Étude et suivi de la résistance des virus influenzae A aux inhibiteurs de la neuraminidase

Abstract : Influenza viruses are important human pathogens that are responsible for flu, whether seasonal, pandemic or zoonotic. Very few therapeutic options are available against these pathogens and neuraminidase inhibitors (NAI) are the only antiviral agents recommended by the WHO for treatment and prophylaxis of influenza virus infections. NAI resistance has already been described and the H274Y, E119V and R292K neuraminidase substitutions are the most frequently encountered substitutions responsible for oseltamivir resistance. During this work, we focused the NAI resistance study around two main objectives: first, we monitored clinical and biological resistance in treated patients and then we studied the impact of substitutions responsible for NAI resistance using avian neuraminidases. For NAI resistance monitoring, viral genomic diversity of a child's influenza A(H1N1)pdm09 was characterized in the context of a severe combined immunodeficiency and a chronic viral excretion despite antiviral treatment. For a better detection of H274Y substitution in A(H1N1) influenza viruses, a digital droplet PCR was developed and evaluated. At a more fundamental level, resistance substitutions (H274Y, R292K, E119V ± I222L) were analysed using all neuraminidase subtypes of influenza A viruses. To summarize, H274Y substitution is preferentially isolated in N1 but also decreases oseltamivir susceptibility in all group 1 neuraminidases (N1, N4, N5 and N8). The E119V substitution impact on oseltamivir susceptibility depends on the neuraminidase and decreases oseltamivir susceptibility especially within N2, N7, N9 and N5. Moreover, the E119V+I222L substitutions has a synergistic effect on oseltamivir resistance profile. The R292K substitution decreases all NAI susceptibility for all group 2 neuraminidases (N2, N3, N6, N7 and N9). The production of a recombinant N9 bearing the R292K substitution allows to highlight the substitution impact on the sialidasic activity. Development of new technological tools are still in progress to allow a more accurate analysis of the mechanisms that underlie the NAI resistance
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Alexandre Gaymard. Étude et suivi de la résistance des virus influenzae A aux inhibiteurs de la neuraminidase. Virologie. Université de Lyon, 2019. Français. ⟨NNT : 2019LYSE1135⟩. ⟨tel-02356404⟩

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