Influenza A/H3N2 virus infection in immunocompromised ferrets and emergence of antiviral resistance

Abstract

Influenza viruses can cause severe life threatening infections in high-risk patients, including young children, the elderly and patients with compromised immunity due to underlying medical conditions or immunosuppressive treatment. The impaired immunity of these patients causes prolonged virus infection and combined with antiviral treatment facilitates the emergence of viruses with resistance mutations. The diverse nature of their immune status makes them a challenging group to study the impact of influenza virus infection and the efficacy of antiviral therapy. Immunocompromised ferrets may represent a suitable animal model to assess influenza virus infection and antiviral treatment strategies in immunocompromised hosts. Here, ferrets were given a daily oral solution of mycophenolate mofetil, tacrolimus and prednisolone sodium phosphate to suppress their immune system. Groups of immunocompromised and immunocompetent ferrets were inoculated with an A/H3N2 influenza virus and were subsequently treated with Oseltamivir or left untreated. Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) was performed on the throat and nose specimens to study virus replication during the course of infection. All immunocompromised ferrets had prolonged presence of viral RNA and a higher total amount of virus shedding compared to the immunocompetent ferrets. Although Oseltamivir reduced the total amount of virus shedding from the nose and throat of treated ferrets, it also resulted in the emergence of the neuraminidase R292K resistance substitution in all these animals, as determined by mutation specific RT-PCR and next-generation sequencing. No additional mutations that could be associated with the emergence of the R292K resistance mutation were detected. The immunocompromised ferret model can be used to study A/H3N2 virus shedding and is a promising model to study new antiviral strategies and the emergence of antiviral resistance in immunocompromised hosts.

The antiviral effects of baloxavir marboxil against influenza A virus infection in ferrets

“…However, there are reports describing that variants with reduced susceptibility to baloxavir are fit and transmissible in ferrets 40,41 . Of note, treatment of immunocompromised ferrets with OSP led to mutant variants 42,43 ; thus, investigation of the antiviral effects of BXM in immunocompromised hosts (either ferrets or humans) would provide additional information for the treatment of high‐risk influenza patients.…”

Viral Kinetics and Resistance Development in Children Treated with Neuraminidase Inhibitors: The Influenza Resistance Information Study (IRIS)

“…Therefore, no conclusions were drawn regarding oseltamivir usage with clinical symptoms. Previous studies have suggested that antiviral therapy is associated with the development of resistance mutations [ 11 , 15 , 26–28 ]. Similarly, in this study, only children infected with A/H1N1pdm09 and A/H3N2 who received oseltamivir treatment acquired resistance mutations.…”

They are what you eat: Shaping of viral populations through nutrition and consequences for virulence

“…Host immunological status is implicated in molding the quasispecies of dengue virus [28], norovirus [29], influenza virus [30], and coronavirus [31], among others. From these findings, empirical studies have found that host features responsible for attenuating immunity are also implicated in shaping the quasispecies and virulence, including aging [32] and immunocompromised status [29,30,33,34].…”

“…Interestingly, high-fidelity foot-and-mouth disease viral variants possess a higher level of resistance to pharmacologics but are attenuated in vivo, suggesting that the resulting restricted quasispecies hampers adaptability in the presence of drug or host pressures [19]. Also, antiviral treatment can lead genetic diversity gains that may precede selection of drug-resistant genotypes, as has been observed with oseltamivir [33,35].…”