biostudies-literatureRoark RSVaccine Research CenterNIAID NIH HHSNHLBI NIH HHSDuke Consortium for HIV Vaccine DevelopmentNational Institutes of HealthDivision of Intramural ResearchTraining Grant in HIV PathogenesisNational Institute of Allergy and Infectious DiseasesBill &amp; Melinda Gates FoundationDuke Human Vaccine InstitutePenn Center for AIDS ResearchGates FoundationNIH HHSe20250638https://www.ebi.ac.uk/biostudies/studies/S-EPMC12379892biostudies-literatureUnknown222(10)Broadly neutralizing antibodies targeting the V2 apex of HIV-1 envelope are desired as vaccine design templates, but few have been described. Here, we report 11 lineages of V2 apex-neutralizing antibodies from simian-human immunodeficiency virus (SHIV)-infected rhesus macaques and determine cryo-EM structures for 9. A single V2 apex-neutralizing lineage accounted for cross-clade breadth in most macaques, and somatic hypermutation relative to breadth was generally low, exemplified by antibody V033-a.01 with <5% nucleotide mutation and 37% breadth (208-strain panel). Envelope complex structures revealed eight different antibody classes (one multi-donor) and the complete repertoire of all five possible recognition topologies, recapitulating canonical human modes of apex insertion and C-strand hydrogen bonding. Despite this diversity in recognition, all rhesus-V2 apex antibodies were derived from reading frame two of the DH3-15*01 gene. Collectively, these results define-in rhesus-the structural and genetic basis of HIV-1 V2 apex recognition and demonstrate unprecedented structural plasticity of a highly selected immunogenetic element.The Journal of experimental medicineStructural and genetic basis of HIV-1 envelope V2 apex recognition by rhesus broadly neutralizing antibodies.PMC12379892INV-041767R01 AI160607T32-AI007632R61 AI 176583P30 AI045008R37 AI 150590R61 AI 161818UM1 AI 144371R01 AI165080INV-007939R01 AI 167716R01 AI 050529Connell AJBibollet-Ruche FAndrabi RRoederer MGuo YLiu TDoria-Rose NAShaw GMPark YHaynes BFRoark RSHahn BHOlia ASCallaghan SHarris DRSeaman MSKulp DWZhang BWolff JJKwong PDSaunders KORando JMLei QPLi HHogarty MPSheng ZBylund TGorman JHabib RSingh ALouder MKShapiro LCerutti GPierson TCQiao YBonsignori MMascola JRHe WMason RDSowers KJLewis ECarey JWfalseStructural and genetic basis of HIV-1 envelope V2 apex recognition by rhesus broadly neutralizing antibodies.Broadly neutralizing antibodies targeting the V2 apex of HIV-1 envelope are desired as vaccine design templates, but few have been described. Here, we report 11 lineages of V2 apex-neutralizing antibodies from simian-human immunodeficiency virus (SHIV)-infected rhesus macaques and determine cryo-EM structures for 9. A single V2 apex-neutralizing lineage accounted for cross-clade breadth in most macaques, and somatic hypermutation relative to breadth was generally low, exemplified by antibody V033-a.01 with <5% nucleotide mutation and 37% breadth (208-strain panel). Envelope complex structures revealed eight different antibody classes (one multi-donor) and the complete repertoire of all five possible recognition topologies, recapitulating canonical human modes of apex insertion and C-strand hydrogen bonding. Despite this diversity in recognition, all rhesus-V2 apex antibodies were derived from reading frame two of the DH3-15*01 gene. Collectively, these results define-in rhesus-the structural and genetic basis of HIV-1 V2 apex recognition and demonstrate unprecedented structural plasticity of a highly selected immunogenetic element.2025-01-01T00:00:00Z2025 Oct2026-05-10T01:47:05.364Z2026-04-08T01:25:23.245ZS-EPMC123798924082424010.1084/jem.20250638