Contemporary HIV-1 consensus Env with AI-assisted redesigned hypervariable loops promote antibody binding

Hongjun Bai, Eric Lewitus, Yifan Li, Paul V. Thomas, Michelle Zemil, Mélanie Merbah, Caroline E. Peterson, Thujitha Thuraisamy, Phyllis A. Rees, Agnes Hajduczki, Vincent Dussupt, Bonnie Slike, Letzibeth Mendez-Rivera, Annika Schmid, Erin Kavusak, Mekhala Rao, Gabriel Smith, Jessica Frey, Alicea Sims, Lindsay Wieczorek, Victoria Polonis, Shelly J. Krebs, Julie A. Ake, Sandhya Vasan, Diane L. Bolton, M. Gordon Joyce, Samantha Townsley and Morgane Rolland ()
Additional contact information
Hongjun Bai: Walter Reed Army Institute of Research
Eric Lewitus: Walter Reed Army Institute of Research
Yifan Li: Walter Reed Army Institute of Research
Paul V. Thomas: Henry M. Jackson Foundation for the Advancement of Military Medicine
Michelle Zemil: Walter Reed Army Institute of Research
Mélanie Merbah: Walter Reed Army Institute of Research
Caroline E. Peterson: Henry M. Jackson Foundation for the Advancement of Military Medicine
Thujitha Thuraisamy: Walter Reed Army Institute of Research
Phyllis A. Rees: Henry M. Jackson Foundation for the Advancement of Military Medicine
Agnes Hajduczki: Henry M. Jackson Foundation for the Advancement of Military Medicine
Vincent Dussupt: Walter Reed Army Institute of Research
Bonnie Slike: Walter Reed Army Institute of Research
Letzibeth Mendez-Rivera: Walter Reed Army Institute of Research
Annika Schmid: Walter Reed Army Institute of Research
Erin Kavusak: Walter Reed Army Institute of Research
Mekhala Rao: Walter Reed Army Institute of Research
Gabriel Smith: Walter Reed Army Institute of Research
Jessica Frey: Walter Reed Army Institute of Research
Alicea Sims: Walter Reed Army Institute of Research
Lindsay Wieczorek: Walter Reed Army Institute of Research
Victoria Polonis: Walter Reed Army Institute of Research
Shelly J. Krebs: Walter Reed Army Institute of Research
Julie A. Ake: Walter Reed Army Institute of Research
Sandhya Vasan: Walter Reed Army Institute of Research
Diane L. Bolton: Walter Reed Army Institute of Research
M. Gordon Joyce: Henry M. Jackson Foundation for the Advancement of Military Medicine
Samantha Townsley: Walter Reed Army Institute of Research
Morgane Rolland: Walter Reed Army Institute of Research

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract An effective HIV-1 vaccine must elicit broadly neutralizing antibodies (bnAbs) against highly diverse Envelope glycoproteins (Env). Since Env with the longest hypervariable (HV) loops is more resistant to the cognate bnAbs than Env with shorter HV loops, we redesigned hypervariable loops for updated Env consensus sequences of subtypes B and C and CRF01_AE. Using modeling with AlphaFold2, we reduced the length of V1, V2, and V5 HV loops while maintaining the integrity of the Env structure and glycan shield, and modified the V4 HV loop. Spacers are designed to limit strain-specific targeting. All updated Env are infectious as pseudoviruses. Preliminary structural characterization suggests that the modified HV loops have a limited impact on Env’s conformation. Binding assays show improved binding to modified subtype B and CRF01_AE Env but not to subtype C Env. Neutralization assays show increases in sensitivity to bnAbs, although not always consistently across clades. Strikingly, the HV loop modification renders the resistant CRF01_AE Env sensitive to 10-1074 despite the absence of a glycan at N332.

Date: 2024
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DOI: 10.1038/s41467-024-48139-x

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