scholarly journals In vitro characterization of multidrug-resistant influenza A(H1N1)pdm09 viruses carrying a dual amino acid substitution associated with reduced susceptibility to neuraminidase inhibitors

2018 ◽  
Author(s):  
Emi Takashita ◽  
Seiichiro Fujisaki ◽  
Masaru Yokoyama ◽  
Masayuki Shirakura ◽  
Kazuya Nakamura ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Substitution ◽  
Influenza A ◽  
Multidrug Resistant ◽  
Cross Resistance ◽  
Neuraminidase Inhibitors ◽  
In Vitro Characterization ◽  
Influenza A H1n1

AbstractWe detected influenza A(H1N1)pdm09 viruses carrying dual H275Y/I223R, H275Y/I223K, or H275Y/G147R substitutions in their neuraminidase protein, respectively. These viruses showed cross-resistance to oseltamivir and peramivir and reduced susceptibility to zanamivir. The H275Y/G147R virus retained its replication capability at least in vitro, but the H275Y/I223R and H275Y/I223K viruses did not.

scholarly journals In Vitro Characterization of Multidrug-Resistant Influenza A(H1N1)pdm09 Viruses Carrying a Dual Neuraminidase Mutation Isolated from Immunocompromised Patients

Pathogens ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 725
Author(s):  
Emi Takashita ◽  
Seiichiro Fujisaki ◽  
Masaru Yokoyama ◽  
Masayuki Shirakura ◽  
Hiroko Morita ◽  
...  
Keyword(s):  
Influenza A ◽  
Multidrug Resistant ◽  
Wild Type Virus ◽  
Cross Resistance ◽  
Immunocompromised Patients ◽  
In Vitro Characterization ◽  
Influenza A H1n1 ◽  
Better Than

Influenza A(H1N1)pdm09 viruses carrying a dual neuraminidase (NA) substitution were isolated from immunocompromised patients after administration of one or more NA inhibitors. These mutant viruses possessed an H275Y/I223R, H275Y/I223K, or H275Y/G147R substitution in their NA and showed enhanced cross-resistance to oseltamivir and peramivir and reduced susceptibility to zanamivir compared to single H275Y mutant viruses. Baloxavir could be a treatment option against the multidrug-resistant viruses because these dual H275Y mutant viruses showed susceptibility to this drug. The G147R substitution appears to stabilize the NA structure, with the fitness of the H275Y/G147R mutant virus being similar or somewhat better than that of the wild-type virus. Since the multidrug-resistant viruses may be able to transmit between humans, surveillance of these viruses must continue to improve clinical management and to protect public health.

scholarly journals Y155H amino acid substitution in influenza A(H1N1)pdm09 viruses does not confer a phenotype of reduced susceptibility to neuraminidase inhibitors

2014 ◽  
Vol 19 (27) ◽  
Author(s):  
U Perez-Sautu ◽  
F Pozo ◽  
I Cuesta ◽  
S Monzon ◽  
A Calderon ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Substitution ◽  
Influenza A ◽  
High Throughput Sequencing ◽  
Biological Significance ◽  
H1n1 Influenza ◽  
Influenza Viruses ◽  
Neuraminidase Inhibitors ◽  
Epidemic Season ◽  
Influenza A H1n1

The Y155H amino acid substitution in the neuraminidase gene (NA) has previously been associated with highly reduced inhibition by neuraminidase inhibitors in the seasonal H1N1 influenza A virus which circulated in humans before the 2009 pandemic. During the 2012/13 epidemic season in Spain, two A(H1N1)pdm09 viruses bearing the specific Y155H substitution in the NA were detected and isolated from two patients diagnosed with severe respiratory syndrome and pneumonia requiring admission to the intensive care unit. Contrary to what was observed in the seasonal A(H1N1) viruses, neither of the Y155H A(H1N1)pdm09 viruses described here showed a phenotype of reduced inhibition by NAIs as determined by the neuraminidase enzyme inhibition assay (MUNANA). High-throughput sequencing of the NA of both Y155H viruses showed that they were composed to >99% of H155 variants. We believe that this report can contribute to a better understanding of the biological significance of amino acid substitutions in the neuraminidase protein with regard to susceptibility of influenza viruses to neuraminidase inhibitors. This is of critical importance for optimal management of influenza disease patients.

