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.
Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia Health Sciences Center, Charlottesville, 22908, USA.
Michael G
MG
Ison
Vasiliy P
VP
Mishin
Thomas J
TJ
Braciale
Frederick G
FG
Hayden
Larisa V
LV
Gubareva
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