scholarly journals Zanamivir-Resistant Influenza Viruses with a Novel Neuraminidase Mutation

2009 ◽  
Vol 83 (20) ◽  
pp. 10366-10373 ◽  
Author(s):  
Aeron C. Hurt ◽  
Jessica K. Holien ◽  
Michael Parker ◽  
Anne Kelso ◽  
Ian G. Barr
Keyword(s):  
Southeast Asia ◽  
Influenza A ◽  
Seasonal Influenza ◽  
Mdck Cells ◽  
The United States ◽  
Influenza Viruses ◽  
Viral Fitness ◽  
Wild Type Virus ◽  
Clinical Specimens ◽  
Influenza A H1n1

ABSTRACT The neuraminidase inhibitors zanamivir and oseltamivir are marketed for the treatment and prophylaxis of influenza and have been stockpiled by many countries for use in a pandemic. Although recent surveillance has identified a striking increase in the frequency of oseltamivir-resistant seasonal influenza A (H1N1) viruses in Europe, the United States, Oceania, and South Africa, to date there have been no reports of significant zanamivir resistance among influenza A (H1N1) viruses or any other human influenza viruses. We investigated the frequency of oseltamivir and zanamivir resistance in circulating seasonal influenza A (H1N1) viruses in Australasia and Southeast Asia. Analysis of 391 influenza A (H1N1) viruses isolated between 2006 and early 2008 from Australasia and Southeast Asia revealed nine viruses (2.3%) that demonstrated markedly reduced zanamivir susceptibility and contained a previously undescribed Gln136Lys (Q136K) neuraminidase mutation. The mutation had no effect on oseltamivir susceptibility but caused approximately a 300-fold and a 70-fold reduction in zanamivir and peramivir susceptibility, respectively. The role of the Q136K mutation in conferring zanamivir resistance was confirmed using reverse genetics. Interestingly, the mutation was not detected in the primary clinical specimens from which these mutant isolates were grown, suggesting that the resistant viruses either occurred in very low proportions in the primary clinical specimens or arose during MDCK cell culture passage. Compared to susceptible influenza A (H1N1) viruses, the Q136K mutant strains displayed greater viral fitness than the wild-type virus in MDCK cells but equivalent infectivity and transmissibility in a ferret model.

scholarly journals A Conformational Restriction in the Influenza A Virus Neuraminidase Binding Site by R152 Results in a Combinational Effect of I222T and H274Y on Oseltamivir Resistance

2013 ◽  
Vol 58 (3) ◽  
pp. 1639-1645 ◽  
Author(s):  
Lan Huang ◽  
Yang Cao ◽  
Jianfang Zhou ◽  
Kun Qin ◽  
Wenfei Zhu ◽  
...  
Keyword(s):  
Binding Site ◽  
Influenza A ◽  
Double Mutant ◽  
Mdck Cells ◽  
Influenza Viruses ◽  
Viral Fitness ◽  
Wild Type Virus ◽  
Close Monitoring ◽  
Conformational Restriction ◽  
Influenza A H1n1

ABSTRACTThe I222K, I222R, and I222T substitutions in neuraminidase (NA) have been found in clinically derived 2009 pandemic influenza A/H1N1 viruses with altered susceptibilities to NA inhibitors (NAIs). The effects of these substitutions, together with the most frequently observed resistance-related substitution, H274Y, on viral fitness and resistance mechanisms were further investigated in this study. Reduced sensitivities to oseltamivir were observed in all three mutants (I222K, I222R, and I222T). Furthermore, the I222K and I222T substitutions had a combinational effect of further increasing resistance in the presence of H274Y, which might result from a conformational restriction in the NA binding site. Of note, by using molecular dynamics simulations, R152, the neighbor of T222, was observed to translate to a position closer to T222, resulting in the narrowing of the binding pocket, which otherwise only subtends the residue substitution of H274Y. Moreover, significantly attenuated NA function and viral growth abilities were found in the I222K+H274Y double mutant, while the I222T+H274Y double mutant exhibited slightly delayed growth but had a peak viral titer similar to that of the wild-type virus in MDCK cells. The relative growth advantage of the I222T mutant versus the I222K mutant and the higher frequency of I222T emerging in N1 subtype influenza viruses raise concerns necessitating close monitoring of the dual substitutions I222T and H274Y.

scholarly journals Zanamivir-resistant influenza viruses with Q136K or Q136R neuraminidase residue mutations can arise during MDCK cell culture creating challenges for antiviral susceptibility monitoring

2015 ◽  
Vol 20 (45) ◽  
Author(s):  
Karen Little ◽  
Sook-Kwan Leang ◽  
Jeff Butler ◽  
Chantal Baas ◽  
Bruce Harrower ◽  
...  
Keyword(s):  
Cell Culture ◽  
Influenza A ◽  
Treatment Guidelines ◽  
Mdck Cells ◽  
Influenza Viruses ◽  
Viral Fitness ◽  
Patient Treatment ◽  
Close Monitoring ◽  
Clinical Specimens

