Treatment of influenza A (H1N1) virus infections in mice and ferrets with cyanovirin-N.

Abstract

Cyanovirin-N (CV-N), a protein derived from Nostoc ellipsosporum, neutralizes influenza virus infectivity by binding to specific high-mannose oligosaccharides (oligomannose-8 and -9) at glycosylation sites on the viral hemagglutinin HA1 subunit. Mouse-adapted viruses lose sensitivity to CV-N due to HA1 mutations that eliminate these glycosylation sites. Recently we created a hybrid (reassortant) influenza A/WSN/33 (H1N1) virus containing the HA gene of A/New Caledonia/20/99 (H1N1) with an Asp225Gly mutation in the HA1, that was lethal to mice yet retained sensitivity to CV-N. We then utilized this model system to test the efficacy of CV-N against influenza. CV-N efficacy was dose-responsive from 0.0625 to 1 mg/kg/day when administered intranasally (i.n.) twice daily for 4 days starting 4h prior to virus exposure. In a second study, survival benefit was seen with CV-N treatments (0.5 mg/kg/day for 4 days) beginning at -4 or +6 h, but was significantly reduced at +12h. The early treatment resulted in up to 100% survival and 1000-fold reduction in lung virus titer on day 3 of the infection. In contrast, ribavirin (a positive control-75 mg/kg/day) treatment resulted in 30% survival and 30-fold decrease in lung virus titers. Lung consolidation scores and lung weights were significantly reduced by CV-N and ribavirin treatment on day 6 of the infection. Ferrets infected with a non-animal adapted influenza A/Charlottesville/31/95 (H1N1) virus were treated intranasally with CV-N (50 microg twice daily for 5 days starting 24 h before virus challenge). They exhibited 100-fold lower viral titers in nasal washes than placebos 1 day after treatment, but virus titers were equivalent on days 2-7. CV-N has the potential for prophylaxis and early initiation of treatment of influenza virus infections.

• Authors: Donald F Smee, Kevin W Bailey, Min-Hui Wong, Barry R O'Keefe, Kirk R Gustafson, Vasiliy P Mishin, Larisa V Gubareva
• Journal: Antiviral research (Antiviral Res) Vol. 80 Issue 3 Pg. 266-71 (Dec 2008) ISSN: 1872-9096 [Electronic] Netherlands
• PMID: 18601954 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Bacterial Proteins
• Carrier Proteins
• cyanovirin N

Topics

• Animals
• Antiviral Agents (administration & dosage)
• Bacterial Proteins (administration & dosage)
• Carrier Proteins (administration & dosage)
• Disease Models, Animal
• Drug Administration Routes
• Female
• Ferrets
• Humans
• Influenza A Virus, H1N1 Subtype (drug effects)
• Influenza, Human (drug therapy, prevention & control)
• Mice
• Mice, Inbred BALB C