scholarly journals Oseltamivir Is Effective against 1918 Influenza Virus Infection of Macaques but Vulnerable to Escape

mBio ◽  
2019 ◽  
Vol 10 (5) ◽  
Author(s):  
Friederike Feldmann ◽  
Darwyn Kobasa ◽  
Carissa Embury-Hyatt ◽  
Allen Grolla ◽  
Tracy Taylor ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Treatment Effectiveness ◽  
Influenza Pandemic ◽  
Severe Disease ◽  
Disease Model ◽  
Influenza Virus Infection ◽  
Macaque Model ◽  
1918 Influenza ◽  
Oseltamivir Phosphate

ABSTRACT The 1918 influenza virus, subtype H1N1, was the causative agent of the most devastating pandemic in the history of infectious diseases. In vitro studies have confirmed that extreme virulence is an inherent property of this virus. Here, we utilized the macaque model for evaluating the efficacy of oseltamivir phosphate against the fully reconstructed 1918 influenza virus in a highly susceptible and relevant disease model. Our findings demonstrate that oseltamivir phosphate is effective in preventing severe disease in macaques but vulnerable to virus escape through emergence of resistant mutants, especially if given in a treatment regimen. Nevertheless, we conclude that oseltamivir would be highly beneficial to reduce the morbidity and mortality rates caused by a highly pathogenic influenza virus although it would be predicted that resistance would likely emerge with sustained use of the drug. IMPORTANCE Oseltamivir phosphate is used as a first line of defense in the event of an influenza pandemic prior to vaccine administration. Treatment failure through selection and replication of drug-resistant viruses is a known complication in the field and was also demonstrated in our study with spread of resistant 1918 influenza virus in multiple respiratory tissues. This emphasizes the importance of early treatment and the possibility that noncompliance may exacerbate treatment effectiveness. It also demonstrates the importance of implementing combination therapy and vaccination strategies as soon as possible in a pandemic situation.

scholarly journals Cross-Protection of Chicken Immunoglobulin Y Antibodies against H5N1 and H1N1 Viruses Passively Administered in Mice

2011 ◽  
Vol 18 (7) ◽  
pp. 1083-1090 ◽  
Author(s):  
Michael G. Wallach ◽  
Richard J. Webby ◽  
Fakhrul Islam ◽  
Stephen Walkden-Brown ◽  
Eva Emmoth ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza Pandemic ◽  
Influenza Virus Infection ◽  
Influenza Viruses ◽  
Antigenic Drift ◽  
Virus Infectivity ◽  
Lethal Challenge ◽  
H5n1 Influenza

ABSTRACTInfluenza viruses remain a major threat to global health due to their ability to undergo change through antigenic drift and antigenic shift. We postulated that avian IgY antibodies represent a low-cost, effective, and well-tolerated approach that can easily be scaled up to produce enormous quantities of protective antibodies. These IgY antibodies can be administered passively in humans (orally and intranasally) and can be used quickly and safely to help in the fight against an influenza pandemic. In this study, we raised IgY antibodies against H1N1, H3N2, and H5N1 influenza viruses. We demonstrated that, using whole inactivated viruses alone and in combination to immunize hens, we were able to induce a high level of anti-influenza virus IgY in the sera and eggs, which lasted for at least 2 months after two immunizations. Furthermore, we found that by use ofin vitroassays to test for the ability of IgY to inhibit hemagglutination (HI test) and virus infectivity (serum neutralization test), IgYs inhibited the homologous as well as in some cases heterologous clades and strains of viruses. Using anin vivomouse model system, we found that, when administered intranasally 1 h prior to infection, IgY to H5N1 protected 100% of the mice against lethal challenge with H5N1. Of particular interest was the finding that IgY to H5N1 cross-protected against A/Puerto Rico/8/34 (H1N1) bothin vitroandin vivo. Based on our results, we conclude that anti-influenza virus IgY can be used to help prevent influenza virus infection.

scholarly journals Neuraminidase Inhibitor-Resistant Recombinant A/Vietnam/1203/04 (H5N1) Influenza Viruses Retain Their Replication Efficiency and Pathogenicity In Vitro and In Vivo