In Vitro Characterization of Influenza A Virus Attachment in the Upper and Lower Respiratory Tracts of Pigs

2012 ◽  
Vol 50 (4) ◽  
pp. 648-658 ◽  
Author(s):  
S. E. Detmer ◽  
M. R. Gramer ◽  
S. M. Goyal ◽  
M. Torremorell
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Virus Attachment ◽  
In Vitro Characterization

scholarly journals A community cluster of influenza A(H1N1)pdm09 virus exhibiting cross-resistance to oseltamivir and peramivir in Japan, November to December 2013

2014 ◽  
Vol 19 (1) ◽  
Author(s):  
E Takashita ◽  
M Ejima ◽  
R Itoh ◽  
M Miura ◽  
A Ohnishi ◽  
...  
Keyword(s):  
Influenza A ◽  
Cross Resistance ◽  
Neuraminidase Inhibitors ◽  
Resistant Virus ◽  
Pdm09 Virus ◽  
Specimen Collection ◽  
Influenza A H1n1 ◽  
Clonal Spread ◽  
Epidemiological Link

Six influenza A(H1N1)pdm09 viruses were detected in Sapporo, Japan, between November and December 2013. All six viruses possessed an H275Y substitution in the neuraminidase protein, which confers cross-resistance to oseltamivir and peramivir. No epidemiological link among the six cases could be identified; none of them had received neuraminidase inhibitors before specimen collection. The haemagglutinin and neuraminidase genes of the six viruses were closely related to one another, suggesting clonal spread of a single resistant virus.

scholarly journals In silico analysis and molecular characterization of Influenza A (H1N1) pdm09 virus circulating and causing major outbreaks in central India, 2009-2019

2020 ◽  
Author(s):  
Arshi Siddiqui ◽  
Rashmi Chowdhary ◽  
Harjeet Singh Maan ◽  
Sudhir Kumar Goel ◽  
Nidhi Tripathi ◽  
...  
Keyword(s):  
Amino Acid ◽  
Vaccine Efficacy ◽  
Influenza A ◽  
In Silico Analysis ◽  
Central India ◽  
Gene Sequences ◽  
Ha Gene ◽  
Influenza A H1n1 ◽  
Silico Analysis

Background and Objectives: Influenza A/H1N1pdm09 causes respiratory illness and remains a concern for public health. Since its first emergence in 2009, the virus has been continuously circulating in the form of its genetic variants. Influenza A/ H1N1pdm09 surveillance is essential for uncovering emerging variants of epidemiologic and vaccine efficacy. The present study attempts in silico analysis and molecular characterization of Influenza A (H1N1) pdm09 virus circulating and causing major outbreaks in central India during 2009-2019. Materials and Methods: We have investigated the antigenic drift analysis of 96 isolates’ hemagglutinin (HA) gene sequences (59 central Indian and 37 local Indian and 28 global reference HA gene sequences) of Influenza A/H1N1pdm09 viruses from 2009 to 2019. The study includes mutational (Multiple sequence Alignment), phylogenetic (Maximum Likelihood Method), and statistical analysis (Covariance and correlation) of HA sequences submitted in NCBI, IRD and GISAID from central India. Results: Phylogenetic analysis indicated maximum clustering of central Indian HA gene sequences in genogroup 6B. Analysis of amino acid sequence alignment revealed changes in receptor binding site (RBS). The frequency of S220T amino acid substitution was found to be high followed by S202T, K300E A273T, K180Q. The Karl Pearson correlation coefficient (r) and covariance between the number of mutations and the death toll was found +0.246 and +100.3 respectively. Conclusion: The study identifies the continuous genetic variations in the HA gene sequences of circulating Influenza A/ H1N1pdm09 in central India from the year 2009 to 2019. Further suggesting importance of monitoring the gradual evolution of the virus with regards to an increase in virulence, pathogenicity and vaccine efficacy timely.

scholarly journals In vitro Characterization of Fitness and Convalescent Antibody Neutralization of SARS-CoV-2 Cluster 5 Variant Emerging in Mink at Danish Farms

2021 ◽  
Vol 12 ◽  
Author(s):  
Ria Lassaunière ◽  
Jannik Fonager ◽  
Morten Rasmussen ◽  
Anders Frische ◽  
Charlotta Polacek ◽  
...  
Keyword(s):  
Amino Acid ◽  
Reference Strain ◽  
Rhesus Macaques ◽  
Amino Acid Residues ◽  
Susceptible Animal ◽  
In Vitro Characterization ◽  
Cynomolgus Macaques ◽  
Animal Hosts

