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Published on: June 3, 2012
Suppression of influenza virus replication in infected mice by protease inhibitors
Abstract:
Administration of the protease inhibitors, epsilon-aminocaproic acid or aprotinins, to mice infected with mouse-adapted influenza virus strain A/PR/8/34 (HON1) and A/Aichi/2/68 (H3N2) reduced virus replication in the lungs. Up to 100-fold reduction of virus titre and virus-induced neuraminidase activity were revealed in mouse lungs under protease inhibitor treatment. As a result, drug-treated mice rapidly cleared the virus from their lungs. The predominant synthesis was of non-infectious virions with uncleaved haemagglutinin in the lungs of drug-treated mice, in contrast to the production of highly infectious virions with proteolytically cleaved haemagglutinin in untreated mice. These observations suggest that protease inhibitors suppress influenza virus replication in mouse lungs due to prevention of haemagglutinin cleavage and virus proteolytic activation.
Insights
Protease inhibitors like epsilon-aminocaproic acid significantly reduced influenza virus replication in mice. This treatment prevented haemagglutinin cleavage, leading to rapid virus clearance and reduced lung infection severity.
Area of Science:
- Virology
- Pharmacology
- Immunology
Background:
- Influenza virus replication relies on the proteolytic cleavage of haemagglutinin for infectivity.
- Protease inhibitors are known to interfere with viral maturation processes.
Purpose of the Study:
- To investigate the efficacy of protease inhibitors in suppressing influenza virus replication in a mouse model.
- To elucidate the mechanism by which protease inhibitors affect viral haemagglutinin processing and infectivity.
Main Methods:
- Mice were infected with mouse-adapted influenza virus strains (A/PR/8/34 and A/Aichi/2/68).
- Mice were treated with protease inhibitors: epsilon-aminocaproic acid or aprotinin.
- Virus replication, titre, neuraminidase activity, and haemagglutinin cleavage were assessed in lung tissues.
Main Results:
- Protease inhibitor treatment led to a significant reduction (up to 100-fold) in lung virus titre and neuraminidase activity.
- Drug-treated mice exhibited rapid viral clearance from the lungs.
- Non-infectious virions with uncleaved haemagglutinin were predominantly synthesized in treated mice, unlike infectious virions in controls.
Conclusions:
- Protease inhibitors effectively suppress influenza virus replication in mouse lungs.
- The mechanism involves the prevention of haemagglutinin cleavage, thereby inhibiting virus proteolytic activation and infectivity.
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