tetano
Editor, Senior Moderator
bioRxiv
[Preprint]. 2026 Jul 26:2026.07.22.739677.
doi: 10.64898/2026.07.22.739677.
H5N1 influenza binding and cell entry via human class II MHC, and blocking by cross-reactive antibodies
Taylor Pursell, Artem Mikelov, Oliver F Wirz, Jordan T Ort, Shuk Hang Li, Reilly K Atkinson, Jefferson J S Santos, Jiabao Zhong, Shilpa A Joshi, Jumana Afaghani, Xiaorui Han, Emily Haraguchi, Ramona A Hoh, Ji-Yeun Lee, Brandon Lam, Alexander Stanford, Andrew T DeLaitsch, Jackson Schuetz, Katharina Röltgen, Donna Smith, Brian Ha, Sean Van Slyck, Claus U Niemann, Scott E Hensley, Scott D Boyd
Highly pathogenic avian influenza (HPAI) H5N1 clade 2.3.4.4b viruses are currently responsible for a multi-species outbreak affecting wild birds, poultry, numerous mammalian species, and humans. Influenza A viruses typically initiate infection through binding to sialic acid, although select bat and human influenza viruses can also exploit class II major histocompatibility complex (MHC-II) molecules for cell entry. Here we show that emerging H5N1 clade 2.3.4.4b viruses, but not historical H5 lineages, bind human MHC-II HLA-DR and mediate sialic acid-independent cell entry. Hemagglutinin binding to primary human immune cells varies with MHC-II expression and is further shaped by HLA-DR allelic variation, identifying host genetic determinants that may influence susceptibility to infection. Mammalian-adaptive substitutions within the hemagglutinin sialic acid receptor-binding domain reduce MHC-II binding, suggesting this interaction is remodeled during clade 2.3.4.4b H5 adaptation to a human host. Lastly, cross-reactive monoclonal antibodies isolated from clade 2.3.4.4b H5-naive humans can block the hemagglutinin-MHC-II interaction. These findings identify a previously unrecognized receptor pathway in contemporary H5N1 viruses and reveal that both human genetic variation and pre-existing humoral immunity can modulate this interaction, with implications for host range, cellular tropism, spillover risk, and therapeutic intervention.
[Preprint]. 2026 Jul 26:2026.07.22.739677.
doi: 10.64898/2026.07.22.739677.
H5N1 influenza binding and cell entry via human class II MHC, and blocking by cross-reactive antibodies
Taylor Pursell, Artem Mikelov, Oliver F Wirz, Jordan T Ort, Shuk Hang Li, Reilly K Atkinson, Jefferson J S Santos, Jiabao Zhong, Shilpa A Joshi, Jumana Afaghani, Xiaorui Han, Emily Haraguchi, Ramona A Hoh, Ji-Yeun Lee, Brandon Lam, Alexander Stanford, Andrew T DeLaitsch, Jackson Schuetz, Katharina Röltgen, Donna Smith, Brian Ha, Sean Van Slyck, Claus U Niemann, Scott E Hensley, Scott D Boyd
- PMID: 42539232
- PMCID: PMC13419755
- DOI: 10.64898/2026.07.22.739677
Highly pathogenic avian influenza (HPAI) H5N1 clade 2.3.4.4b viruses are currently responsible for a multi-species outbreak affecting wild birds, poultry, numerous mammalian species, and humans. Influenza A viruses typically initiate infection through binding to sialic acid, although select bat and human influenza viruses can also exploit class II major histocompatibility complex (MHC-II) molecules for cell entry. Here we show that emerging H5N1 clade 2.3.4.4b viruses, but not historical H5 lineages, bind human MHC-II HLA-DR and mediate sialic acid-independent cell entry. Hemagglutinin binding to primary human immune cells varies with MHC-II expression and is further shaped by HLA-DR allelic variation, identifying host genetic determinants that may influence susceptibility to infection. Mammalian-adaptive substitutions within the hemagglutinin sialic acid receptor-binding domain reduce MHC-II binding, suggesting this interaction is remodeled during clade 2.3.4.4b H5 adaptation to a human host. Lastly, cross-reactive monoclonal antibodies isolated from clade 2.3.4.4b H5-naive humans can block the hemagglutinin-MHC-II interaction. These findings identify a previously unrecognized receptor pathway in contemporary H5N1 viruses and reveal that both human genetic variation and pre-existing humoral immunity can modulate this interaction, with implications for host range, cellular tropism, spillover risk, and therapeutic intervention.