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

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.

• Authors: Michael G Ison, Vasiliy P Mishin, Thomas J Braciale, Frederick G Hayden, Larisa V Gubareva
• Journal: The Journal of infectious diseases (J Infect Dis) Vol. 193 Issue 6 Pg. 765-72 (Mar 15 2006) ISSN: 0022-1899 [Print] United States
• PMID: 16479509 (Publication Type: Comparative Study, Journal Article)

Chemical References

• A-322278
• Acetamides
• Pyrrolidines
• Oseltamivir
• Neuraminidase

Topics

• Acetamides (pharmacology, therapeutic use)
• Amino Acid Substitution
• Animals
• Disease Models, Animal
• Drug Resistance, Viral
• Immunocompetence (immunology)
• Immunocompromised Host (immunology)
• Influenza A virus (drug effects, enzymology, genetics, pathogenicity)
• Mice
• Mice, Inbred BALB C
• Mice, SCID
• Neuraminidase (antagonists & inhibitors, metabolism)
• Orthomyxoviridae Infections (drug therapy)
• Oseltamivir
• Pyrrolidines (pharmacology, therapeutic use)