Effect of an Asparagine-to-Serine Mutation at Position 294 in Neuraminidase on the Pathogenicity of Highly Pathogenic H5N1 Influenza A Virus

Kiso, Maki; Ozawa, Makoto; Le, Mai Thi Quynh; Imai, Hideki; Takahashi, Kei; Kakugawa, Satoshi; Noda, Takeshi; Horimoto, Taisuke; Kawaoka, Yoshihiro

doi:10.1128/jvi.00047-11

Cited by 33 publications

(28 citation statements)

References 34 publications

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“…Evaluation of different doses for viral inoculation has been described for mice, ferrets, and occasionally in humans, but not yet for nonhuman primates (5)(6)(7)(8)(9)(10)(17)(18)(19)(20)(21). These studies were either directed at finding the minimal infectious dose or minimal lethal dose or, in case of evaluation of attenuated viruses in humans, at finding the dose that resulted in adequate levels of infection while limiting development of clinical symptoms and fever.…”

Section: Discussionmentioning

confidence: 99%

“…Novel candidate influenza vaccines are commonly tested for safety and efficacy in mice and ferrets and/or macaques before they are evaluated for immunogenicity in humans (2,3). However, whereas for mice and ferrets dose-finding studies have been described and implemented for testing of vaccines and antiviral agents (4)(5)(6)(7)(8)(9)(10)(11), for macaques usually a standard challenge dose is used, typically in the range between 10 6 and 10 7 50% tissue culture infective doses (TCID 50 ) (12)(13)(14)(15).…”

mentioning

confidence: 99%

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Correlation between Virus Replication and Antibody Responses in Macaques following Infection with Pandemic Influenza A Virus

Koopman

Mooij

Dekking

et al. 2016

J Virol

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Influenza virus infection of nonhuman primates is a well-established animal model for studying pathogenesis and for evaluating prophylactic and therapeutic intervention strategies. However, usually a standard dose is used for the infection, and there is no information on the relation between challenge dose and virus replication or the induction of immune responses. Such information is also very scarce for humans and largely confined to evaluation of attenuated virus strains. Here, we have compared the effect of a commonly used dose (4 ؋ 10 6 50% tissue culture infective doses) versus a 100-fold-higher dose, administered by intrabronchial installation, to two groups of 6 cynomolgus macaques. Animals infected with the high virus dose showed more fever and had higher peak levels of gamma interferon in the blood. However, virus replication in the trachea was not significantly different between the groups, although in 2 out of 6 animals from the high-dose group it was present at higher levels and for a longer duration. The virus-specific antibody response was not significantly different between the groups. However, antibody enzyme-linked immunosorbent assay, virus neutralization, and hemagglutination inhibition antibody titers correlated with cumulative virus production in the trachea. In conclusion, using influenza virus infection in cynomolgus macaques as a model, we demonstrated a relationship between the level of virus production upon infection and induction of functional antibody responses against the virus. IMPORTANCEThere is only very limited information on the effect of virus inoculation dose on the level of virus production and the induction of adaptive immune responses in humans or nonhuman primates. We found only a marginal and variable effect of virus dose on virus production in the trachea but a significant effect on body temperature. The induction of functional antibody responses, including virus neutralization titer, hemagglutination inhibition titer, and antibody-dependent cell-mediated cytotoxicity, correlated with the level of virus replication measured in the trachea. The study reveals a relationship between virus production and functional antibody formation, which could be relevant in defining appropriate criteria for new influenza virus vaccine candidates.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Correlation between Virus Replication and Antibody Responses in Macaques following Infection with Pandemic Influenza A Virus

Koopman

Mooij

Dekking

et al. 2016

J Virol

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“…Early studies suggested that seasonal influenza virus resistant to NA inhibitors would be less infective and transmissible in vivo (11,23); however, the unexpected dominance (ϳ98%) of oseltamivir-resistant H1N1 viruses from 2007 to 2009 demonstrated that NA inhibitor resistance could enhance fitness and transmissibility (14,29). Recent data have shown that NA inhibitor-resistant H5N1 variants retain the replication efficiency and pathogenicity of a wild-type virus in vitro and in mice (44), and some data have suggested that NA inhibitor-resistant H5N1 variants are more virulent in a ferret animal model (17,18). Understanding the mechanisms by which resistance to NA inhibitors may contribute to virulence and transmissibility of H5N1 influenza virus is a key defensive strategy to be prepared for an H5N1 pandemic.…”

mentioning

confidence: 99%

Decreased Neuraminidase Activity Is Important for the Adaptation of H5N1 Influenza Virus to Human Airway Epithelium

