The polymerase complex genes contribute to the high virulence of the human H5N1 influenza virus isolate A/Vietnam/1203/04

Salomon, Rachelle; Franks, John; Govorkova, Elena A.; Ilyushina, Natalia A.; Yen, Hui-Ling; Hulse-Post, D. J.; Humberd, Jennifer; Trichet, Michel; Rehg, Jerold E.; Webby, Richard J.; Webster, Robert G.; Hoffmann, Erich

doi:10.1084/jem.20051938

Cited by 330 publications

(331 citation statements)

References 41 publications

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“…Over the last decade, reconstitution of recombinant vRNP complexes in transfected cells from co-expressed PB1, PB2 and PA polymerase subunits, NP and vRNA, followed by the analysis of reporter gene expression/activity or a direct analysis of accumulating viral RNAs by a primer extension assay, has become the method of choice for studying influenza virus polymerase activity in vivo (Deng et al, 2006;Fodor et al, 2002;Gabriel et al, 2005;Labadie et al, 2007;Mullin et al, 2004;Pleschka et al, 1996;Salomon et al, 2006;Vreede et al, 2004). However, as the RNP reconstitution assay involves only the minimal components required for viral transcription and replication, it might not reflect all of the regulatory events that occur during transcription and replication in virus-infected cells.…”

Section: Regulation Of Viral Rna Accumulation During Infection and Inmentioning

confidence: 99%

NS2/NEP protein regulates transcription and replication of the influenza virus RNA genome

Robb

Smith

Vreede

et al. 2009

Journal of General Virology

191

192

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The influenza virus RNA polymerase transcribes the negative-sense viral RNA segments (vRNA) into mRNA and replicates them via complementary RNA (cRNA) intermediates into more copies of vRNA. It is not clear how the relative amounts of the three RNA products, mRNA, cRNA and vRNA, are regulated during the viral life cycle. We found that in viral ribonucleoprotein (vRNP) reconstitution assays involving only the minimal components required for viral transcription and replication (the RNA polymerase, the nucleoprotein and a vRNA template), the relative levels of accumulation of RNA products differed from those observed in infected cells, suggesting a regulatory role for additional viral proteins. Expression of the viral NS2/NEP protein in RNP reconstitution assays affected viral RNA levels by reducing the accumulation of transcription products and increasing the accumulation of replication products to more closely resemble those found during viral infection. This effect was functionally conserved in influenza A and B viruses and was influenza-virus-type-specific, demonstrating that the NS2/NEP protein changes RNA levels by specific alteration of the viral transcription and replication machinery, rather than through an indirect effect on the host cell. Although NS2/NEP has been shown previously to play a role in the nucleocytoplasmic export of viral RNPs, deletion of the nuclear export sequence region that is required for its transport function did not affect the ability of the protein to regulate RNA levels. A role for the NS2/NEP protein in the regulation of influenza virus transcription and replication that is independent of its viral RNP export function is proposed.

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Section: Regulation Of Viral Rna Accumulation During Infection and Inmentioning

confidence: 99%

NS2/NEP protein regulates transcription and replication of the influenza virus RNA genome

Robb

Smith

Vreede

et al. 2009

Journal of General Virology

191

192

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“…The haemagglutinins of the two viral strains were found to have six amino acid differences, identical cleavage sites, and avian-like alpha-(2,3)-linked receptor specificity (68). Surprisingly, it was found that exchanging haemagglutinin and neuraminidase genes did not alter pathogenicity, but substituting CH58 polymerase genes completely attenuated VN1203 virulence and reduced viral polymerase activity (68).…”

Section: Evolution Of Virulence Properties In Influenza Virusesmentioning

confidence: 99%

“…Yet another type of high-virulence character that has been found in some of those dangerous H5N1 strains that now circulate in birds is located in viral RNA polymerase complex genes (67,68). It was shown in one study that a single amino acid substitution, from glutamic acid to lysine at position 627 of the PB2 protein (which is one of the components of the viral RNA polymerase), was enough to convert a non-lethal H5N1 influenza A virus isolated from a human to a lethal virus in mice (67).…”