In addition to humans, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can transmit to animals that include hamsters, cats, dogs, mink, ferrets, tigers, lions, cynomolgus macaques, rhesus macaques, and treeshrew. Among these, mink are particularly susceptible. Indeed, 10 countries in Europe and North America reported SARS-CoV-2 infection among mink on fur farms. In Denmark, SARS-CoV-2 spread rapidly among mink farms and spilled-over back into humans, acquiring mutations/deletions with unknown consequences for virulence and antigenicity. Here we describe a mink-associated SARS-CoV-2 variant (Cluster 5) characterized by 11 amino acid substitutions and four amino acid deletions relative to Wuhan-Hu-1. Temporal virus titration, together with genomic and subgenomic viral RNA quantitation, demonstrated a modest in vitro fitness attenuation of the Cluster 5 virus in the Vero-E6 cell line. Potential alterations in antigenicity conferred by amino acid changes in the spike protein that include three substitutions (Y453F, I692V, and M1229I) and a loss of two amino acid residues 69 and 70 (ΔH69/V70), were evaluated in a virus microneutralization assay. Compared to a reference strain, the Cluster 5 variant showed reduced neutralization in a proportion of convalescent human COVID-19 samples. The findings underscore the need for active surveillance SARS-CoV-2 infection and virus evolution in susceptible animal hosts.

scholarly journals Influenza viruses resistant to neuraminidase inhibitors.

2014 ◽  
Vol 61 (3) ◽  
Author(s):  
Aneta Nitsch-Osuch ◽  
Lidia Bernadeta Brydak
Keyword(s):  
Influenza A ◽  
Seasonal Influenza ◽  
Influenza Viruses ◽  
Response To Treatment ◽  
Cross Resistance ◽  
Published Data ◽  
Neuraminidase Inhibitors ◽  
Viral Particles ◽  
Clinical Resistance ◽  
Influenza A H1n1

Neuraminidase inhibitors (NAIs) are antiviral drugs for treatment and prophylaxis of influenza. By blocking the activity of the enzyme neuraminidase, NAIs prevent new viral particles from being released. The increasing use of NAIs brings into focus the risk of drug resistance arising to the class. There are three levels of antiviral resistance according to the way that resistance can be detected or inferred: genotypic, phenotypic and clinical resistance. For many years seasonal influenza viruses resistance to NAIs was low (0.33%). Recently, there has been described an increasing number of resistant seasonal influenza strains to oseltamivir (2% in adults, 5-18% in children). In 2007 there were published data describing 14% resistant to oseltamivir strains of influenza A/H1N1/ in Europe. Approximately 0.5-1.0% of influenza A/H1N1/pdm09 isolates are currently resistant to oseltamivir. The established markers of the resistance to oseltamivir were found in 2.4% of human and 0.8% of avian isolates of influenza A/H5N1/. It has been not observed a cross resistance among oseltamivir and zanamivir. NAIs resistance in influenza viruses is relative and despite its presence patients with resistant viruses may still benefit from receiving these antivirals. The response to treatment with antivirals remains the most important proof of antiviral effectiveness. The rational use of NAIs is essential to preserve the best choice for treatment and prophylaxis of seasonal, avian and pandemic influenza.

scholarly journals Synergistic Antiviral Activity of S-033188/S-033447, a Novel Inhibitor of Influenza Virus Cap-Dependent Endonuclease, in Combination with Neuraminidase Inhibitors In Vitro

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S371-S371 ◽  
Author(s):  
Mitsutaka Kitano ◽  
Atsuko Yamamoto ◽  
Takeshi Noshi ◽  
Makoto Kawai ◽  
Ryu Yoshida ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Cultured Cells ◽  
H1n1 Virus ◽  
Mdck Cells ◽  
Active Form ◽  
Neuraminidase Inhibitors ◽  
Dependent Endonuclease ◽  
Influenza A H1n1

