Structure and Function of Influenza Virus Ribonucleoprotein

Lo, Chi‐Fai; Tang, Yuchen; Shaw, Pang‐Chui

doi:10.1007/978-981-10-8456-0_5

Cited by 35 publications

(32 citation statements)

References 99 publications

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“…For investigating the driving force that increases the odds of any identified low-frequency variant to emerge at the consensus level, we tested three parameters: variant genomic position, its prevalence among patients, and its prevalence across years using Fisher s exact tests for categorical variables embedded in Prism7 [47]. p-values < 0.01 were considered statistically significant.…”

Section: Discussionmentioning

confidence: 99%

Inter-Versus Intra-Host Sequence Diversity of pH1N1 and Associated Clinical Outcomes

et al. 2020

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The diversity of RNA viruses dictates their evolution in a particular host, community or environment. Here, we reported within- and between-host pH1N1virus diversity at consensus and sub-consensus levels over a three-year period (2015–2017) and its implications on disease severity. A total of 90 nasal samples positive for the pH1N1 virus were deep-sequenced and analyzed to detect low-frequency variants (LFVs) and haplotypes. Parallel evolution of LFVs was seen in the hemagglutinin (HA) gene across three scales: among patients (33%), across years (22%), and at global scale. Remarkably, investigating the emergence of LFVs at the consensus level demonstrated that within-host virus evolution recapitulates evolutionary dynamics seen at the global scale. Analysis of virus diversity at the HA haplotype level revealed the clustering of low-frequency haplotypes from early 2015 with dominant strains of 2016, indicating rapid haplotype evolution. Haplotype sharing was also noticed in all years, strongly suggesting haplotype transmission among patients infected during a specific influenza season. Finally, more than half of patients with severe symptoms harbored a larger number of haplotypes, mostly in patients under the age of five. Therefore, patient age, haplotype diversity, and the presence of certain LFVs should be considered when interpreting illness severity. In addition to its importance in understanding virus evolution, sub-consensus virus diversity together with whole genome sequencing is essential to explain variabilities in clinical outcomes that cannot be explained by either analysis alone.

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Section: Discussionmentioning

confidence: 99%

Inter-Versus Intra-Host Sequence Diversity of pH1N1 and Associated Clinical Outcomes

et al. 2020

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“…The influenza virus RNA polymerase is composed of the proteins polymerase basic 1 (PB1), PB2, and polymerase acidic (PA) (P3 in influenza C and D viruses) ( Fig. 2A; te Pflug et al 2017;Lo et al 2018). X-ray crystallography and cryo-EM studies showed that the RNA polymerase consists of a core domain and several peripheral domains that are connected to the core through highly flexible linkers (Pflug et al 2014;Reich et al 2014;Chang et al 2015;Hengrung et al 2015;Thierry et al 2016;Fan et al 2019;Peng et al 2019).…”

Section: Architecture Of the Rna Polymerasementioning

confidence: 99%

“…provided novel insights into the mechanisms by which influenza viruses transcribe and replicate their RNA genome (te Pflug et al 2017;Lo et al 2018). These studies have answered fundamental questions about influenza RNA polymerase function and contributed to our understanding of the dependence of the influenza virus on host factors for the transcription and replication of its genome.…”

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confidence: 99%

Structure and Function of the Influenza Virus Transcription and Replication Machinery

Fodor

Velthuis

2019

Cold Spring Harb Perspect Med

102

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Transcription and replication of the influenza virus RNA genome is catalyzed by the viral heterotrimeric RNA-dependent RNA polymerase in the context of viral ribonucleoprotein (vRNP) complexes. Atomic resolution structures of the viral RNA synthesis machinery have offered insights into the initiation mechanisms of viral transcription and genome replication, and the interaction of the viral RNA polymerase with host RNA polymerase II, which is required for the initiation of viral transcription. Replication of the viral RNA genome by the viral RNA polymerase depends on host ANP32A, and host-specific sequence differences in ANP32A underlie the poor activity of avian influenza virus polymerases in mammalian cells. A failure to faithfully copy the viral genome segments can lead to the production of aberrant viral RNA products, such as defective interfering (DI) RNAs and mini viral RNAs (mvRNAs). Both aberrant RNA types have been implicated in innate immune responses against influenza virus infection. This review discusses recent insights into the structure-function relationship of the viral RNA polymerase and its role in determining host range and virulence.

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“…Influenza viruses contain an eight segmented negative-sense, single-stranded viral RNA genome that encodes for at least eleven essential viral proteins. Each RNA segment is encapsulated into a ribonucleoprotein (RNP) molecule, consisting of the nucleoprotein (NP) and a trimeric RNA-dependent RNA polymerase (RdRp) complex composed by PA, PB1, and PB2 [ 6 ]. Inside the nucleus, the RdRp carries out transcription and replication using the vRNA as a template for both transcription to mRNA and synthesis of complementary RNA (cRNA) that serves as the template for novel vRNAs.…”

Section: Introductionmentioning

confidence: 99%

Semisynthetic Cardenolides Acting as Antiviral Inhibitors of Influenza A Virus Replication by Preventing Polymerase Complex Formation

et al. 2020

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Influenza virus infections represent a major public health issue by causing annual epidemics and occasional pandemics that affect thousands of people worldwide. Vaccination is the main prophylaxis to prevent these epidemics/pandemics, although the effectiveness of licensed vaccines is rather limited due to the constant mutations of influenza virus antigenic characteristics. The available anti-influenza drugs are still restricted and there is an increasing viral resistance to these compounds, thus highlighting the need for research and development of new antiviral drugs. In this work, two semisynthetic derivatives of digitoxigenin, namely C10 (3β-((N-(2-hydroxyethyl)aminoacetyl)amino-3-deoxydigitoxigenin) and C11 (3β-(hydroxyacetyl)amino-3-deoxydigitoxigenin), showed anti-influenza A virus activity by affecting the expression of viral proteins at the early and late stages of replication cycle, and altering the transcription and synthesis of new viral proteins, thereby inhibiting the formation of new virions. Such antiviral action occurred due to the interference in the assembly of viral polymerase, resulting in an impaired polymerase activity and, therefore, reducing viral replication. Confirming the in vitro results, a clinically relevant ex vivo model of influenza virus infection of human tumor-free lung tissues corroborated the potential of these compounds, especially C10, to completely abrogate influenza A virus replication at the highest concentration tested (2.0 µM). Taken together, these promising results demonstrated that C10 and C11 can be considered as potential new anti-influenza drug candidates.

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Structure and Function of Influenza Virus Ribonucleoprotein

Cited by 35 publications

References 99 publications

Inter-Versus Intra-Host Sequence Diversity of pH1N1 and Associated Clinical Outcomes

Inter-Versus Intra-Host Sequence Diversity of pH1N1 and Associated Clinical Outcomes

Structure and Function of the Influenza Virus Transcription and Replication Machinery

Semisynthetic Cardenolides Acting as Antiviral Inhibitors of Influenza A Virus Replication by Preventing Polymerase Complex Formation

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