1. Contemporary HIV-1 consensus Env with AI-assisted redesigned hypervariable loops promote antibody binding.
- Author
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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, and Rolland M
- Subjects
- Humans, AIDS Vaccines immunology, Neutralization Tests, HEK293 Cells, Consensus Sequence, HIV Infections virology, HIV Infections immunology, Protein Binding, Epitopes immunology, HIV-1 immunology, env Gene Products, Human Immunodeficiency Virus immunology, env Gene Products, Human Immunodeficiency Virus chemistry, env Gene Products, Human Immunodeficiency Virus metabolism, HIV Antibodies immunology, Antibodies, Neutralizing immunology
- 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., (© 2024. The Author(s).)
- Published
- 2024
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