2007 ◽  
Vol 81 (22) ◽  
pp. 12418-12426 ◽  
Author(s):  
Hui-Ling Yen ◽  
Natalia A. Ilyushina ◽  
Rachelle Salomon ◽  
Erich Hoffmann ◽  
Robert G. Webster ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza Pandemic ◽  
Influenza Virus Infection ◽  
Influenza Viruses ◽  
Wild Type Virus ◽  
H5n1 Influenza Virus ◽  
Wild Type ◽  
Replication Efficiency ◽  
H5n1 Influenza

ABSTRACT Effective antiviral drugs are essential for early control of an influenza pandemic. It is therefore crucial to evaluate the possible threat posed by neuraminidase (NA) inhibitor-resistant influenza viruses with pandemic potential. Four NA mutations (E119G, H274Y, R292K, and N294S) that have been reported to confer resistance to NA inhibitors were each introduced into recombinant A/Vietnam/1203/04 (VN1203) H5N1 influenza virus. For comparison, the same mutations were introduced into recombinant A/Puerto Rico/8/34 (PR8) H1N1 influenza virus. The E119G and R292K mutations significantly compromised viral growth in vitro, but the H274Y and N294S mutations were stably maintained in VN1203 and PR8 viruses. In both backgrounds, the H274Y and N294S mutations conferred resistance to oseltamivir carboxylate (50% inhibitory concentration [IC50] increases, >250-fold and >20-fold, respectively), and the N294S mutation reduced susceptibility to zanamivir (IC50 increase, >3.0-fold). Although the H274Y and N294S mutations did not compromise the replication efficiency of VN1203 or PR8 viruses in vitro, these mutations slightly reduced the lethality of PR8 virus in mice. However, the VN1203 virus carrying either the H274Y or N294S mutation exhibited lethality similar to that of the wild-type VN1203 virus. The different enzyme kinetic parameters (V max and Km ) of avian-like VN1203 NA and human-like PR8 NA suggest that resistance-associated NA mutations can cause different levels of functional loss in NA glycoproteins of the same subtype. Our results suggest that NA inhibitor-resistant H5N1 variants may retain the high pathogenicity of the wild-type virus in mammalian species. Patients receiving NA inhibitors for H5N1 influenza virus infection should be closely monitored for the emergence of resistant variants.

scholarly journals Anti-influenza Sesquiterpene from the Roots of Reynoutria japonica

2014 ◽  
Vol 9 (3) ◽  
pp. 1934578X1400900 ◽  
Author(s):  
Nguyen Xuan Nhiem ◽  
Phan Van Kiem ◽  
Chau Van Minh ◽  
Nguyen Thi Hoai ◽  
Ho Viet Duc ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Mdck Cells ◽  
Influenza Infection ◽  
Influenza Virus Infection ◽  
Therapeutic Index ◽  
Reynoutria Japonica ◽  
Influenza Activity ◽  
Oseltamivir Phosphate

One new flavonol glycoside, 4′- O-methylmyricitrin 3′- O-β-D-glucopyranoside (1), one new sesquiterpene, reynoudiol (11), as well as the 12 known compounds (2–10, 12–14) quercetin 3- O-methyl ether (2), quercitrin (3), isorhamnetin 3- α-L-rhamnopyranoside (4), tamarixetin 3- α-L-rhamnopyranoside (5), myricitrin (6), 4′- O-methylmyricitrin (7), isorhamnetin 3- O-β-D-xylopyranosyl (1→2)- O-β-D-glucopyranoside (8), isorhamnetin 3- O-β-D-apiofuranosyl-(1→2)- O-β-D-glucopyranoside (9), (+)-catechin (10), 7-drimene-3,11,12-triol (12), clovane-2 β,9 α-diol (13), and α-cadinol (14), were isolated from the methanol extract of Reynoutria japonica roots. Based on in vitro screening of the anti-influenza activity of the isolated compounds, reynoudiol showed significantly higher activity than that of oseltamivir phosphate at the same concentration, and did not induce any detectable cytopathic effect in MDCK cells. The CC50 of reynoudiol was above 50 μM and could inhibit influenza virus infection with an IC50 of 0.29 ± 0.01 μM. The therapeutic index (TI) of reynoudiol against influenza infection was 172.4, and thus, this compound can be potentially used to treat oseltamivir-resistant influenza virus infection.

scholarly journals MicroRNA Expression and Virulence in Pandemic Influenza Virus-Infected Mice