Abstract Background S-033447, an active form of orally available prodrug S-033188, is a novel small molecule inhibitor of cap-dependent endonuclease that is essential for influenza virus transcription and replication. In this study, we evaluated the inhibitory effect of S-033188 in combination with neuraminidase inhibitors on the replication of influenza A/H1N1 virus in cultured cells. Methods The inhibitory effects of S-033447 in combination with NA inhibitors on the cytopathic effect of A/PR/8/34 strain in Madin–Darby canine kidney cells cultured for 2 days were tested and EC50 were determined. The combination index (CI), which were obtained when S-033188 and NA inhibitor were added at the closest ratio of each EC50 value, were used for the evaluation of these combinational effects (Table 1). CI values were calculated by the Chou and Talalay method, in which combinational effect were determined according to the criteria as follows: synergistic if CI ≤ 0.8, additive if 0.8 < CI < 1.2, and antagonistic if CI ≥ 1.2. CI = (DA/A + B)/DA + (DB/A + B)/DB + (DA/A + B × DB/A + B)/(DA × DB) DA: the EC50 of S-033447 DB: the EC50 of NA inhibitor DA/A + B: the concentration of S-033447 giving 50% inhibition in combination with NA inhibitor at the closest ratio of each EC50 value DB/A + B: the concentration of NA inhibitor giving 50% inhibition in combination with S-033447 at the closest ratio of each EC50 value Results All CI values were lower than 0.8, under the condition that both S-033447 and NA inhibitor (oseltamivir acid, zanamivir hydrate, laninamivir, or peramivir trihydrate) were added at the closest ratio of each EC50 value (Table 1). Conclusion S-033447 in combination with oseltamivir acid, zanamivir hydrate, laninamivir, or peramivir trihydrate synergistically inhibited the replication of influenza A/H1N1 virus in MDCK cells. Disclosures All authors: No reported disclosures.

scholarly journals In Vitro Properties and Virulence of Contemporary Recombinant Influenza B Viruses Harboring Mutations of Cross-Resistance to Neuraminidase Inhibitors

Viruses ◽  
2018 ◽  
Vol 11 (1) ◽  
pp. 6 ◽  
Author(s):  
Clément Fage ◽  
Yacine Abed ◽  
Liva Checkmahomed ◽  
Marie-Christine Venable ◽  
Guy Boivin
Keyword(s):  
Influenza A ◽  
Mdck Cells ◽  
Viral Fitness ◽  
World Health ◽  
Cross Resistance ◽  
Influenza B ◽  
Neuraminidase Inhibitors ◽  
Clinical Markers ◽  
The Impact

Three neuraminidase inhibitors (NAIs: Oseltamivir, zanamivir and peramivir) are currently approved in many countries for the treatment of influenza A and B infections. The emergence of influenza B viruses (IBVs) containing mutations of cross-resistance to these NAIs constitutes a serious clinical threat. Herein, we used a reverse genetics system for the current B/Phuket/3073/2013 vaccine strain to investigate the impact on in vitro properties and virulence of H136N, R152K, D198E/N, I222T and N294S NA substitutions (N2 numbering), reported by the World Health Organization (WHO) as clinical markers of reduced or highly-reduced inhibition (RI/HRI) to multiple NAIs. Recombinant viruses were tested by NA inhibition assays. Their replicative capacity and virulence were evaluated in ST6GalI-MDCK cells and BALB/c mice, respectively. All NA mutants (excepted D198E/N) showed RI/HRI phenotypes against ≥ 2 NAIs. These mutants grew to comparable titers of the recombinant wild-type (WT) IBV in vitro, and some of them (H136N, I222T and N294S mutants) induced more weight loss and mortality in BALB/c mice in comparison to the recombinant WT IBV. These results demonstrate that, in contemporary IBVs, some NA mutations may confer RI/HRI phenotypes to existing NAIs without altering the viral fitness. This reinforces the need for development of novel antiviral strategies with different mechanisms of action.

scholarly journals Molecular Characterization of rpoBMutations Conferring Cross-Resistance to Rifamycins on Methicillin-Resistant Staphylococcus aureus

1999 ◽  
Vol 43 (11) ◽  
pp. 2813-2816 ◽  
Author(s):  
Thomas A. Wichelhaus ◽  
Volker Schäfer ◽  
Volker Brade ◽  
Boris Böddinghaus
Keyword(s):  
Staphylococcus Aureus ◽  
Amino Acid ◽  
Molecular Characterization ◽  
Amino Acid Substitution ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Cross Resistance ◽  
Methicillin Resistant ◽  
Low Level ◽  
Level Resistance

ABSTRACT Mutations of the rpoB gene conferring resistance to rifampin were analyzed in 40 methicillin-resistant Staphylococcus aureus isolates obtained from six countries. Interestingly, the majority of clinical isolates showed multiple mutations withinrpoB. The amino acid substitution 481His→Asn was the most prevalent one, capable of conferring low-level resistance on its own. Cross-resistance to rifampin, rifabutin, and rifapentine was demonstrated for all mutants identified. The level of resistance to rifamycins correlated with both the mutation position and type of amino acid substitution.

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