ABSTRACT
We show that human myxovirus resistance protein 1 (MxA) suppresses replication of highly pathogenic avian influenza A(H5N1) viruses isolated from mammals in vitro and in MxA-transgenic mice. However, H5N1 can evade MxA restriction through replacement of individual viral polymerase complex components from a human-adapted MxA-resistant strain in vitro.
Since 2022, clade 2.3.4.4b highly pathogenic avian influenza (HPAI) viruses of the H5N1 subtype have caused an increasing number of outbreaks in mammals worldwide (1). Since spring 2024, outbreaks of H5N1 clade 2.3.4.4b viruses have occurred in dairy cows in the United States, leading to the transmission of the virus to dairy farm workers, likely through close contact with infected cows or milk (2,3). Those events have raised concerns that H5N1 clade 2.3.4.4b viruses may further adapt to humans. Indeed, some current mammal H5N1 clade 2.3.4.4b isolates already carry adaptive mutations associated with enhanced binding to mammalian entry receptors, increased viral polymerase activity in mammalian cells, or escape from the recently identified BTN3A3 restriction factor (1,2,4). However, for sustained human-to-human transmission, HPAI H5N1 must overcome additional host barriers, including human myxovirus resistance protein 1 (MxA).