Comparative Activities of Oseltamivir and A-322278 in Immunocompetent and Immunocompromised Murine Models of Influenza Virus Infection
Identifieur interne : 001524 ( Main/Exploration ); précédent : 001523; suivant : 001525Comparative Activities of Oseltamivir and A-322278 in Immunocompetent and Immunocompromised Murine Models of Influenza Virus Infection
Auteurs : Michael G. Ison ; Vasiliy P. Mishin ; Thomas J. Braciale ; Frederick G. Hayden ; Larisa V. GubarevaSource :
- The Journal of Infectious Diseases [ 0022-1899 ] ; 2006.
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
Url:
DOI: 10.1086/500464
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Gubareva</name><affiliation><wicri:noCountry code="subField"></wicri:noCountry></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">The Journal of Infectious Diseases</title><title level="j" type="abbrev">The Journal of Infectious Diseases</title><idno type="ISSN">0022-1899</idno><idno type="eISSN">1537-6613</idno><imprint><publisher>The University of Chicago Press</publisher><date when="2006-03-15">2006</date><biblScope unit="vol">193</biblScope><biblScope unit="issue">6</biblScope><biblScope unit="page" from="765">765</biblScope><biblScope unit="page" to="772">772</biblScope></imprint><idno type="ISSN">0022-1899</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-1899</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="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</div></front></TEI><affiliations><list></list><tree><noCountry><name sortKey="Braciale, Thomas J" sort="Braciale, Thomas J" uniqKey="Braciale T" first="Thomas J." last="Braciale">Thomas J. Braciale</name><name sortKey="Gubareva, Larisa V" sort="Gubareva, Larisa V" uniqKey="Gubareva L" first="Larisa V." last="Gubareva">Larisa V. Gubareva</name><name sortKey="Hayden, Frederick G" sort="Hayden, Frederick G" uniqKey="Hayden F" first="Frederick G." last="Hayden">Frederick G. Hayden</name><name sortKey="Ison, Michael G" sort="Ison, Michael G" uniqKey="Ison M" first="Michael G." last="Ison">Michael G. Ison</name><name sortKey="Mishin, Vasiliy P" sort="Mishin, Vasiliy P" uniqKey="Mishin V" first="Vasiliy P." last="Mishin">Vasiliy P. 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