Surveillance of circulating influenza strains for antiviral susceptibility is important to ensure patient treatment guidelines remain appropriate. Influenza A(H3N2) and A(H1N1)pdm09 virus isolates containing mutations at the Q136 residue of the neuraminidase (NA) that conferred reduced susceptibility to the NA inhibitor (NAI) zanamivir were detected during antiviral susceptibility monitoring. Interestingly, the mutations were not detectable in the viruses from respective clinical specimens, only in the cultured isolates. We showed that variant viruses containing the Q136K and Q136R NA mutations were preferentially selected in Madin-Darby canine kidney epithelial (MDCK) cells, but were less well supported in MDCK-SIAT1 cells and embryonated eggs. The effect of Q136K, Q136R, Q136H and Q136L substitutions in NA subtypes N1 and N2 on NAI susceptibility and in vitro viral fitness was assessed. This study highlights the challenges that cell culture derived mutations can pose to the NAI susceptibility analysis and interpretation and reaffirms the need to sequence viruses from respective clinical specimens to avoid misdiagnosis. However, we also demonstrate that NA mutations at residue Q136 can confer reduced zanamivir, peramivir or laninamivir susceptibility, and therefore close monitoring of viruses for mutations at this site from patients being treated with these antivirals is important.

scholarly journals 97. Competition Experiments for the Baloxavir-Resistant I38T Influenza A Mutant

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S9-S9
Author(s):  
Liva Checkmahomed ◽  
Zeineb Mhamdi ◽  
Julie Carbonneau ◽  
Mariana Baz ◽  
Yacine Abed ◽  
...  
Keyword(s):  
Weight Loss ◽  
Influenza A ◽  
Mdck Cells ◽  
Digital Pcr ◽  
The United States ◽  
Influenza Viruses ◽  
Viral Fitness ◽  
Copy Numbers

Abstract Background Baloxavir marboxil (BXM), a cap-dependent endonuclease inhibitor, has been recently approved in the United States for the treatment of influenza infections. It is superior to oseltamivir for reducing the time of viral shedding but is reported to have a low barrier of resistance. We sought to evaluate the viral fitness of the predominant BXM-resistant I38T PA mutant in the A/H1N1 and A/H3N2 viral backgrounds. Methods Recombinant A/Quebec/144147/2009 (H1N1) and A/Switzerland/9715293/2013 (H3N2) influenza viruses and their respective I38T PA mutants were generated by reverse genetics. Standardized inoculums (500 PFUs) of wild-type (WT) and mutant mixtures were inoculated on α2,6 MDCK cells. On day 3 post-infection (pi), the supernatants were collected and the ratios of WT/mutant viruses were determined by droplet digital PCR using specific LNA probes. Single infections and competitive experiments were also performed in C56/BL6 mice with quantification of lung viral titers on days 3 and 6 pi. Results In vitro A/H1N1 studies showed similar total copy numbers for the WT and mutant viruses on day 3 pi (1.2 × 109 and 1.3 × 109 copies/mL, respectively). The initial 50%/50% mixture became 70%/30% (WT/mutant) after one passage in cells. For A/H3N2, the total copy numbers were 8.1 × 109 and 1.0 × 109 copies/mL for the WT and mutant viruses. The initial 50%/50% mixture became 94%/6% (WT/mutant) after one passage. The I38T mutants remained stable after 4 passages in α2,6 MDCK cells. In mice, the A/H1N1 WT and I38T mutant induced similar weight loss and generated comparable lung titers on days 3 and 6 pi. In contrast, the weight loss of the A/H3N2 mutant was greater than that of the WT between days 3 and 7 pi with comparable lung titers on days 3 and 6. Following infection with 50%/50% mixtures, the mutant virus predominated over the WT on day 3 pi (73% A/H1N1 and 58% A/H3N2). Conclusion The BXM-resistant I38T PA mutant replicates well both in vitro and in vivo in the A/H1N1 and A/H3N2 backgrounds. Surveillance for the emergence and transmission of such mutant in the community is required. Disclosures All Authors: No reported Disclosures.

scholarly journals Interaction Among Influenza Viruses A/H1N1, A/H3N2, and B in Japan

2019 ◽  
Vol 16 (21) ◽  
pp. 4179 ◽  
Author(s):  
Ayako Suzuki ◽  
Kenji Mizumoto ◽  
Andrei R. Akhmetzhanov ◽  
Hiroshi Nishiura
Keyword(s):  
Influenza Virus ◽  
Virus Type ◽  
Influenza A ◽  
Seasonal Influenza ◽  
Winter Season ◽  
The United States ◽  
Influenza Viruses ◽  
Statistical Correlations ◽  
Epidemic Size ◽  
Influenza A H1n1