2010 ◽  
Vol 84 (6) ◽  
pp. 3023-3032 ◽  
Author(s):  
Yu Li ◽  
Eric Y. Chan ◽  
Jiangning Li ◽  
Chester Ni ◽  
Xinxia Peng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Influenza Virus ◽  
Expression Profiles ◽  
Influenza Pandemic ◽  
Expression Patterns ◽  
Gene Expression Pattern ◽  
Influenza Virus Infection ◽  
Underlying Mechanism ◽  
Microrna Expression ◽  
1918 Influenza

ABSTRACT The worst known H1N1 influenza pandemic in history resulted in more than 20 million deaths in 1918 and 1919. Although the underlying mechanism causing the extreme virulence of the 1918 influenza virus is still obscure, our previous functional genomics analyses revealed a correlation between the lethality of the reconstructed 1918 influenza virus (r1918) in mice and a unique gene expression pattern associated with severe immune responses in the lungs. Lately, microRNAs have emerged as a class of crucial regulators for gene expression. To determine whether differential expression of cellular microRNAs plays a role in the host response to r1918 infection, we compared the lung cellular “microRNAome” of mice infected by r1918 virus with that of mice infected by a nonlethal seasonal influenza virus, A/Texas/36/91. We found that a group of microRNAs, including miR-200a and miR-223, were differentially expressed in response to influenza virus infection and that r1918 and A/Texas/36/91 infection induced distinct microRNA expression profiles. Moreover, we observed significant enrichment in the number of predicted cellular target mRNAs whose expression was inversely correlated with the expression of these microRNAs. Intriguingly, gene ontology analysis revealed that many of these mRNAs play roles in immune response and cell death pathways, which are known to be associated with the extreme virulence of r1918. This is the first demonstration that cellular gene expression patterns in influenza virus-infected mice may be attributed in part to microRNA regulation and that such regulation may be a contributing factor to the extreme virulence of the r1918.

scholarly journals Characterization of the In Vitro and In Vivo Efficacy of Baloxavir Marboxil against the H5 Highly Pathogenic Avian Influenza Virus Infection

2021 ◽  
Author(s):  
Keiichi Taniguchi ◽  
Yoshinori Ando ◽  
Masanori Kobayashi ◽  
Shinsuke Toba ◽  
Haruaki Nobori ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Avian Influenza ◽  
Avian Influenza Virus ◽  
Highly Pathogenic Avian Influenza ◽  
Influenza Virus Infection ◽  
Highly Pathogenic ◽  
Pathogenic Avian Influenza ◽  
Antiviral Efficacy ◽  
Pathogenic Avian Influenza Virus

Human infections with the H5 highly pathogenic avian influenza virus (HPAIV) sporadically threatens public health. The susceptibility of HPAIVs to baloxavir acid (BXA), which is a new class of inhibitor for the influenza virus cap-dependent endonuclease, has been confirmed in vitro, but has not yet been characterized fully. Here, the efficacy of BXA against HPAIVs, including recent H5N8 variants in vitro was assessed. The antiviral efficacy of baloxavir marboxil (BXM) in H5N1 virus-infected mice was also investigated. BXA exhibited similar in vitro activities against H5N1, H5N6, and H5N8 variants tested to those of seasonal and other zoonotic strains. BXM monotherapy in mice infected with the H5N1 HPAIV clinical isolate; A/Hong Kong/483/1997 (H5N1) strain, also caused a significant reduction in viral titers in the lungs, brains, and kidneys, followed by prevention of acute lung inflammation and improvement of mortality compared with oseltamivir phosphate (OSP). Furthermore, combination treatments with BXM and OSP, using a 48-hour delayed treatment model showed a more potent effect on viral replication in organs, accompanied by improved survival compared to BXM or OSP monotherapy. From each test, no resistant virus (e.g., I38T in the PA) emerged in any BXM-treated mouse. These results therefore support the conclusion that BXM has potent antiviral efficacy against H5 HPAIV infections.

scholarly journals Linear polysialoside outperforms dendritic analogs for inhibition of influenza virus infection in vitro and in vivo

Biomaterials ◽  
2017 ◽  
Vol 138 ◽  
pp. 22-34 ◽  
Author(s):  
Sumati Bhatia ◽  
Daniel Lauster ◽  
Markus Bardua ◽  
Kai Ludwig ◽  
Stefano Angioletti-Uberti ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Influenza Virus Infection

scholarly journals Emergence of H7N9 Influenza A Virus Resistant to Neuraminidase Inhibitors in Nonhuman Primates

