scholarly journals Laninamivir-Interferon Lambda 1 Combination Treatment Promotes Resistance by Influenza A Virus More Rapidly than Laninamivir Alone

2020 ◽  
Vol 64 (7) ◽  
Author(s):  
Simone E. Adams ◽  
Vladimir Y. Lugovtsev ◽  
Anastasia Kan ◽  
Nicolai V. Bovin ◽  
Raymond P. Donnelly ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A Virus ◽  
Combination Treatment ◽  
Influenza A ◽  
Influenza Virus Infection ◽  
The United States ◽  
Epithelial Cell Line ◽  
Drug Resistant ◽  
Interferon Lambda

ABSTRACT Each year, 5% to 20% of the population of the United States becomes infected with influenza A virus. Combination therapy with two or more antiviral agents has been considered a potential treatment option for influenza virus infection. However, the clinical results derived from combination treatment with two or more antiviral drugs have been variable. We examined the effectiveness of cotreatment with two distinct classes of anti-influenza drugs, i.e., neuraminidase (NA) inhibitor, laninamivir, and interferon lambda 1 (IFN-λ1), against the emergence of drug-resistant virus variants in vitro. We serially passaged pandemic A/California/04/09 [A(H1N1)pdm09] influenza virus in a human lung epithelial cell line (Calu-3) in the presence or absence of increasing concentrations of laninamivir or laninamivir plus IFN-λ1. Surprisingly, laninamivir used in combination with IFN-λ1 promoted the emergence of the E119G NA mutation five passages earlier than laninamivir alone (passage 2 versus passage 7, respectively). Acquisition of this mutation resulted in significantly reduced sensitivity to the NA inhibitors laninamivir (∼284-fold) and zanamivir (∼1,024-fold) and decreased NA enzyme catalytic activity (∼5-fold) compared to the parental virus. Moreover, the E119G NA mutation emerged together with concomitant hemagglutinin (HA) mutations (T197A and D222G), which were selected more rapidly by combination treatment with laninamivir plus IFN-λ1 (passages 2 and 3, respectively) than by laninamivir alone (passage 10). Our results show that treatment with laninamivir alone or in combination with IFN-λ1 can lead to the emergence of drug-resistant influenza virus variants. The addition of IFN-λ1 in combination with laninamivir may promote acquisition of drug resistance more rapidly than treatment with laninamivir alone.

scholarly journals Δ12-Prostaglandin J2 Is a Potent Inhibitor of Influenza A Virus Replication

2000 ◽  
Vol 44 (1) ◽  
pp. 200-204 ◽  
Author(s):  
Francesca Pica ◽  
Anna Teresa Palamara ◽  
Antonio Rossi ◽  
Alessandra De Marco ◽  
Carla Amici ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Heat Shock ◽  
Influenza A Virus ◽  
Influenza A ◽  
Potent Inhibitor ◽  
Influenza Virus Infection ◽  
H1n1 Infection ◽  
Shock Proteins

ABSTRACT 9-Deoxy-Δ9,Δ12-13,14-dihydro-prostaglandin D2 (Δ12-PGJ2), a natural cyclopentenone metabolite of prostaglandin D2, is shown to possess therapeutic efficacy against influenza A virus A/PR8/34 (H1N1) infection in vitro and in vivo. The results indicate that the antiviral activity is associated with induction of cytoprotective heat shock proteins and suggest novel strategies for treatment of influenza virus infection.

scholarly journals In Vitro System for Modeling Influenza A Virus Resistance under Drug Pressure

2010 ◽  
Vol 54 (8) ◽  
pp. 3442-3450 ◽  
Author(s):  
Ashley N. Brown ◽  
James J. McSharry ◽  
Qingmei Weng ◽  
Elizabeth M. Driebe ◽  
David M. Engelthaler ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A Virus ◽  
Virus Replication ◽  
Influenza A ◽  
Mdck Cells ◽  
Influenza Virus Infection ◽  
Infection Model ◽  
Virus Infections ◽  
Drug Pressure

