biostudies-literatureBai HHenry M. Jackson FoundationNIAID NIH HHS3924https://www.ebi.ac.uk/biostudies/studies/S-EPMC11082178biostudies-literatureUnknown15(1)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 binNature communicationsContemporary HIV-1 consensus Env with AI-assisted redesigned hypervariable loops promote antibody binding.PMC11082178WW81XWH-18-2-0040R01 AI176520Peterson CESchmid AThuraisamy TRolland MVasan SKavusak EThomas PVTownsley SMerbah MDussupt VWieczorek LRao MBai HLewitus ESims AAke JAJoyce MGFrey JPolonis VSlike BZemil MSmith GMendez-Rivera LRees PALi YKrebs SJHajduczki ABolton DLfalseContemporary HIV-1 consensus Env with AI-assisted redesigned hypervariable loops promote antibody binding.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 bin2024-01-01T00:00:00Z2024 May2026-06-01T20:22:15.848Z2026-05-22T03:08:29.648ZS-EPMC110821783872451810.1038/s41467-024-48139-x