Antigen persistence and TLR stimulation contribute to induction of a durable HIV-1-specific neutralizing antibody response

Kenta Matsuda, Mitra Harrison, Eleanor Wettstein, Jessica Pederson, Alyssa A. Pullano, Lyuba Bolkhovitinov, Breanna Kim, Isabel Steinberg, Trevor Griesman, Sarah Stuccio, Daniel Rogan, Andy Patamawenu, Tulley Shofner, Nathaniel E. Wright, Jonathan D. Webber, Freya van’t Veer, Rachel Roenicke, Emma Koory, Peyton M. Roeder, Ellison Ober, Benjamin Leach, Yaroslav Tsybovsky, Tyler Stephens, Ivan Moral-Sanchez, Ilja Bontjer, Lori W. McGinnes-Cullen, Eric Chu, Jason Liang, Jonathan L. Torres, Ryan N. Lin, Andy S. Tran, Gabrielle Dziubla, Leonid Serebryannyy, Sandeep Narpala, Bob Lin, Mike Castro, Gabriel Ozorowski, Andrew B. Ward, Rogier W. Sanders, Peter D. Kwong, Javier Guenaga, Richard Wyatt, Trudy Morrison and Mark Connors ()
Additional contact information
Kenta Matsuda: National Institutes of Health
Mitra Harrison: National Institutes of Health
Eleanor Wettstein: National Institutes of Health
Jessica Pederson: National Institutes of Health
Alyssa A. Pullano: National Institutes of Health
Lyuba Bolkhovitinov: National Institutes of Health
Breanna Kim: National Institutes of Health
Isabel Steinberg: National Institutes of Health
Trevor Griesman: National Institutes of Health
Sarah Stuccio: National Institutes of Health
Daniel Rogan: National Institutes of Health
Andy Patamawenu: National Institutes of Health
Tulley Shofner: National Institutes of Health
Nathaniel E. Wright: National Institutes of Health
Jonathan D. Webber: National Institutes of Health
Freya van’t Veer: National Institutes of Health
Rachel Roenicke: National Institutes of Health
Emma Koory: National Institutes of Health
Peyton M. Roeder: National Institutes of Health
Ellison Ober: National Institutes of Health
Benjamin Leach: National Institutes of Health
Yaroslav Tsybovsky: Frederick National Laboratory for Cancer Research
Tyler Stephens: Frederick National Laboratory for Cancer Research
Ivan Moral-Sanchez: University of Amsterdam
Ilja Bontjer: University of Amsterdam
Lori W. McGinnes-Cullen: University of Massachusetts Medical School
Eric Chu: National Institutes of Health
Jason Liang: National Institutes of Health
Jonathan L. Torres: The Scripps Research Institute
Ryan N. Lin: The Scripps Research Institute
Andy S. Tran: The Scripps Research Institute
Gabrielle Dziubla: National Institutes of Health
Leonid Serebryannyy: National Institutes of Health
Sandeep Narpala: National Institutes of Health
Bob Lin: National Institutes of Health
Mike Castro: National Institutes of Health
Gabriel Ozorowski: The Scripps Research Institute
Andrew B. Ward: The Scripps Research Institute
Rogier W. Sanders: University of Amsterdam
Peter D. Kwong: National Institutes of Health
Javier Guenaga: The Scripps Research Institute
Richard Wyatt: The Scripps Research Institute
Trudy Morrison: University of Massachusetts Medical School
Mark Connors: National Institutes of Health

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract HIV-1 Env glycoprotein (Env) immunogenicity is limited in part by structural instability and extensive glycan shielding and is likely the greatest obstacle to an HIV-1 vaccine. Stabilized Env trimers can elicit serum neutralizing antibodies, but the response is short-lived. Here we use Newcastle Disease Virus-like particle (NDV-VLP) platform to present stabilized versions of HIV-1 Env at high valency and in the context of varied conformational stability, adjuvants, dose, and antigen persistence. Influenza virus hemagglutinin, or SARS-CoV2 Spike-bearing VLPs rapidly induce neutralizing antibodies, in contrast, they were not induced by those bearing Env. A replicating adenovirus type 4 expressing Env rapidly induces autologous neutralizing antibodies. However, durable neutralizing antibodies are induced only when multiple features of a replicating virus infection are combined, with the largest impact from dose and escalating dose. In summary, we show here immunogenicity of HIV-1 Env could be improved by reproducing features of virus infection.

Date: 2025
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DOI: 10.1038/s41467-025-60481-2

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