ABSTRACT One of the biggest challenges in the effort to treat and contain influenza A virus infections is the emergence of resistance during treatment. It is well documented that resistance to amantadine arises rapidly during the course of treatment due to mutations in the gene coding for the M2 protein. To address this problem, it is critical to develop experimental systems that can accurately model the selection of resistance under drug pressure as seen in humans. We used the hollow-fiber infection model (HFIM) system to examine the effect of amantadine on the replication of influenza virus, A/Albany/1/98 (H3N2), grown in MDCK cells. At 24 and 48 h postinfection, virus replication was inhibited in a dose-dependent fashion. At 72 and 96 h postinfection, virus replication was no longer inhibited, suggesting the emergence of amantadine-resistant virus. Sequencing of the M2 gene revealed that mutations appeared at between 48 and 72 h of drug treatment and that the mutations were identical to those identified in the clinic for amantadine-resistant viruses (e.g., V27A, A30T, and S31N). Interestingly, we found that the type of mutation was strongly affected by the dose of the drug. The data suggest that the HFIM is a good model for influenza virus infection and resistance generation in humans. The HFIM has the advantage of being a highly controlled system where multiplicity parameters can be directly and accurately controlled and measured.

scholarly journals Characterization of Drug-Resistant Influenza Virus A(H1N1) and A(H3N2) Variants SelectedIn Vitrowith Laninamivir

2014 ◽  
Vol 58 (9) ◽  
pp. 5220-5228 ◽  
Author(s):  
Mélanie Samson ◽  
Yacine Abed ◽  
François-Marc Desrochers ◽  
Stephanie Hamilton ◽  
Angela Luttick ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Solomon Islands ◽  
The United States ◽  
Drug Resistant ◽  
Virus Infections ◽  
Influenza A Viruses ◽  
Oseltamivir Resistance ◽  
Susceptibility Profiles

ABSTRACTNeuraminidase inhibitors (NAIs) play a major role for managing influenza virus infections. The widespread oseltamivir resistance among 2007-2008 seasonal A(H1N1) viruses and community outbreaks of oseltamivir-resistant A(H1N1)pdm09 strains highlights the need for additional anti-influenza virus agents. Laninamivir is a novel long-lasting NAI that has demonstratedin vitroactivity against influenza A and B viruses, and its prodrug (laninamivir octanoate) is in phase II clinical trials in the United States and other countries. Currently, little information is available on the mechanisms of resistance to laninamivir. In this study, we first performed neuraminidase (NA) inhibition assays to determine the activity of laninamivir against a set of influenza A viruses containing NA mutations conferring resistance to one or many other NAIs. We also generated drug-resistant A(H1N1) and A(H3N2) viruses underin vitrolaninamivir pressure. Laninamivir demonstrated a profile of susceptibility that was similar to that of zanamivir. More specifically, it retained activity against oseltamivir-resistant H275Y and N295S A(H1N1) variants and the E119V A(H3N2) variant.In vitro, laninamivir pressure selected the E119A NA substitution in the A/Solomon Islands/3/2006 A(H1N1) background, whereas E119K and G147E NA changes along with a K133E hemagglutinin (HA) substitution were selected in the A/Quebec/144147/2009 A(H1N1)pdm09 strain. In the A/Brisbane/10/2007 A(H3N2) background, a large NA deletion accompanied by S138A/P194L HA substitutions was selected. This H3N2 variant had altered receptor-binding properties and was highly resistant to laninamivir in plaque reduction assays. Overall, we confirmed the similarity between zanamivir and laninamivir susceptibility profiles and demonstrated that both NA and HA changes can contribute to laninamivir resistancein vitro.

scholarly journals Influenza A Virus Hemagglutinin and Other Pathogen Glycoprotein Interactions with NK Cell Natural Cytotoxicity Receptors NKp46, NKp44, and NKp30

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 156
Author(s):  
Jasmina M. Luczo ◽  
Sydney L. Ronzulli ◽  
Stephen M. Tompkins
Keyword(s):  
Influenza Virus ◽  
Nk Cells ◽  
Influenza A Virus ◽  
Influenza A ◽  
Nk Cell ◽  
Influenza Virus Infection ◽  
Target Cells ◽  
Natural Cytotoxicity ◽  
Activating Receptors ◽  
Natural Cytotoxicity Receptors

