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Influenza A virus resistance to 4'-fluorouridine coincides with viral attenuation in vitro and in vivo.
Lieber, Carolin M; Kang, Hae-Ji; Aggarwal, Megha; Lieberman, Nicole A; Sobolik, Elizabeth B; Yoon, Jeong-Joong; Natchus, Michael G; Cox, Robert M; Greninger, Alexander L; Plemper, Richard K.
Affiliation
  • Lieber CM; Center for Translational Antiviral Research, Georgia State University Institute for Biomedical Sciences, Atlanta, Georgia, United States of America.
  • Kang HJ; Center for Translational Antiviral Research, Georgia State University Institute for Biomedical Sciences, Atlanta, Georgia, United States of America.
  • Aggarwal M; Center for Translational Antiviral Research, Georgia State University Institute for Biomedical Sciences, Atlanta, Georgia, United States of America.
  • Lieberman NA; Virology Division, Department of Laboratory Medicine and Pathology, University of Washington Medical Center, Seattle, Washington, United States of America.
  • Sobolik EB; Virology Division, Department of Laboratory Medicine and Pathology, University of Washington Medical Center, Seattle, Washington, United States of America.
  • Yoon JJ; Center for Translational Antiviral Research, Georgia State University Institute for Biomedical Sciences, Atlanta, Georgia, United States of America.
  • Natchus MG; Emory Institute for Drug Development, Emory University School of Medicine, Atlanta, Georgia, United States of America.
  • Cox RM; Center for Translational Antiviral Research, Georgia State University Institute for Biomedical Sciences, Atlanta, Georgia, United States of America.
  • Greninger AL; Virology Division, Department of Laboratory Medicine and Pathology, University of Washington Medical Center, Seattle, Washington, United States of America.
  • Plemper RK; Center for Translational Antiviral Research, Georgia State University Institute for Biomedical Sciences, Atlanta, Georgia, United States of America.
PLoS Pathog ; 20(2): e1011993, 2024 Feb.
Article in En | MEDLINE | ID: mdl-38300953
ABSTRACT
Pre-existing or rapidly emerging resistance of influenza viruses to approved antivirals makes the development of novel therapeutics to mitigate seasonal influenza and improve preparedness against future influenza pandemics an urgent priority. We have recently identified the chain-terminating broad-spectrum nucleoside analog clinical candidate 4'-fluorouridine (4'-FlU) and demonstrated oral efficacy against seasonal, pandemic, and highly pathogenic avian influenza viruses in the mouse and ferret model. Here, we have resistance-profiled 4'-FlU against a pandemic A/CA/07/2009 (H1N1) (CA09). In vitro viral adaptation yielded six independently generated escape lineages with distinct mutations that mediated moderate resistance to 4'-FlU in the genetically controlled background of recombinant CA09 (recCA09). Mutations adhered to three distinct structural clusters that are all predicted to affect the geometry of the active site of the viral RNA-dependent RNA polymerase (RdRP) complex for phosphodiester bond formation. Escape could be achieved through an individual causal mutation, a combination of mutations acting additively, or mutations functioning synergistically. Fitness of all resistant variants was impaired in cell culture, and all were attenuated in the mouse model. Oral 4'-FlU administered at lowest-efficacious (2 mg/kg) or elevated (10 mg/kg) dose overcame moderate resistance when mice were inoculated with 10 LD50 units of parental or resistant recCA09, demonstrated by significantly reduced virus load and complete survival. In the ferret model, invasion of the lower respiratory tract by variants representing four adaptation lineages was impaired. Resistant variants were either transmission-incompetent, or spread to untreated sentinels was fully blocked by therapeutic treatment of source animals with 4'-FlU.
Subject(s)

Full text: 1 Database: MEDLINE Main subject: Influenza A virus / Uracil Nucleotides / Orthomyxoviridae Infections / Influenza, Human / Influenza A Virus, H1N1 Subtype Type of study: Prognostic_studies Limits: Animals / Humans Language: En Year: 2024 Type: Article

Full text: 1 Database: MEDLINE Main subject: Influenza A virus / Uracil Nucleotides / Orthomyxoviridae Infections / Influenza, Human / Influenza A Virus, H1N1 Subtype Type of study: Prognostic_studies Limits: Animals / Humans Language: En Year: 2024 Type: Article