Defective interfering type A equine influenza virus (H3N8) protects mice from morbidity and mortality caused by homologous and heterologous subtypes of influenza A virus

Noble, Simon; Dimmock, Nigel J.

doi:10.1099/0022-1317-75-12-3485

Cited by 18 publications

(22 citation statements)

References 24 publications

(21 reference statements)

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“…Subsequent virions that carry such an incomplete genome are known as defective interfering (DI) viruses. It has been demonstrated that DI influenza viruses in vivo provide protection against homologous and heterologous influenza virus infection in laboratory animals (37)(38)(39). The presence of DIs in HPAI-infected poultry could attenuate the virulence for exposed humans, possibly aided by enhanced interferon (IFN) host response (40,41).…”

Section: Discussionmentioning

confidence: 99%

Emergence of the Virulence-Associated PB2 E627K Substitution in a Fatal Human Case of Highly Pathogenic Avian Influenza Virus A(H7N7) Infection as Determined by Illumina Ultra-Deep Sequencing

Jonges

Welkers

Jeeninga

et al. 2014

J Virol

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dAvian influenza viruses are capable of crossing the species barrier and infecting humans. Although evidence of human-to-human transmission of avian influenza viruses to date is limited, evolution of variants toward more-efficient human-to-human transmission could result in a new influenza virus pandemic. In both the avian influenza A(H5N1) and the recently emerging avian influenza A(H7N9) viruses, the polymerase basic 2 protein (PB2) E627K mutation appears to be of key importance for human adaptation. During a large influenza A(H7N7) virus outbreak in the Netherlands in 2003, the A(H7N7) virus isolated from a fatal human case contained the PB2 E627K mutation as well as a hemagglutinin (HA) K416R mutation. In this study, we aimed to investigate whether these mutations occurred in the avian or the human host by Illumina Ultra-Deep sequencing of three previously uninvestigated clinical samples obtained from the fatal case. In addition, we investigated three chicken samples, two of which were obtained from the source farm. Results showed that the PB2 E627K mutation was not present in any of the chicken samples tested. Surprisingly, the avian samples were characterized by the presence of influenza virus defective RNA segments, suggestive for the synthesis of defective interfering viruses during infection in poultry. In the human samples, the PB2 E627K mutation was identified with increasing frequency during infection. Our results strongly suggest that human adaptation marker PB2 E627K has emerged during virus infection of a single human host, emphasizing the importance of reducing human exposure to avian influenza viruses to reduce the likelihood of viral adaptation to humans.

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Section: Discussionmentioning

confidence: 99%

Emergence of the Virulence-Associated PB2 E627K Substitution in a Fatal Human Case of Highly Pathogenic Avian Influenza Virus A(H7N7) Infection as Determined by Illumina Ultra-Deep Sequencing

Jonges

Welkers

Jeeninga

et al. 2014

J Virol

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“…Table 1 summarises data obtained for two noncloned DI preparations. Although the WSN-DI protection appeared to be strain-specific (failed to protect against another H1N1 strain, PR8; [58]), EQV-DI was cross-protective against WSN and PR8 challenges [57]. The standard experimental protocol used DI virus delivered simultaneously with the virus challenge.…”

Section: Segmented Rna Viruses: Influenza a Virusmentioning

confidence: 99%

Defective interfering viruses and their potential as antiviral agents

Marriott

Dimmock

2009

Reviews in Medical Virology

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118

125

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Defective interfering (DI) virus is simply defined as a spontaneously generated virus mutant from which a critical portion of the virus genome has been deleted. At least one essential gene of the virus is deleted, either in its entirety, or sufficiently to make it non-functional. The resulting DI genome is then defective for replication in the absence of the product(s) of the deleted gene(s), and its replication requires the presence of the complete functional virus genome to provide the missing functions. In addition to being defective DI virus suppresses production of the helper virus in co-infected cells, and this process of interference can readily be observed in cultured cells. In some cases, DI virus has been observed to attenuate disease in virus-infected animals. In this article, we review the properties of DI virus, potential mechanisms of interference and progress in using DI virus (in particular that derived from influenza A virus) as a novel type of antiviral agent.