Natural killer (NK) cells are part of the innate immunity repertoire, and function in the recognition and destruction of tumorigenic and pathogen-infected cells. Engagement of NK cell activating receptors can lead to functional activation of NK cells, resulting in lysis of target cells. NK cell activating receptors specific for non-major histocompatibility complex ligands are NKp46, NKp44, NKp30, NKG2D, and CD16 (also known as FcγRIII). The natural cytotoxicity receptors (NCRs), NKp46, NKp44, and NKp30, have been implicated in functional activation of NK cells following influenza virus infection via binding with influenza virus hemagglutinin (HA). In this review we describe NK cell and influenza A virus biology, and the interactions of influenza A virus HA and other pathogen lectins with NK cell natural cytotoxicity receptors (NCRs). We review concepts which intersect viral immunology, traditional virology and glycobiology to provide insights into the interactions between influenza virus HA and the NCRs. Furthermore, we provide expert opinion on future directions that would provide insights into currently unanswered questions.

scholarly journals Routine blood parameters are helpful for early identification of influenza infection in children

2020 ◽  
Author(s):  
Ronghe Zhu ◽  
Cuie Chen ◽  
Qiu Wang ◽  
Xixi Zhang ◽  
Chaosheng Lu ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Influenza A Virus ◽  
Early Identification ◽  
Influenza A ◽  
Influenza Infection ◽  
Influenza Virus Infection ◽  
Cutoff Value ◽  
Routine Blood ◽  
Influenza A Virus Infection

Abstract Purpose Routine blood parameters, such as the lymphocyte (LYM) count, platelet (PLT) count, lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR), LYM*PLT and mean platelet volume-to-platelet ratio (MPV/PLT), are widely used to predict the prognosis of infectious diseases. We aimed to explore the value of these parameters in the early identification of influenza virus infection in children.Methods We conducted a single-center, retrospective, observational study of fever with influenza-like symptoms in pediatric outpatients from different age groups and evaluated the predictive value of various routine blood parameters measured within 48 hours of the onset of fever for influenza virus infection.Results The LYM count, PLT count, LMR and LYM*PLT were lower, and the NLR and MPV/PLT were higher in children with an influenza infection (PCR-confirmed and symptomatic). The LYM count, LMR and LYM*PLT in the influenza infection group were lower in the 1- to 6-year-old subgroup, and the LMR and LYM*PLT in the influenza infection group were lower in the >6-year-old subgroup. In the 1- to 6-year-old subgroup, the cutoff value of the LMR for predicting influenza A virus infection was 3.75, the sensitivity was 81.87%, the specificity was 84.31%, and the area under the curve (AUC) was 0.886; the cutoff value of the LMR for predicting influenza B virus infection was 3.71, the sensitivity was 73.58%, the specificity was 84.31%, and the AUC was 0.843. In the >6-year-old subgroup, the cutoff value of the LMR for predicting influenza A virus infection was 3.05, the sensitivity was 89.27%, the specificity was 89.61%, and the AUC was 0.949; the cutoff value of the LMR for predicting influenza B virus infection was 2.88, the sensitivity was 83.19%, the specificity was 92.21%, and the AUC was 0.924.Conclusions Routine blood tests are simple, inexpensive and easy to perform, and they are useful for the early identification of influenza virus infection in children. The LMR had the strongest predictive value for influenza virus infection in children older than 1 year, particularly influenza A virus infection.

scholarly journals In VitroSusceptibility of Canine Influenza A (H3N8) Virus to Nitazoxanide and Tizoxanide

2010 ◽  
Vol 2010 ◽  
pp. 1-5 ◽  
Author(s):  
Laura V. Ashton ◽  
Robert L. Callan ◽  
Sangeeta Rao ◽  
Gabriele A. Landolt
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
The United States ◽  
Canine Influenza Virus ◽  
Valuable Adjunct ◽  
Canine Influenza ◽  
The Impact ◽  
H3n8 Virus

