Functional balance between hemagglutinin and neuraminidase shapes the adaptive evolution of influenza A virus.

The adaptive evolution of influenza A virus is strongly influenced by the functional balance between its two major surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA). Although previous studies have demonstrated the importance of HA/NA interplay in receptor binding, virion release, cross-host transmission, and antiviral resistance, most have focused on individual proteins, specific residues, or discrete stages of infection. Consequently, how HA/NA functional balance responds to selective pressures and contributes to viral adaptive evolution remains incompletely understood. Here, we propose a dynamic 'balance-imbalance-rebalance' framework centred on the coordination between HA-mediated receptor binding and NA-mediated receptor cleavage. We systematically examine how HA/NA functional balance influences viral attachment, release, and transmission, cross-species adaptation, pathogenicity, immune escape, and antiviral resistance. We further discuss how changes in receptor availability, immune pressure, and antiviral selection may disrupt a pre-existing HA/NA balance and how coordinated changes in HA and NA may compensate for these perturbations to establish new adaptive states. Future studies integrating structural biology, virology, animal models, and large-scale evolutionary analyses will be essential for quantitatively defining the molecular principles and adaptive boundaries of HA/NA coevolution, thereby improving our ability to assess the evolutionary potential and cross-host transmission risk of emerging influenza viruses.