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; Morgane Rolland

doi:10.1038/s41467-024-48139-x

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 WieczorekVictoria Polonis, Shelly J. Krebs, Julie A. Ake, Sandhya Vasan, Diane L. Bolton, M. Gordon Joyce, Samantha Townsley, Morgane Rolland^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	3924
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-48139-x
State	Published - Dec 2024
Externally published	Yes

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Bai, H., Lewitus, E., Li, Y., Thomas, P. V., Zemil, M., Merbah, M., Peterson, C. E., Thuraisamy, T., Rees, P. A., Hajduczki, A., Dussupt, V., Slike, B., Mendez-Rivera, L., Schmid, A., Kavusak, E., Rao, M., Smith, G., Frey, J., Sims, A., ... Rolland, M. (2024). Contemporary HIV-1 consensus Env with AI-assisted redesigned hypervariable loops promote antibody binding. Nature Communications, 15(1), Article 3924. https://doi.org/10.1038/s41467-024-48139-x

@article{20fad3fca9384aeeb5861e92a5a0f420,

title = "Contemporary HIV-1 consensus Env with AI-assisted redesigned hypervariable loops promote antibody binding",

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{\textquoteright}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.",

author = "Hongjun Bai and Eric Lewitus and Yifan Li and Thomas, {Paul V.} and Michelle Zemil and M{\'e}lanie Merbah and Peterson, {Caroline E.} and Thujitha Thuraisamy and Rees, {Phyllis A.} and Agnes Hajduczki and Vincent Dussupt and Bonnie Slike and Letzibeth Mendez-Rivera and Annika Schmid and Erin Kavusak and Mekhala Rao and Gabriel Smith and Jessica Frey and Alicea Sims and Lindsay Wieczorek and Victoria Polonis and Krebs, {Shelly J.} and Ake, {Julie A.} and Sandhya Vasan and Bolton, {Diane L.} and Joyce, {M. Gordon} and Samantha Townsley and Morgane Rolland",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = dec,

doi = "10.1038/s41467-024-48139-x",

language = "English",

volume = "15",

journal = "Nature Communications",

issn = "2041-1723",

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Bai, H, Lewitus, E, Li, Y, Thomas, PV, Zemil, M, Merbah, M, Peterson, CE, Thuraisamy, T, Rees, PA, Hajduczki, A, Dussupt, V, Slike, B, Mendez-Rivera, L, Schmid, A, Kavusak, E, Rao, M, Smith, G, Frey, J, Sims, A, Wieczorek, L, Polonis, V, Krebs, SJ, Ake, JA, Vasan, S, Bolton, DL, Joyce, MG, Townsley, S & Rolland, M 2024, 'Contemporary HIV-1 consensus Env with AI-assisted redesigned hypervariable loops promote antibody binding', Nature Communications, vol. 15, no. 1, 3924. https://doi.org/10.1038/s41467-024-48139-x

TY - JOUR

T1 - Contemporary HIV-1 consensus Env with AI-assisted redesigned hypervariable loops promote antibody binding

AU - Bai, Hongjun

AU - Lewitus, Eric

AU - Li, Yifan

AU - Thomas, Paul V.

AU - Zemil, Michelle

AU - Merbah, Mélanie

AU - Peterson, Caroline E.

AU - Thuraisamy, Thujitha

AU - Rees, Phyllis A.

AU - Hajduczki, Agnes

AU - Dussupt, Vincent

AU - Slike, Bonnie

AU - Mendez-Rivera, Letzibeth

AU - Schmid, Annika

AU - Kavusak, Erin

AU - Rao, Mekhala

AU - Smith, Gabriel

AU - Frey, Jessica

AU - Sims, Alicea

AU - Wieczorek, Lindsay

AU - Polonis, Victoria

AU - Krebs, Shelly J.

AU - Ake, Julie A.

AU - Vasan, Sandhya

AU - Bolton, Diane L.

AU - Joyce, M. Gordon

AU - Townsley, Samantha

AU - Rolland, Morgane

PY - 2024/12

Y1 - 2024/12

N2 - 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.

AB - 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.

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U2 - 10.1038/s41467-024-48139-x

DO - 10.1038/s41467-024-48139-x

M3 - Article

C2 - 38724518

AN - SCOPUS:85192524206

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3924

ER -

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

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