Abstract
In late 2024, two individuals in Canada and the United States were treated in intensive care for acute respiratory distress caused by infection with the avian Influenza A Virus H5N1 2.3.4.4b genotype D1.1. Viral sequence data obtained from sampling these patients indicated mixed alleles at haemagglutinin (HA) positions 190 and 226. Mutations at these positions are key determinants of HA usage of α2,6-linked sialic acids (SA), the most abundant influenza receptors in human upper respiratory tracts. Thus, these mutations raised concerns about human adaptation and pandemic potential of the H5N1 virus. In this study, we investigated the impact of the mutations at residues 190 and 226 in H5 HA. We studied the receptor binding properties, cell entry phenotypes and fitness impacts of the mutations using recombinant proteins, pseudotyped lentiviruses, and in the context of influenza viruses using reverse genetics. The mutations did not confer any detectable α2,6-linked sialic acid receptor usage either alone or in combination. Rather, viruses carrying these mutations exhibit weakened binding towards α2,3-linked sialic acid receptors. This correlated with an enhanced capacity to evade human airway mucus, and a reduced susceptibility to oseltamivir and zanamivir. This research underscores that in addition to the way HA interacts with SA as entry receptors, other factors that impact the HA/NA balance might influence the evolutionary trajectory of a zoonotic virus in the human respiratory tract. This study presents a new paradigm for the evolutionary drivers of HA, where reduced sialic acid binding can serve as an advantage for escape from host barriers and antivirals.
Competing Interest Statement
The authors have declared no competing interest.
Funder Information Declared
Medical Research Council, https://ror.org/03x94j517, MR/Y03368X/1, MR/Y015061/1, CC2127
Biotechnology and Biological Sciences Research Council, BB/Y007298/1, APP104179, BBS/E/PI/23NB000, BBS/E/PI/23NB0003
Wellcome Trust, https://ror.org/029chgv08, CC2127, 218304/Z/19/Z
Department for Environment Food and Rural Affairs, BB/Y007298/1
The Pirbright Institute, BBS/E/PI/230002A, BBS/E/PI/230001C, BBS/E/PI/230002B
Cancer Research UK, CC2127
UK Research and Innovation, https://ror.org/001aqnf71, UKRI3602
Source:
Link: https://www.biorxiv.org/content/10.64898/2026.07.28.740943v1
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