Adrien Delpal, University of Alberta

Adrien Delpal, Arlo Loutan, Dana Kocincova, Matthias Götte Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2E1, Canada

Expressing & Multiplying

Influenza A Viruses (IAV) are pathogens that pose seasonal and pandemic threats to human health globally. Although IAV H5N1 and H5N5 primarily infects avian hosts, adaptive mutations can allow these viruses to expand their host range into mammals. Acidic Nuclear Phosphoprotein 32 (ANP32) is a host factor that plays a critical role in this regard. These proteins interact with the viral polymerase complex and promote dimer formation allowing a functional switch from transcription to replication. Here, we studied the effects of mutations identified in the Polymerase Basic Protein 2 (PB2) of Highly Pathogenic Avian Influenza (HPAI) H5N1 (British Columbia, Canada) and H5N5 (Washington, United States) strains that caused severe disease in humans. The signature mutation for human adaptation, PB2-E627K, is present in the H5N1 strain and absent in the H5N5 strain. We used a minigenome-assay to identify novel mutation that may partially compensate for the lack of 627K in H5N5. However, it is evident that E627K shows that strongest increase in replication in presence of human ANP32. We also studied the effect of Polymerase Acidic protein mutations on the efficiency of the cap-snatching inhibitor baloxavir. Baloxavir remains potent against H5 strains tested in this study. Baloxavir was used as part of cocktail of three antiviral drugs to treat the H5N1 infected individual in BC. The drug is approved by Health Canada, but not readily available. The mechanistic data presented in this study provide further support for the establishment of processes that ensure adequate access to this life-saving drug in Canada.