Comparative activities of oseltamivir and A-322278 in immunocompetent and immunocompromised murine models of influenza virus infection

Michael G. Ison, Vasiliy P. Mishin, Thomas J. Braciale, Frederick G. Hayden, Larisa V. Gubareva*

*Corresponding author for this work

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

We developed an immunocompromised murine model of influenza virus infection and demonstrated comparable efficacy of oral oseltamivir and A-322278 (both given at dosages of 10 mg/kg/day) in reducing viral replication, decreasing weight loss, and prolonging survival. Once the treatment was discontinued, severe combined immunodeficient (SCID) mice had progressive viral replication and clinical decline. Drug-resistant variants were detected in 4 (29%) of 14 and 2 (13%) of 15 mice (both BALB/c and SCID) treated with oseltamivir or A-322278, respectively; no resistant variants were detected in placebo-treated mice. Amino acid substitutions in the hemagglutinin receptor-binding site at aa 137 or 225 were detected in cloned resistant isolates. A substitution in the neuraminidase (NA) active site (Arg292Lys) was detected in the cloned virus recovered from an oseltamivir-treated mouse. This model would be useful for elucidation of the molecular mechanisms of resistance to NA inhibitors and for testing of anti-influenza therapy options that might prevent the emergence of resistant variants.

Original languageEnglish (US)
Pages (from-to)765-772
Number of pages8
JournalJournal of Infectious Diseases
Volume193
Issue number6
DOIs
StatePublished - Mar 15 2006

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

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