2015 ◽  
Vol 59 (8) ◽  
pp. 4962-4973 ◽  
Author(s):  
Yasushi Itoh ◽  
Shintaro Shichinohe ◽  
Misako Nakayama ◽  
Manabu Igarashi ◽  
Akihiro Ishii ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Cynomolgus Macaque ◽  
Influenza Virus Infection ◽  
Influenza Viruses ◽  
H7n9 Virus ◽  
Macaque Model ◽  
H7n9 Influenza Virus ◽  
Number Of Patients ◽  
H7n9 Influenza

ABSTRACTThe number of patients infected with H7N9 influenza virus has been increasing since 2013. We examined the efficacy of neuraminidase (NA) inhibitors and the efficacy of a vaccine against an H7N9 influenza virus, A/Anhui/1/2013 (H7N9), isolated from a patient in a cynomolgus macaque model. NA inhibitors (oseltamivir and peramivir) barely reduced the total virus amount because of the emergence of resistant variants with R289K or I219T in NA [residues 289 and 219 in N9 of A/Anhui/1/2013 (H7N9) correspond to 292 and 222 in N2, respectively] in three of the six treated macaques, whereas subcutaneous immunization of an inactivated vaccine derived from A/duck/Mongolia/119/2008 (H7N9) prevented propagation of A/Anhui/1/2013 (H7N9) in all vaccinated macaques. The percentage of macaques in which variant H7N9 viruses with low sensitivity to the NA inhibitors were detected was much higher than that of macaques in which variant H5N1 highly pathogenic influenza virus was detected after treatment with one of the NA inhibitors in our previous study. The virus with R289K in NA was reported in samples from human patients, whereas that with I219T in NA was identified for the first time in this study using macaques, though no variant H7N9 virus was reported in previous studies using mice. Therefore, the macaque model enables prediction of the frequency of emerging H7N9 virus resistant to NA inhibitorsin vivo. Since H7N9 strains resistant to NA inhibitors might easily emerge compared to other influenza viruses, monitoring of the emergence of variants is required during treatment of H7N9 influenza virus infection with NA inhibitors.

scholarly journals Modification of Cysteine Residues In Vitro and In Vivo Affects the Immunogenicity and Antigenicity of Major Histocompatibility Complex Class I–restricted Viral Determinants

1999 ◽  
Vol 189 (11) ◽  
pp. 1757-1764 ◽  
Author(s):  
Weisan Chen ◽  
Jonathan W. Yewdell ◽  
Rodney L. Levine ◽  
Jack R. Bennink
Keyword(s):  
Influenza Virus ◽  
Posttranslational Modifications ◽  
Synthetic Peptides ◽  
Influenza Virus Infection ◽  
Lymphocytic Choriomeningitis ◽  
Reducing Agents ◽  
Cysteine Residues ◽  
T Cell Lines

In studying the subdominant status of two cysteine-containing influenza virus nuclear protein (NP) determinants (NP39–47 and NP218–226) restricted by H-2Kd, we found that the antigenicity of synthetic peptides was enhanced 10–100-fold by treatment with reducing agents, despite the fact that the affinity for Kd was not enhanced. Reducing agents also markedly enhanced the immunogenicity of cysteine-containing peptides, as measured by propagation of long-term T cell lines in vitro. Similar enhancing effects were obtained by substituting cysteine with alanine or serine in the synthetic peptides, demonstrating that sulfhydryl modification of cysteine is responsible for the impaired antigenicity and immunogenicity of NP39–47 and NP218–226. We found similar effects for two widely studied, cysteine-containing peptides from lymphocytic choriomeningitis virus. The major modifications of cysteine-containing synthetic peptides are cysteinylation and dimerization occurring through cysteine residues. We demonstrate that both of these modifications occur in cells synthesizing a cytosolic NP218–226 minigene product and, further, that T cells specific for cysteinylated NP218–226 are induced by influenza virus infection in mice, demonstrating that this modification occurs in vivo. These findings demonstrate that posttranslational modifications affect the immunogenicity and antigenicity of cysteine-containing viral peptides and that this must be considered in studying the status of such peptides in immunodominance hierarchies.

Sign in / Sign up

Export Citation Format

Share Document