Determinants of Antiviral Effectiveness in Influenza Virus A Subtype H5N1

Chan, Paul K.S.; Lee, Nelson; Zaman, Mukhtiar; Adisasmito, Wiku; Coker, Richard; Hanshaoworakul, Wanna; Gasimov, Viktor; Öner, Ahmet Faik; Doğan, Nazım; Tsang, Owen Tak‐Yin; Phommasack, Bounlay; Touch, Sok; Bamgboye, Ebun L.; Swenson, Anna; Toovey, Stephen; Dreyer, Nancy A

doi:10.1093/infdis/jis509

Cited by 62 publications

(54 citation statements)

References 24 publications

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“…Similar adaptive changes have been reported to occur human virus isolates of other avian viruses (e.g., clade 0 or clade 1 H5N1 viruses) as they adapt in humans (31). In contrast, PB2-E627K changes are fixed within avian viruses of the clade 2.2 lineage that are now endemic in Egypt, with evidence of reduced severity of human disease caused by this lineage (32).…”

Section: Discussionsupporting

confidence: 66%

Amino Acid Substitutions in Polymerase Basic Protein 2 Gene Contribute to the Pathogenicity of the Novel A/H7N9 Influenza Virus in Mammalian Hosts

Mok

Lee

Lestra

et al. 2014

J Virol

148

126

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A novel avian-origin influenza A/H7N9 virus emerged in 2013 to cause more than 130 cases of zoonotic human disease, with an overall case fatality rate of around 30% in cases detected. It has been shown that an E-to-K amino acid change at residue 627 of polymerase basic protein 2 (PB2) occurred frequently in the H7N9 isolates obtained from humans but not in viruses isolated from poultry. Although this mutation has been reported to confer increased mammalian pathogenicity in other avian influenza subtypes, it has not been experimentally investigated in the H7N9 virus. In this study, we determined the contribution of PB2-E627K in H7N9 virus to its pathogenicity in mammalian hosts. In addition, the compensatory role of the PB2 mutations T271A, Q591K, and D701N in H7N9 virus was investigated. We characterized the activity of polymerase complexes with these PB2 mutations and found that they enhance the polymerase activity in human 293T cells. The rescued mutants enhanced growth in mammalian cells in vitro. Mice infected with the H7N9 mutant containing the avian signature protein PB2-627E showed a marked decrease in disease severity (weight loss) and pathology compared to mice infected with the wild-type strain (PB2-627K) or other PB2 mutants. Also, mutants with PB2-627E showed lower virus replication and proinflammatory cytokine responses in the lungs of the virus-infected mice, which may contribute to pathogenicity. Our results suggest that these amino acid substitutions contribute to mouse pathogenicity and mammalian adaptation. IMPORTANCEA novel avian H7N9 influenza A virus emerged in east China in 2013 to cause zoonotic human disease associated with significant mortality. It is important to understand the viral genetic markers of mammalian adaptation and disease severity in this H7N9 virus. Since many human (but not avian) H7N9 virus isolates have an amino acid substitution at position E627K in the polymerase basic protein 2 (PB2) gene, we investigated the role of this and other functionally related mutations for polymerase activity in vitro, virus replication competence, and pathogenicity in the mouse model. We found that E627K and functionally related mutations are associated with increased polymerase activity, increased viral replication competence, and increased disease severity in mice.

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Section: Discussionsupporting

confidence: 66%

Amino Acid Substitutions in Polymerase Basic Protein 2 Gene Contribute to the Pathogenicity of the Novel A/H7N9 Influenza Virus in Mammalian Hosts

Mok

Lee

Lestra

et al. 2014

J Virol

148

126

View full text Add to dashboard Cite

show abstract

“…In addition, Oseltamivir therapy starting on day 7 of illness did not prevent death, although the NA sequence data predicted susceptibility. It may be related to the delay in starting antiviral therapy as antiviral therapy can shorten the duration of viral shedding and reduced mortality in hospitalized patients with severe influenza if prescribed during the first 3 days of illness (30)(31)(32).…”

Section: Epidemiological Investigationmentioning

confidence: 99%

Human infection with a novel, highly pathogenic avian influenza A (H5N6) virus: Virological and clinical findings

Pan

Gao

et al. 2016

Journal of Infection

162

132

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“…In Indonesia the case fatality rate is 83% (153/185) [1]. We recently reported the impact of treatment on the clinical course of influenza H5N1 and showed that though treatment with oseltamivir within 48 hours offers significant benefits in terms of survival; the benefits of treatment persist in terms of reduced case fatality rates, though to a lesser extent, even if treatment is delayed up to 6 to 8 days after symptom onset [2,3]. Given the very high mortality rates associated with H5N1 infection in Indonesia and the known association with delays in initiating treatment, it is important to determine whether delays occur across the country or whether some provinces experience longer delays than others, and whether delays are the result of patients delaying seeking health care or whether delays in the health care service itself are important.…”

Section: Introductionmentioning

confidence: 99%

Human influenza A H5N1 in Indonesia: health care service-associated delays in treatment initiation

et al. 2013

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BackgroundIndonesia has had more recorded human cases of influenza A H5N1 than any other country, with one of the world’s highest case fatality rates. Understanding barriers to treatment may help ensure life-saving influenza-specific treatment is provided early enough to meaningfully improve clinical outcomes.MethodsData for this observational study of humans infected with influenza A H5N1 were obtained primarily from Ministry of Health, Provincial and District Health Office clinical records. Data included time from symptom onset to presentation for medical care, source of medical care provided, influenza virology, time to initiation of influenza-specific treatment with antiviral drugs, and survival.ResultsData on 124 human cases of virologically confirmed avian influenza were collected between September 2005 and December 2010, representing 73% of all reported Indonesia cases. The median time from health service presentation to antiviral drug initiation was 7.0 days. Time to viral testing was highly correlated with starting antiviral treatment (p < 0.0001). We found substantial variability in the time to viral testing (p = 0.04) by type of medical care provider. Antivirals were started promptly after diagnosis (median 0 days).ConclusionsDelays in the delivery of appropriate care to human cases of avian influenza H5N1 in Indonesia appear related to delays in diagnosis rather than presentation to health care settings. Either cases are not suspected of being H5N1 cases until nearly one week after presenting for medical care, or viral testing and/or antiviral treatment is not available where patients are presenting for care. Health system delays have increased since 2007.

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Determinants of Antiviral Effectiveness in Influenza Virus A Subtype H5N1

Abstract: Oseltamivir is especially effective for treating H5N1 infection when given early and before onset of respiratory failure. The effect of viral clade on fatality and treatment response deserves further investigation.

Cited by 62 publications

References 24 publications

Amino Acid Substitutions in Polymerase Basic Protein 2 Gene Contribute to the Pathogenicity of the Novel A/H7N9 Influenza Virus in Mammalian Hosts

Amino Acid Substitutions in Polymerase Basic Protein 2 Gene Contribute to the Pathogenicity of the Novel A/H7N9 Influenza Virus in Mammalian Hosts

Human infection with a novel, highly pathogenic avian influenza A (H5N6) virus: Virological and clinical findings

Human influenza A H5N1 in Indonesia: health care service-associated delays in treatment initiation

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