Treatment of influenza A (H1N1) virus infections in mice and ferrets with cyanovirin-N.
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.
Smee
Donald F
DF
Institute for Antiviral Research, Utah State University, Logan, UT, USA. dsmee@cc.usu.edu
Bailey
Kevin W
KW
Wong
Min-Hui
MH
O'Keefe
Barry R
BR
Gustafson
Kirk R
KR
Mishin
Vasiliy P
VP
Gubareva
Larisa V
LV
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage*; D001426:Bacterial Proteins / Q000008:administration & dosage*; D002352:Carrier Proteins / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D005260:Female; D005289:Ferrets; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects*; D007251:Influenza, Human / Q000188:drug therapy* / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C
D000998:Antiviral Agents; D001426:Bacterial Proteins; D002352:Carrier Proteins; C107733:cyanovirin N