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bioRxiv · 10.64898/2026.07.17.738765

Defining the molecular interaction between influenza hemagglutinin and MHC-II

Dadonaite, B.·Dosey, A.·Ahn, J. J.·Yu, T. C.·Sunshine, S. A.·Farrell, A. G.·King, N. P.·Bloom, J. D.
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Abstract

The hemagglutinin (HA) of some influenza viruses can interact with major histocompatibility complex class II (MHC-II), but how these proteins interact is unclear. Here we demonstrate that diverse H5 HAs can use MHC-II to enter cells, with avian MHC-II enabling more efficient entry than human MHC-II for most H5 HAs. To define the molecular interface, we use pseudovirus deep mutational scanning to measure how mutations to H5 HA affect its interaction with tufted duck MHC-II, and identify mutations that restrict HA to exclusively MHC-II or sialic acid receptors. We leverage identification of H5 HA mutations that increase binding to tufted duck MHC-II to determine a 4.8 [A] cryo-EM model of the complex. To support the structural model, we measure how all mutations to tufted duck MHC-II affect its interaction with H5 HA, and find the alpha chain is the dominant determinant but beta chain sites near the peptide-binding groove also contribute. To generalize these findings, we use deep mutational scanning to show that a H7 HA interacts with MHC-II similarly to H5 HA. Finally, we show that H1, H2, H3, and H9 HAs interact with avian or human MHC-II, although interactions vary among strains that evolved in different hosts.

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Dadonaite, B., Dosey, A., Ahn, J. J., Yu, T. C., Sunshine, S. A., Farrell, A. G., King, N. P., Bloom, J. D.. 2026-07-22. Defining the molecular interaction between influenza hemagglutinin and MHC-II. https://doi.org/10.64898/2026.07.17.738765

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