Adaptation of H5N1 virus to dairy cattle and other mammals
ANP32 proteins (Acidic Nuclear Phosphoprotein 32) are a family of evolutionarily conserved proteins involved in various cellular processes, including gene regulation, apoptosis, and chromatin remodeling. ANP32 proteins have also been implicated in supporting influenza virus replication. The human acidic nuclear phosphoproteins ANP32A and ANP32B are functionally redundant but essential host factors for the replication of mammalian-adapted influenza A virus (IAV) and influenza B virus (IBV) in human cells. When both proteins are absent, influenza polymerases fail to replicate the viral genome, preventing the propagation of infectious virus particles. A recent preprint study published on bioRxiv provides evidence of several mammalian adaptations in H5N1 avian influenza viruses detected in cattle (B3.13 genotype H5N1 viruses). These adaptations include the PB2 M631L mutation, present in all H5N1 cattle sequences, and the PA K497R mutation, observed in the majority of sequences. Structurally, PB2 M631L maps to the polymerase-ANP32 interface, a critical site for viral genome replication. The study demonstrates that this mutation allows the virus to co-opt bovine ANP32 proteins, enhancing viral replication in both bovine and primary human airway cells.Further evolution in the PB2 gene during 2024, including the convergently arising D740N substitution (which significantly boosts polymerase activity in bovine, human, and swine cells), has further increased polymerase activity across various mammalian hosts. Thus, the continued circulation of H5N1 in dairy cattle is facilitating viral adaptation, improving replicative capacity in cattle, and increasing the risk of zoonotic spillover.
