Selection of Multi-Drug Resistant Influenza A and B Viruses under Zanamivir Pressure and their Replication Fitness in Ferrets

Oh, Ding Yuan; Panozzo, Jacqueline; Vitesnik, Sophie; Farrukee, Rubaiyea; Piedrafita, David; Mosse, Jennifer; Hurt, Aeron C.

doi:10.3851/imp3135

Cited by 12 publications

(8 citation statements)

References 34 publications

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“…However, RO-7-induced resistance emerges later than has been observed for the adamantanes (the first generation of anti-influenza antiviral drugs, which were clinically ineffective and not recommended for prophylaxis or treatment due to widespread resistance), where resistance occurs as early as one passage experimentally and after only a few days of antiviral therapy in patients ( 16 – 18 ). The rate of RO-7 resistance acquisition is more in line with that seen with the clinically used NAIs, where substitutions mediating reduced susceptibility appear at ≥6 passages in a virus subtype-dependent manner: P7 to P9 for A(H1N1)pdm09 ( 19 ), P6 for A(H5N1) ( 20 ), P8 for A(H4N2) ( 21 ), and P6 to P9 for influenza B viruses ( 22 ). Additionally, recent data from a phase 2 clinical trial with an endonuclease inhibitor (S-033188/baloxavir marboxil), structurally similar to RO-7, reported the detection of I38T/F PA N substitutions in four S-033188-treated patients (I38T, n = 2; I38F, n = 2) of 300 total patients from which virus genotypes could be obtained.…”

Section: Observationmentioning

confidence: 56%

Identification of the I38T PA Substitution as a Resistance Marker for Next-Generation Influenza Virus Endonuclease Inhibitors

Kumar

Barman

et al. 2018

mBio

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The clinical severity and annual occurrence of influenza virus epidemics, combined with the availability of just a single class of antivirals to treat infections, underscores the urgent need to develop new anti-influenza drugs. The endonuclease activity within the viral acidic polymerase (PA) protein is an attractive target for drug discovery due to the critical role it plays in viral gene transcription. RO-7 is a next-generation PA endonuclease inhibitor of influenza A and B viruses, but its drug resistance potential is unknown. Through serial passage of influenza A(H1N1) viruses in MDCK cells under selective pressure of RO-7, we identified an I38T substitution within the PA endonuclease domain that conferred in vitro resistance to RO-7 (up to a 287-fold change in 50% effective concentration [EC50]). I38T emerged between 5 and 10 passages, and when introduced into recombinant influenza A(H1N1) viruses, alone conferred RO-7 resistance (up to an 81-fold change in EC50). Cocrystal structures of mutant and wild-type endonuclease domains with RO-7 provided the structural basis of resistance, where a key hydrophobic interaction between RO-7 and the Ile38 side chain is compromised when mutated to the polar threonine. While Ile38 does not have a crucial role in coordinating the endonuclease active site, the switch to threonine does affect the polymerase activity of some viruses and influences RO-7 affinity for the PAN target (i.e., the ≈200-residue N-terminal domain of PA). However, the change does not lead to a complete loss of replication activity in vitro. Our results predict that RO-7-resistant influenza viruses carrying the I38T substitution may emerge under treatment. This should be taken into consideration for clinical surveillance and in refinement of these drugs.

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Section: Observationmentioning

confidence: 56%

Identification of the I38T PA Substitution as a Resistance Marker for Next-Generation Influenza Virus Endonuclease Inhibitors

Kumar

Barman

et al. 2018

mBio

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“…Often, the first step in developing novel vaccines and anti-viral reagents is the establishment of preclinical mouse models that allow rapid and well-controlled analyses of efficacy. There have been a number of recent studies of this type [43,[101][102][103][104][105][106][107][108][109]. However, there have been limited analyses of the impact on the antigen-specific adaptive responses and in particular CD4 T cell responses, which are the critical regulators of both B cell and CD8 T cell immunity.…”

Section: Discussionmentioning

confidence: 99%

Development of a Mouse Model to Explore CD4 T Cell Specificity, Phenotype, and Recruitment to the Lung after Influenza B Infection

et al. 2022

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The adaptive T cell response to influenza B virus is understudied, relative to influenza A virus, for which there has been considerable attention and progress for many decades. Here, we have developed and utilized the C57BL/6 mouse model of intranasal infection with influenza B (B/Brisbane/60/2008) virus and, using an iterative peptide discovery strategy, have identified a series of robustly elicited individual CD4 T cell peptide specificities. The CD4 T cell repertoire encompassed at least eleven major epitopes distributed across hemagglutinin, nucleoprotein, neuraminidase, and non-structural protein 1 and are readily detected in the draining lymph node, spleen, and lung. Within the lung, the CD4 T cells are localized to both lung vasculature and tissue but are highly enriched in the lung tissue after infection. When studied by flow cytometry and MHC class II: peptide tetramers, CD4 T cells express prototypical markers of tissue residency including CD69, CD103, and high surface levels of CD11a. Collectively, our studies will enable more sophisticated analyses of influenza B virus infection, where the fate and function of the influenza B-specific CD4 T cells elicited by infection and vaccination can be studied as well as the impact of anti-viral reagents and candidate vaccines on the abundance, functionality, and localization of the elicited CD4 T cells.

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“…3,4 Zanamivir is a widely used, broad-spectrum and effective antiviral drug. 5,6 Nevertheless, it has a strong molecular polarity, which leads to low absorbability by oral administration, making its administering inconvenient for children. 7 Selenium (Se) is an essential trace element in human body.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of H1N1 influenza virus by selenium nanoparticles loaded with zanamivir through p38 and JNK signaling pathways

Lin

Guo

et al. 2017

RSC Adv.

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Selection of Multi-Drug Resistant Influenza A and B Viruses under Zanamivir Pressure and their Replication Fitness in Ferrets

Abstract: The NA mutations E119D in influenza A(H1N1)pdm09 and E117D in influenza B viruses that arose under zanamivir pressure conferred resistance to multiple NA inhibitors but had compromised viral replication in ferrets compared to wild-type virus without antiviral drug pressure.

Cited by 12 publications

References 34 publications

Identification of the I38T PA Substitution as a Resistance Marker for Next-Generation Influenza Virus Endonuclease Inhibitors

Identification of the I38T PA Substitution as a Resistance Marker for Next-Generation Influenza Virus Endonuclease Inhibitors

Development of a Mouse Model to Explore CD4 T Cell Specificity, Phenotype, and Recruitment to the Lung after Influenza B Infection

Inhibition of H1N1 influenza virus by selenium nanoparticles loaded with zanamivir through p38 and JNK signaling pathways

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