Section: Evolution Of Virulence Properties In Influenza Virusesmentioning

confidence: 99%

“…Reverse genetics was applied in another study to generate H5N1 reassortants combining genes of lethal A/Vietnam/1203/04 (VN1203), a fatal human case isolate, and non-lethal A/chicken/Vietnam/C58/ 04 (CH58) and test their pathogenicity in ferrets and mice (68). The haemagglutinins of the two viral strains were found to have six amino acid differences, identical cleavage sites, and avian-like alpha-(2,3)-linked receptor specificity (68).…”

Section: Evolution Of Virulence Properties In Influenza Virusesmentioning

confidence: 99%

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Why is the world so poorly prepared for a pandemic of hypervirulent avian influenza?

Christophersen¹,

Haug

2006

Microbial Ecology in Health and Disease

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The world is now extremely poorly prepared to counter a possible pandemic of hypervirulent H5N1 influenza. Most countries are planning for nothing worse than the Spanish flu pandemic. It may be possible that this can in large measure be explained as a consequence of an epidemic of wishful thinking, which may already have infected the health authorities (and parts of the scientific community as well) in most countries in the world. However, it may also be possible that it can have happened as a consequence of too little contact between medical scientists and more general biologists (natural scientists) from disciplines such as ornithology, ecology and evolutionary biology. This may have led to a lack of proper understanding among medical scientists (and health bureaucrats) of the nature of evolutionary processes affecting influenza viruses, as regards the evolution of host species adaptation, infectivity and virulence properties, and also a lack of appreciation of the ways in which such forms of evolutionary adaptation depend on ecological boundary conditions that have radically changed, comparing the world in 2006 to the world in 1918. While the Spanish flu virus possibly might be compared to a one-headed monster, it may be possible that highly virulent varieties of H5N1 virus might better be compared to a three-headed one Á because there is evidence of at least three independent virulence factors connected with three different genes. It is highly unlikely that all of the high-virulence alleles will simultaneously mutate and disappear if and when the haemagglutinin gene changes so as to make the haemagglutinin molecule better adapted for the human-type (alpha-2,6-linked) receptor (which is a necessary prerequisite in order that a pandemic with H5N1 virus may start). It is more probable that evolutionary adaptation of the haemagglutinin of H5N1 viruses to the human-type receptor will happen without any simultaneous change in those other genetic properties that now are important for explaining the exceptionally high virulence of certain strains of avian-adapted H5N1 influenza virus. The change of the haemagglutinin molecule from avian adaptation to human adaptation must be expected to act as an additional virulence factor because it will enhance the total number of cells that can be infected (per host organism), increase the total rate of virus replication and potentiate the effects of the other virulence factors already present. The monster will then have four heads, not three, and case fatality rates must be expected to become even higher than they have been until now, perhaps reaching as high as 98 Á99% (at least in poor countries with less than optimal nutrition).

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“…101 The polymerase complex genes 102 contribute to the high virulence of the human H5N1 infl uenza virus isolate A/Vietnam/1203/04. This observation underscores the importance of novel antivirals targeting the polymerase for further development for the therapy and prophylaxis of human and avian infl uenza virus infections.…”

Section: Influenza Virus Rna Polymerase Inhibitorsmentioning

confidence: 99%

Existing Influenza Antivirals: Their Mechanisms of Action and Potential in the Face of Avian Influenza

Clercq

2007

Combating the Threat of Pandemic Influenza

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The polymerase complex genes contribute to the high virulence of the human H5N1 influenza virus isolate A/Vietnam/1203/04

Cited by 330 publications

References 41 publications

NS2/NEP protein regulates transcription and replication of the influenza virus RNA genome

NS2/NEP protein regulates transcription and replication of the influenza virus RNA genome

Why is the world so poorly prepared for a pandemic of hypervirulent avian influenza?

Existing Influenza Antivirals: Their Mechanisms of Action and Potential in the Face of Avian Influenza

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