman primates. WIN332 binds to precursors of canonical human Asn332-glycan-dependent (type-I) V3-glycan bNAbs but also of a first-of-its-class Asn332-glycan-independent (type-II) V3-glycan bNAb. A single immunization elicits low inhibitory serum and monoclonal antibodies that are boosted and affinity matured with a heterologous immunogen. Electron microscopy polyclonal epitope mapping analysis of serum antibodies, antibody cloning and cryogenic electron microscopy analysis reveals that WIN332 elicits Asn332-glycan-independent antibodies with striking sequence and binding similarities with the most potent human type-I and type-II V3-glycan bNAbs. Thus, WIN332 is a promising vaccine candidate to streamline V3-glycan bNAb elicitation.

Abstract

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