Journal Article

Phenotypic and genotypic characterization of influenza virus mutants selected with the sialidase fusion protein DAS181

Gallen B. Triana-Baltzer, Rebecca L. Sanders, Maria Hedlund, Kellie A. Jensen, Laura M. Aschenbrenner, Jeffrey L. Larson and Fang Fang

in Journal of Antimicrobial Chemotherapy

Published on behalf of British Society for Antimicrobial Chemotherapy

Volume 66, issue 1, pages 15-28
Published in print January 2011 | ISSN: 0305-7453
Published online November 2010 | e-ISSN: 1460-2091 | DOI: https://dx.doi.org/10.1093/jac/dkq387
Phenotypic and genotypic characterization of influenza virus mutants selected with the sialidase fusion protein DAS181

Show Summary Details

Preview

Background

Influenza viruses (IFVs) frequently achieve resistance to antiviral drugs, necessitating the development of compounds with novel mechanisms of action. DAS181 (Fludase®), a sialidase fusion protein, may have a reduced potential for generating drug resistance due to its novel host-targeting mechanism of action.

Methods

IFV strains B/Maryland/1/59 and A/Victoria/3/75 (H3N2) were subjected to >30 passages under increasing selective pressure with DAS181. The DAS181-selected IFV isolates were characterized in vitro and in mice.

Results

Despite extensive passaging, DAS181-selected viruses exhibited a very low level of resistance to DAS181, which ranged between 3- and 18-fold increase in EC50. DAS181-selected viruses displayed an attenuated phenotype in vitro, as exhibited by slower growth, smaller plaque size and increased particle to pfu ratios relative to wild-type virus. Further, the DAS181 resistance phenotype was unstable and was substantially reversed over time upon DAS181 withdrawal. In mice, the DAS181-selected viruses exhibited no greater virulence than their wild-type counterparts. Genotypic and phenotypic analysis of DAS181-selected viruses revealed mutations in the haemagglutinin (HA) and neuraminidase (NA) molecules and also changes in HA and NA function.

Conclusions

Results indicate that resistance to DAS181 is minimal and unstable. The DAS181-selected IFV isolates exhibit reduced fitness in vitro, likely due to altered HA and NA functions.

Keywords: resistance; antiviral; haemagglutinin; neuraminidase; sialic acid

Journal Article.  7713 words.  Illustrated.

Subjects: Medical Oncology ; Critical Care

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content. subscribe or login to access all content.