Infection of dogs with canine influenza virus (CIV) is considered widespread throughout the United States following the first isolation of CIV in 2004. While vaccination against influenza A infection is a common and important practice for disease control, antiviral therapy can serve as a valuable adjunct in controlling the impact of the disease. In this study, we examined the antiviral activity of nitazoxanide (NTZ) and tizoxanide (TIZ) against three CIV isolatesin vitro. NTZ and TIZ inhibited virus replication of all CIVs with 50% and 90% inhibitory concentrations ranging from 0.17 to 0.21 μMand from 0.60 to 0.76 μM, respectively. These results suggest that NTZ and TIZ are effective against CIV and may be useful for treatment of canine influenza in dogs but further investigation of thein vivoefficacy against CIV as well as the drug's potential for toxicity in dogs is needed.

scholarly journals Antiviral Activity of Benzoic Acid Derivative NC-5 Against Influenza A Virus and Its Neuraminidase Inhibition

2019 ◽  
Vol 20 (24) ◽  
pp. 6261
Author(s):  
Min Guo ◽  
Jiawei Ni ◽  
Jie Yu ◽  
Jing Jin ◽  
Lingman Ma ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Benzoic Acid ◽  
Influenza A Virus ◽  
Influenza A ◽  
Matrix Protein ◽  
Influenza Viruses ◽  
Drug Candidate ◽  
Dependent Manner ◽  
Drug Resistant

The currently available drugs against influenza A virus primarily target neuraminidase (NA) or the matrix protein 2 (M2) ion channel. The emergence of drug-resistant viruses requires the development of new antiviral chemicals. Our study applied a cell-based approach to evaluate the antiviral activity of a series of newly synthesized benzoic acid derivatives, and 4-(2,2-Bis(hydroxymethyl)-5-oxopyrrolidin-l-yl)-3-(5-cyclohexyl-4H-1,2,4-triazol-3-yl)amino). benzoic acid, termed NC-5, was found to possess antiviral activity. NC-5 inhibited influenza A viruses A/FM/1/47 (H1N1), A/Beijing/32/92 (H3N2) and oseltamivir-resistant mutant A/FM/1/47-H275Y (H1N1-H275Y) in a dose-dependent manner. The 50% effective concentrations (EC50) for H1N1 and H1N1-H275Y were 33.6 μM and 32.8 μM, respectively, which showed that NC-5 had a great advantage over oseltamivir in drug-resistant virus infections. The 50% cytotoxic concentration (CC50) of NC-5 was greater than 640 μM. Orally administered NC-5 protected mice infected with H1N1 and H1N1-H275Y, conferring 80% and 60% survival at 100 mg/kg/d, reducing body weight loss, and alleviating virus-induced lung injury. NC-5 could suppress NP and M1 protein expression levels during the late stages of viral biosynthesis and inhibit NA activity, which may influence virus release. Our study proved that NC-5 has potent anti-influenza activity in vivo and in vitro, meaning that it could be regarded as a promising drug candidate to treat infection with influenza viruses, including oseltamivir-resistant viruses.

scholarly journals Deep Mutational Scan of the Highly Conserved Influenza A Virus M1 Matrix Protein Reveals Substantial Intrinsic Mutational Tolerance

2019 ◽  
Vol 93 (13) ◽  
Author(s):  
Nancy Hom ◽  
Lauren Gentles ◽  
Jesse D. Bloom ◽  
Kelly K. Lee
Keyword(s):  
Cell Culture ◽  
Influenza Virus ◽  
Amino Acid ◽  
Viral Replication ◽  
Influenza A Virus ◽  
Influenza A ◽  
Matrix Protein ◽  
Influenza Virus Infection ◽  
Sequence Diversity ◽  
Virus Protein

