Comparative activities of oseltamivir and A-322278 in immunocompetent and immunocompromised murine models of influenza virus infection.
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.
Ison
Michael G
MG
Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia Health Sciences Center, Charlottesville, 22908, USA.
Mishin
Vasiliy P
VP
Braciale
Thomas J
TJ
Hayden
Frederick G
FG
Gubareva
Larisa V
LV
D000081:Acetamides / Q000494:pharmacology* / Q000627:therapeutic use; D019943:Amino Acid Substitution; D000818:Animals; D004195:Disease Models, Animal; D024882:Drug Resistance, Viral; D007121:Immunocompetence / Q000276:immunology*; D016867:Immunocompromised Host / Q000276:immunology*; D009980:Influenza A virus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000472:pathogenicity; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009976:Orthomyxoviridae Infections / Q000188:drug therapy; D053139:Oseltamivir; D011759:Pyrrolidines / Q000494:pharmacology / Q000627:therapeutic use
C510679:A-322278; D000081:Acetamides; D011759:Pyrrolidines; D053139:Oseltamivir; D009439:Neuraminidase