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“…The following higher doses of other subtypes were required to cause disease: for A/Japan/305/57 (H2N2), 3 ϫ 10 5 50% egg infectious doses per mouse were used; and for 7a (H3N2; a reassortant between A/England/939/69 [H3N2] and A/PR8 [33]), 2.5 ϫ 10 4 50% tissue culture infective doses per mouse were used. The health of the mice was assessed by loss of weight and by previously described clinical criteria (23). Mice were weighed as a group.…”

Section: Methodsmentioning

confidence: 99%

“…Adult C3H/He-mg (H-2 k ) mice (4 to 5 weeks old; 16 to 20 g) were inoculated intranasally under light ether anesthesia as previously described (23,24) with a 40-l inoculum divided between the two nares. Helper virus infectivity can be eliminated without reducing protection by a short (20-s) burst of UV irradiation at 253.7 nm because of the difference in UV target sizes-13,600 nt for infectivity and 395 nt for the protecting RNA.…”

Section: Methodsmentioning

confidence: 99%

“…It has been known for some time that noninfectious preparations of influenza A DI viruses can protect laboratory animals from a lethal challenge with homologous or heterologous influenza A viruses (20,23,24). However, it has not been possible to experimentally elucidate the process by which noncloned DI influenza A viruses reduce the yield of infectious virus, inhibit virus-induced cytopathology, and protect animals from clinical disease (7), because most populations of DI virus contain many different defective RNA sequences derived from different genome segments and with a variety of central deletions (11,16).…”

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confidence: 99%

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Influenza Virus Protecting RNA: an Effective Prophylactic and Therapeutic Antiviral

Dimmock

Rainsford

Scott

et al. 2008

J Virol

205

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Another influenza pandemic is inevitable, and new measures to combat this and seasonal influenza are urgently needed. Here we describe a new concept in antivirals based on a defined, naturally occurring defective influenza virus RNA that has the potential to protect against any influenza A virus in any animal host. This "protecting RNA" (244 RNA) is incorporated into virions which, although noninfectious, deliver the RNA to those cells of the respiratory tract that are naturally targeted by infectious influenza virus. A 120-ng intranasal dose of this 244 protecting virus completely protected mice against a simultaneous challenge of 10 50% lethal doses with influenza A/WSN (H1N1) virus. The 244 virus also protected mice against strong challenge doses of all other subtypes tested (i.e., H2N2, H3N2, and H3N8). This prophylactic activity was maintained in the animal for at least 1 week prior to challenge. The 244 virus was 10-to 100-fold more active than previously characterized defective influenza A viruses, and the protecting activity was confirmed to reside in the 244 RNA molecule by recovering a protecting virus entirely from cloned cDNA. There was a clear therapeutic benefit when the 244 virus was administered 24 to 48 h after a lethal challenge, an effect which has not been previously observed with any defective virus. Protecting virus reduced, but did not abolish, replication of challenge virus in mouse lungs during both prophylactic and therapeutic treatments. Protecting virus is a novel antiviral, having the potential to combat human influenza virus infections, particularly when the infecting strain is not known or is resistant to antiviral drugs.

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Defective interfering type A equine influenza virus (H3N8) protects mice from morbidity and mortality caused by homologous and heterologous subtypes of influenza A virus

Cited by 18 publications

References 24 publications

Emergence of the Virulence-Associated PB2 E627K Substitution in a Fatal Human Case of Highly Pathogenic Avian Influenza Virus A(H7N7) Infection as Determined by Illumina Ultra-Deep Sequencing

Emergence of the Virulence-Associated PB2 E627K Substitution in a Fatal Human Case of Highly Pathogenic Avian Influenza Virus A(H7N7) Infection as Determined by Illumina Ultra-Deep Sequencing

Defective interfering viruses and their potential as antiviral agents

Influenza Virus Protecting RNA: an Effective Prophylactic and Therapeutic Antiviral

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