Antiviral drug resistance in avian influenza viruses

One of the circulating avian influenza H5N1 viruses, clade 2.3.4.4b, has the unique capability to infect many species of mammals such as cats, racoons, dogs, minks and marine mammals. As of July 3, 2024, 4 US individuals tied to dairy cattle have been infected with this strain but none from Canada so far. Contamination with raw cow's milk is a potential transmission route although pasteurization was shown to inactivate H5N1 viruses. Despite the fact that those recent human cases were not very sick (they mainly had conjunctivitis), there is a risk of dissemination of this highly pathogenic strain to humans considering the detection of mammalian adaptation mutations already present in those viruses. Besides vaccines, antivirals have an important role in the control of influenza viruses. However, the need of early intervention (typically within 48 hours) and the emergence of resistance are well-known limitations of these agents targeting the viral neuraminidase (NA) or polymerase (pol). The recent H5N1 clade has been shown to be susceptible to these classes of antivirals, although prior H5N1 strains resistant to neuraminidase inhibitors have been reported so that active surveillance for drug resistance mutations is a priority. The objective of this proposal is to develop safe and rapid strategies to assess the drug phenotype associated with NA and pol mutations leading to antiviral drug resistance previously reported in other viral subtypes (such as H1N1) or those of unknown significance found in clinical and animal samples. At term, such rapid genotype to phenotype assays should result in improved treatment and will inform on drug stockpiling strategy in case of pandemic.