The mammalian-adaptive PB2-E627K substitution preserves viral fitness of clade 2.3.4.4b H5N1 HPAIV in birds.

The clade 2.3.4.4b H5N1 high pathogenicity avian influenza virus (HPAIV) has spread worldwide since 2020, infecting wild birds and poultry and causing mass mortalities in some instances. Spill-over events into mammals can lead to mammalian-adaptive mutations that heighten the risk to humans. The most well-known of these is the glutamate to lysine change at position 627 in the polymerase basic 2 protein (PB2-627K).

While PB2-627K enhances viral replication in mammalian cells, it is relatively uncommon in avian populations. This study examined how PB2-627K affects viral fitness in birds, aiming to gauge the likelihood of mammalian-adapted viruses re-establishing in avian species, similar to how PB2-627K has emerged in mammals after scavenging on them.

The researchers used a representative H5N1 virus (European genotype AB) and discovered that PB2-627K boosted polymerase activity and replication in human cells without hindering replication in avian cells. An isolate from a fox with PB2-627K had replication rates and transmission efficiency in chickens and ducks comparable to a closely related PB2-627E virus.

Of particular note, PB2-627K remained genetically stable following infection and transmission in both avian hosts. These findings indicate that mammalian-adaptive mutations acquired during spill-over can persist in avian populations, potentially increasing the risk of zoonotic transmission and highlighting the need for surveillance of such mutations in birds.