ABSTRACTInfluenza A virus matrix protein M1 is involved in multiple stages of the viral infectious cycle. Despite its functional importance, our present understanding of this essential viral protein is limited. The roles of a small subset of specific amino acids have been reported, but a more comprehensive understanding of the relationship between M1 sequence, structure, and virus fitness remains elusive. In this study, we used deep mutational scanning to measure the effect of every amino acid substitution in M1 on viral replication in cell culture. The map of amino acid mutational tolerance we have generated allows us to identify sites that are functionally constrained in cell culture as well as sites that are less constrained. Several sites that exhibit low tolerance to mutation have been found to be critical for M1 function and production of viable virions. Surprisingly, significant portions of the M1 sequence, especially in the C-terminal domain, whose structure is undetermined, were found to be highly tolerant of amino acid variation, despite having extremely low levels of sequence diversity among natural influenza virus strains. This unexpected discrepancy indicates that not all sites in M1 that exhibit high sequence conservation in nature are under strong constraint during selection for viral replication in cell culture.IMPORTANCEThe M1 matrix protein is critical for many stages of the influenza virus infection cycle. Currently, we have an incomplete understanding of this highly conserved protein’s function and structure. Key regions of M1, particularly in the C terminus of the protein, remain poorly characterized. In this study, we used deep mutational scanning to determine the extent of M1’s tolerance to mutation. Surprisingly, nearly two-thirds of the M1 sequence exhibits a high tolerance for substitutions, contrary to the extremely low sequence diversity observed across naturally occurring M1 isolates. Sites with low mutational tolerance were also identified, suggesting that they likely play critical functional roles and are under selective pressure. These results reveal the intrinsic mutational tolerance throughout M1 and shape future inquiries probing the functions of this essential influenza A virus protein.

scholarly journals The mechanism of resistance to favipiravir in influenza

2018 ◽  
Vol 115 (45) ◽  
pp. 11613-11618 ◽  
Author(s):  
Daniel H. Goldhill ◽  
Aartjan J. W. te Velthuis ◽  
Robert A. Fletcher ◽  
Pinky Langat ◽  
Maria Zambon ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A Virus ◽  
Influenza A ◽  
H1n1 Influenza ◽  
Viral Fitness ◽  
Virus Infections ◽  
Virus Rna ◽  
Evolution Of Resistance ◽  
Emergence Of Resistance

Favipiravir is a broad-spectrum antiviral that has shown promise in treatment of influenza virus infections. While emergence of resistance has been observed for many antiinfluenza drugs, to date, clinical trials and laboratory studies of favipiravir have not yielded resistant viruses. Here we show evolution of resistance to favipiravir in the pandemic H1N1 influenza A virus in a laboratory setting. We found that two mutations were required for robust resistance to favipiravir. We demonstrate that a K229R mutation in motif F of the PB1 subunit of the influenza virus RNA-dependent RNA polymerase (RdRP) confers resistance to favipiravir in vitro and in cell culture. This mutation has a cost to viral fitness, but fitness can be restored by a P653L mutation in the PA subunit of the polymerase. K229R also conferred favipiravir resistance to RNA polymerases of other influenza A virus strains, and its location within a highly conserved structural feature of the RdRP suggests that other RNA viruses might also acquire resistance through mutations in motif F. The mutations identified here could be used to screen influenza virus-infected patients treated with favipiravir for the emergence of resistance.

scholarly journals Antiviral Activity of Aspalathus linearis against Human Influenza Virus

2017 ◽  
Vol 12 (4) ◽  
pp. 1934578X1701200 ◽  
Author(s):  
Ratika Rahmasari ◽  
Takahiro Haruyama ◽  
Siriwan Charyasriwong ◽  
Tomoki Nishida ◽  
Nobuyuki Kobayashi
Keyword(s):  
Influenza Virus ◽  
Influenza A Virus ◽  
Influenza A ◽  
Time Course ◽  
Influenza Viruses ◽  
Replication Process ◽  
Human Influenza Virus ◽  
Alkaline Extract ◽  
Aspalathus Linearis

Influenza A viruses are responsible for annual epidemics and occasional pandemics, which cause significant morbidity and mortality. The limited protection offered by influenza vaccination, and the emergence of drug-resistant influenza strains, highlight the urgent need for the development of novel anti-influenza drugs. However, the search for antiviral substances from the library of low molecular weight chemical compounds is limited. Thus, because of their natural diversity and accessibility, plants or plant-derived materials are rapidly becoming valuable sources for the discovery and development of new antiviral drugs. In this study, crude extracts of Aspalathus linearis, a plant reported to have anti-HIV activity, were evaluated in vitro for their activity against the influenza A virus. Of the extracts tested, an alkaline extract of Aspalathus linearis demonstrated the strongest inhibition against influenza A virus and could also inhibit different types of influenza viruses, including Oseltamivir-resistant influenza viruses A and B. Our time course of addition studies indicated that the alkaline extract of Aspalathus linearis exerts its antiviral effect predominantly during the late stages of the influenza virus replication process.

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