Emergence of a novel drug resistant H7N9 influenza virus: evidence based clinical potential of a natural IFN-α for infection control and treatment

Abstract

The novel avian H7N9 influenza virus has caused more than 130 human infections with 43 deaths (as of September, 2013) in China. Because of the lack of existing immunity against H7 subtype influenza viruses in the human population and the absence of a licensed commercial vaccine, antiviral drugs are critical tools for the treatment of infection with this novel H7N9. Both M2-ion channel blockers and neuraminidase inhibitors are used as antiviral drugs for influenza infections of humans. The emerging H7N9 viruses are resistant to the M2-ion channel blockers because of a S31N mutation in the M2 protein; additionally, some H7N9 isolates have gained neuraminidase R292K substitution resulting in broad resistance to neuraminidase inhibitors. In this study we report that Alferon N can inhibit wild type and 292K H7N9 viruses replication in vitro. Since Alferon N is approved for clinical use, this would allow a rapid regulatory approval process for this drug under pandemic threat.

Keywords::

• Alferon N
• antiviral drug
• H7N9
• influenza
• neuraminidase inhibitors
• oseltamivir resistance
• tamiflu

Acknowledgements

We would like to thank RJ Webby from St Jude Children's Research Hospital for supplying us with the A/Anhui/1/2013 virus stock and A García-Sastre from Icahn School of Medicine at Mount Sinai for supplying A/Shanghai/1/2013 virus stock. We would also like to thank Haixia Liu and laboratory coordinators from Biosecurity Research Institute (BSL3/BSL3Ag) located at Kansas State for providing technical support and NM Bouvier for cell culture compatible Tamiflu®.

Financial & competing interests disclosure

This work was partially funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contract numbers HHSN266200700005C, by the U.S. Department of Homeland Security under Grant Award Number 2010-ST-AG0001, and by Hemispherx Biopharma Inc (HEB). Q Liu is a scientific adviser to Hemispherx Biopharma (HEB); JA Richt is a scientific adviser and received funds from HEB; DR Strayer and WA Carter are management employees and shareholders of HEB; WM Mitchell is in independent member of HEB BOD and HEB shareholder. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Antiviral treatment is an important strategy in controlling and preventing influenza viral infections. Current pharmaceuticals approved for the prophylaxis and/or treatment of influenza inhibit the function of the neuraminidase and M2-ion channel viral proteins.

• High mutational rates are characteristic of influenza viruses, resulting in viruses with resistance to neuraminidase or M2 inhibitors. Such viruses present a high-risk human public health threat for emerging avian influenza viruses with high pathogenicity for humans such as H7N9.

• Some H7N9 isolates have gained resistance to neuraminidase inhibitors. Alferon N (natural interferon) has broad anti-viral activities and inhibits the replication of both wild-type and neuraminidase inhibitor-resistant H7N9 viruses.

• An imminent pandemic threat from H7N9 or other avian influenza viruses with resistance to neuraminidase and M2 inhibitor demands research on novel anti-influenza drugs targeting different viral genes and/or innate immune responses.

Notes