| Autor: |
Jiang L; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical Schoolgrid.168645.8, Worcester, Massachusetts, USA., Samant N; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical Schoolgrid.168645.8, Worcester, Massachusetts, USA., Liu P; Department of Medicine, University of Massachusetts Medical Schoolgrid.168645.8, Worcester, Massachusetts, USA., Somasundaran M; Department of Medicine, University of Massachusetts Medical Schoolgrid.168645.8, Worcester, Massachusetts, USA., Jensen JD; School of Life Sciences, Arizona State Universitygrid.215654.1, Tempe, Arizona, USA., Marasco WA; Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, USA., Kowalik TF; Microbiology and Physiological Systems, University of Massachusetts Medical Schoolgrid.168645.8, Worcester, Massachusetts, USA., Schiffer CA; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical Schoolgrid.168645.8, Worcester, Massachusetts, USA., Finberg RW; Department of Medicine, University of Massachusetts Medical Schoolgrid.168645.8, Worcester, Massachusetts, USA., Wang JP; Department of Medicine, University of Massachusetts Medical Schoolgrid.168645.8, Worcester, Massachusetts, USA., Bolon DNA; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical Schoolgrid.168645.8, Worcester, Massachusetts, USA. |
| Abstrakt: |
Many oseltamivir resistance mutations exhibit fitness defects in the absence of drug pressure that hinders their propagation in hosts. Secondary permissive mutations can rescue fitness defects and facilitate the segregation of resistance mutations in viral populations. Previous studies have identified a panel of permissive or compensatory mutations in neuraminidase (NA) that restore the growth defect of the predominant oseltamivir resistance mutation (H275Y) in H1N1 influenza A virus. In prior work, we identified a hyperactive mutation (Y276F) that increased NA activity by approximately 70%. While Y276F had not been previously identified as a permissive mutation, we hypothesized that Y276F may counteract the defects caused by H275Y by buffering its reduced NA expression and enzyme activity. In this study, we measured the relative fitness, NA activity, and surface expression, as well as sensitivity to oseltamivir, for several oseltamivir resistance mutations, including H275Y in the wild-type and Y276F genetic background. Our results demonstrate that Y276F selectively rescues the fitness defect of H275Y by restoring its NA surface expression and enzymatic activity, elucidating the local compensatory structural impacts of Y276F on the adjacent H275Y. IMPORTANCE The potential for influenza A virus (IAV) to cause pandemics makes understanding evolutionary mechanisms that impact drug resistance critical for developing surveillance and treatment strategies. Oseltamivir is the most widely used therapeutic strategy to treat IAV infections, but mutations in IAV can lead to drug resistance. The main oseltamivir resistance mutation, H275Y, occurs in the neuraminidase (NA) protein of IAV and reduces drug binding as well as NA function. Here, we identified a new helper mutation, Y276F, that can rescue the functional defects of H275Y and contribute to the evolution of drug resistance in IAV. |