Ilyushina

Bovin

Webster

2012

J Virol

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Highly pathogenic avian H5N1 influenza viruses remain a pandemic threat. Antiviral drugs such as neuraminidase (NA) inhibitors will be crucial for disease control in the event of a pandemic. Should drug-resistant H5N1 viruses develop, all defense strategies will be compromised. To determine the likelihood and mechanisms of emergence of NA inhibitor-resistant H5N1 variants in humans, we serially passaged two H5N1 viruses, A/Hong Kong/213/03 and A/Turkey/65-1242/06, in normal human bronchial epithelial (NHBE) cells in the presence of oseltamivir, zanamivir, or peramivir. To monitor the emergence of changes associated with the adaptation of H5N1 viruses to humans, we passaged the strains in the absence of drugs. Under pressure of each NA inhibitor, A/Turkey/65-1242/06 developed mutations in the hemagglutinin (HA) (H28R and P194L/T215I) and NA (E119A) proteins that reduced virus binding to α2,3-sialyl receptor and NA activity. Oseltamivir pressure selected a variant of A/Hong Kong/213/03 virus with HA P194S mutation that decreased viral binding to α2,6 receptor. Under peramivir pressure, A/Hong Kong/213/03 virus developed a novel NA mutation, R156K, that reduced binding to all three drugs, caused about 90% loss of NA activity, and compromised replication in NHBE cells. Both strains were eliminated in NHBE cells when they were cultivated in the absence of drugs. Here, we show for the first time that decreased NA activity mediated through NA inhibitors is essential for the adaptation of pandemic H5N1 influenza virus to humans. This ability of decreased NA activity to promote H5N1 infection underlines the necessity to optimize management strategies for a plausible H5N1 pandemic.

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“…The R292K substitution in the NA protein has previously been reported to confer resistance to oseltamivir (Kiso et al, 2011). The strain A/Taiwan/2/2013 has an Arg at position 301 (equivalent to 292 in N2 numbering), suggesting that the virus is sensitive to oseltamivir.…”

Section: T H K Qmentioning

confidence: 98%

Origin and molecular characterization of the human-infecting H6N1 influenza virus in Taiwan

Shi

et al. 2013

Protein Cell

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In June 2013, the fi rst human H6N1 infl uenza virus infection was confirmed in Taiwan. However, the origin and molecular characterization of this virus, A/Taiwan/2/2013 (H6N1), have not been well studied thus far. In the present report, we performed phylogenetic and coalescent analyses of this virus and compared its molecular profi le/characteristics with other closely related strains. Molecular characterization of H6N1 revealed that it is a typical avian infl uenza virus of low pathogenicity, which might not replicate and propagate well in the upper airway in mammals. Phylogenetic analysis revealed that the virus clusters with A/chicken/Taiwan/A2837/2013 (H6N1) in seven genes, except PB1. For the PB1 gene, A/Taiwan/2/2013 was clustered with a different H6N1 lineage from A/chicken/Taiwan/ A2837/2013. Although a previous study demonstrated that the PB2, PA, and M genes of A/Taiwan/2/2013 might be derived from the H5N2 viruses, coalescent analyses revealed that these H5N2 viruses were derived from more recent strains than that of the ancestor of A/Taiwan/2/2013. Therefore, we propose that A/Taiwan/2/2013 is a reassortant from different H6N1 lineages circulating in chickens in Taiwan. Furthermore, compared to avian isolates, a single P186L (H3 numbering) substitution in the hemagglutinin H6 of the human isolate might increase the mammalian receptor binding and, hence, this strain's pathogenicity in humans. Overall, human infection with this virus seems an accidental event and is unlikely to cause an infl uenza pandemic. However, its co-circulation and potential reassortment with other infl uenza subtypes are still worthy of attention.

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Effect of an Asparagine-to-Serine Mutation at Position 294 in Neuraminidase on the Pathogenicity of Highly Pathogenic H5N1 Influenza A Virus

Cited by 33 publications

References 34 publications

Correlation between Virus Replication and Antibody Responses in Macaques following Infection with Pandemic Influenza A Virus

Correlation between Virus Replication and Antibody Responses in Macaques following Infection with Pandemic Influenza A Virus

Decreased Neuraminidase Activity Is Important for the Adaptation of H5N1 Influenza Virus to Human Airway Epithelium

Origin and molecular characterization of the human-infecting H6N1 influenza virus in Taiwan

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