Seasonal influenza epidemics occur each winter season in temperate zones, involving up to 650,000 deaths each year globally. A published study demonstrated that the circulation of one influenza virus type during early influenza season in the United States interferes with the activity of other influenza virus types. However, this finding has yet to be validated in other settings. In the present work, we investigated the interaction among seasonal influenza viruses (A/H1N1, A/H3N2 and B) in Japan. Sentinel and virus surveillance data were used to estimate the type-specific incidence from 2010 to 2019, and statistical correlations among the type-specific incidence were investigated. We identified significant negative correlations between incidence of the dominant virus and the complementary incidence. When correlation was identified during the course of an epidemic, a linear regression model accurately predicted the epidemic size of a particular virus type before the epidemic peak. The peak of influenza type B took place later in the season than that of influenza A, although the epidemic peaks of influenza A/H1N1 and A/H3N2 nearly coincided. Given the interaction among different influenza viruses, underlying mechanisms including age and spatial dependence should be explored in future.

scholarly journals Cluster analysis of the origins of the new influenza A(H1N1) virus

2009 ◽  
Vol 14 (21) ◽  
Author(s):  
A Solovyov ◽  
G Palacios ◽  
T Briese ◽  
W I Lipkin ◽  
R Rabadan
Keyword(s):  
Cluster Analysis ◽  
Influenza A ◽  
H1n1 Virus ◽  
Swine Influenza ◽  
The United States ◽  
Influenza Viruses ◽  
World Health ◽  
Influenza A H1n1 ◽  
The World ◽  
Health Organization

In March and April 2009, a new strain of influenza A(H1N1) virus has been isolated in Mexico and the United States. Since the initial reports more than 10,000 cases have been reported to the World Health Organization, all around the world. Several hundred isolates have already been sequenced and deposited in public databases. We have studied the genetics of the new strain and identified its closest relatives through a cluster analysis approach. We show that the new virus combines genetic information related to different swine influenza viruses. Segments PB2, PB1, PA, HA, NP and NS are related to swine H1N2 and H3N2 influenza viruses isolated in North America. Segments NA and M are related to swine influenza viruses isolated in Eurasia.

scholarly journals In Vitro Antiviral Activity of Favipiravir (T-705) against Drug-Resistant Influenza and 2009 A(H1N1) Viruses

2010 ◽  
Vol 54 (6) ◽  
pp. 2517-2524 ◽  
Author(s):  
Katrina Sleeman ◽  
Vasiliy P. Mishin ◽  
Varough M. Deyde ◽  
Yousuke Furuta ◽  
Alexander I. Klimov ◽  
...  
Keyword(s):  
Influenza A ◽  
Seasonal Influenza ◽  
Mdck Cells ◽  
Antiviral Effect ◽  
Plaque Formation ◽  
Influenza Viruses ◽  
New Drugs ◽  
Yield Reduction ◽  
Wide Range

ABSTRACT Favipiravir (T-705) has previously been shown to have a potent antiviral effect against influenza virus and some other RNA viruses in both cell culture and in animal models. Currently, favipiravir is undergoing clinical evaluation for the treatment of influenza A and B virus infections. In this study, favipiravir was evaluated in vitro for its ability to inhibit the replication of a representative panel of seasonal influenza viruses, the 2009 A(H1N1) strains, and animal viruses with pandemic (pdm) potential (swine triple reassortants, H2N2, H4N2, avian H7N2, and avian H5N1), including viruses which are resistant to the currently licensed anti-influenza drugs. All viruses were tested in a plaque reduction assay with MDCK cells, and a subset was also tested in both yield reduction and focus inhibition (FI) assays. For the majority of viruses tested, favipiravir significantly inhibited plaque formation at 3.2 μM (0.5 μg/ml) (50% effective concentrations [EC50s] of 0.19 to 22.48 μM and 0.03 to 3.53 μg/ml), and for all viruses, with the exception of a single dually resistant 2009 A(H1N1) virus, complete inhibition of plaque formation was seen at 3.2 μM (0.5 μg/ml). Due to the 2009 pandemic and increased drug resistance in circulating seasonal influenza viruses, there is an urgent need for new drugs which target influenza. This study demonstrates that favipiravir inhibits in vitro replication of a wide range of influenza viruses, including those resistant to currently available drugs.

scholarly journals Contemporary Seasonal Influenza A (H1N1) Virus Infection Primes for a More Robust Response To Split Inactivated Pandemic Influenza A (H1N1) Virus Vaccination in Ferrets

