Date of Award:

2012

Document Type:

Thesis

Degree Name:

Master of Science (MS)

Advisor/Chair:

E. Bart Tarbet

Abstract

Influenza viruses cause between 3 and 5 million cases of respiratory infection each year and are responsible for between 250 and 500 thousand deaths. There are principally two avenues for the treatment and prevention of influenza. They are vaccination and antiviral regimens. Prevention of infection is largely accomplished through vaccination. While vaccines remain the preferred method for controlling the spread of influenza, treatment with antiviral drugs is important for treatment of severe infections that are caused by viruses that are different from the vaccination strains. The two major classes of antiviral drugs for influenza treatment are the adamantanes and the neuraminidase inhibitors. While most viruses have become resistant to the adamantanes, the neuraminidase inhibitors remain the primary choice for treatment of infections. Oseltamivir is the most important of the neuraminidase inhibitors. Data from an experiment run at Utah State University displayed a characteristic that is reflected in other published data. Oseltamivir, which has been shown to be effective against influenza virus strains in vitro, is unable to sufficiently protect mice from lethal infections. The focus of the present research was to identify viral differences that might explain for this discrepancy. Four viral strains were chosen that display differing susceptibilities to oseltamivir in mice. The viruses used were Influenza A/Duck/MN/1525/81 (H5N1), A/Victoria/3/75 (H3N2), A/NWS/33 (H1N1) and A/California/04/2009 (Pandemic H1N1). Oseltamivir was unable to protect mice that were infected with the A/Duck/MN/1525/81 and A/Victoria/3/75 viruses. These two viruses, along with the A/NWS/33 and the A/California/04/2009 viruses, were compared in vitro using virus replication kinetics, neuraminidase inhibition assays, and antiviral assays in cell culture. The viruses were studied in vivo by comparing survival, weight loss, lung scores and weights, lung virus titers, complete blood counts, cytokine assays, and histopathology. A second in vivo experiment was run to determine the effects of oseltamivir on survival, weight loss, lung scores and weights, lung virus titers, and histopathology. The two in vivo experiments summarized in this study confirmed previous data since oseltamivir was unable to protect mice infected with the influenza A/Duck and A/Victoria viruses. Overall, the virus infections behaved remarkably similar. The most interesting difference was that the A/Duck/MN/1525/81 and A/Victoria/3/75 viruses were able to induce more severe histopathological damage in mouse lungs earlier in the infection. The ability to cause severe disease more quickly might explain why the A/Duck/MN/1525/81 and A/Victoria/3/75 viruses remain lethal, despite oseltamivir treatment.

Comments

This work made publicly available electronically on May 11, 2012.

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