2010 ◽  
Vol 17 (12) ◽  
pp. 1998-2006 ◽  
Author(s):  
Ali H. Ellebedy ◽  
Thomas P. Fabrizio ◽  
Ghazi Kayali ◽  
Thomas H. Oguin ◽  
Scott A. Brown ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Pandemic Influenza ◽  
Influenza A ◽  
Seasonal Influenza ◽  
H1n1 Virus ◽  
H1n1 Influenza ◽  
Influenza Viruses ◽  
Inactivated Vaccine ◽  
H1n1 Influenza Virus ◽  
Influenza A H1n1

ABSTRACT Human influenza pandemics occur when influenza viruses to which the population has little or no immunity emerge and acquire the ability to achieve human-to-human transmission. In April 2009, cases of a novel H1N1 influenza virus in children in the southwestern United States were reported. It was retrospectively shown that these cases represented the spread of this virus from an ongoing outbreak in Mexico. The emergence of the pandemic led to a number of national vaccination programs. Surprisingly, early human clinical trial data have shown that a single dose of nonadjuvanted pandemic influenza A (H1N1) 2009 monovalent inactivated vaccine (pMIV) has led to a seroprotective response in a majority of individuals, despite earlier studies showing a lack of cross-reactivity between seasonal and pandemic H1N1 viruses. Here we show that previous exposure to a contemporary seasonal H1N1 influenza virus and to a lesser degree a seasonal influenza virus trivalent inactivated vaccine is able to prime for a higher antibody response after a subsequent dose of pMIV in ferrets. The more protective response was partially dependent on the presence of CD8+ cells. Two doses of pMIV were also able to induce a detectable antibody response that provided protection from subsequent challenge. These data show that previous infection with seasonal H1N1 influenza viruses likely explains the requirement for only a single dose of pMIV in adults and that vaccination campaigns with the current pandemic influenza vaccines should reduce viral burden and disease severity in humans.

scholarly journals Do Vaccines Need a Gender Perspective? Influenza Says Yes!

2021 ◽  
Vol 12 ◽  
Author(s):  
Laura Sánchez-de Prada ◽  
Raúl Ortiz de Lejarazu-Leonardo ◽  
Javier Castrodeza-Sanz ◽  
Eduardo Tamayo-Gómez ◽  
José María Eiros-Bouza ◽  
...  
Keyword(s):  
Young Adults ◽  
Influenza A ◽  
Seasonal Influenza ◽  
Elderly Women ◽  
Seroconversion Rate ◽  
Humoral Response ◽  
Influenza Viruses ◽  
Influenza A H1n1 ◽  
Males And Females ◽  
Humoral Responses

BackgroundSex differences in immune responses are well known. However, the humoral response in males and females in the case of influenza vaccination is yet to be characterized since studies have shown uneven results.MethodsA retrospective study was conducted in 2,243 individuals (46.9% males) divided by age (15–64 and ≥65 years old). A serological analysis was performed by hemagglutination inhibition assay (HI) just before and 28 days after annual vaccination against seasonal influenza viruses in people vaccinated during the 2006–2018 seasons. A comparison of the humoral responses against influenza A and B viruses contained in the vaccine, between male and female individuals in young adults and elderly was conducted.ResultsSignificative higher humoral response against classical influenza A (H1N1), A(H1N1)pdm09 subtype and B/Victoria lineage in terms of seroconversion rate were found in elderly women. No significant differences were found in the case of A(H3N2) subtype.ConclusionsElderly women seem to display a greater humoral response against classical A(H1N1), pandemic A(H1N1)pmd09 and B/Victoria lineage than elderly men. Sex dimorphism does not affect young adults.

scholarly journals What will the next influenza season bring about: seasonal influenza or the new A(H1N1)v? An analysis of German influenza surveillance data

2009 ◽  
Vol 14 (32) ◽  
Author(s):  
H Uphoff ◽  
S Geis ◽  
A Grüber ◽  
A M Hauri
Keyword(s):  
Influenza A ◽  
Seasonal Influenza ◽  
Influenza Season ◽  
Influenza Viruses ◽  
Moderate Intensity ◽  
Influenza Surveillance ◽  
Influenza B ◽  
Low Intensity ◽  
Influenza A H1n1 ◽  
Using Data

For the next influenza season (winter 2009-10) the relative contributions to virus circulation and influenza-associated morbidity of the seasonal influenza viruses A(H3N2), A(H1N1) and B, and the new influenza A(H1N1)v are still unknown. We estimated the chances of seasonal influenza to circulate during the upcoming season using data of the German influenza sentinel scheme from 1992 to 2009. We calculated type and subtype-specific indices for past exposure and the corresponding morbidity indices for each season. For the upcoming season 2009-10 our model suggests that it is unlikely that influenza A(H3N2) will circulate with more than a low intensity, seasonal A(H1N1) with more than a low to moderate intensity, and influenza B with more than a low to median intensity. The probability of a competitive circulation of seasonal influenza A with the new A(H1N1)v is low, increasing the chance for the latter to dominate the next influenza season in Germany.

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