Influenza virus DI particles: Defective interfering or delightfully interesting?

Alnaji, Fadi G.; Brooke, Christopher B.

doi:10.1371/journal.ppat.1008436

Cited by 41 publications

(42 citation statements)

References 25 publications

(33 reference statements)

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“…Recent studies have correlated the abundance of DIPs within clinical samples with severity of both IAV and RSV infection, suggesting a role for DIPs in modulating viral pathogenicity (8,9). Despite being discovered over 60 years ago, the specific molecular processes that drive DIP formation, as well as the effects of DIPs on the collective behavior and pathogenicity of viral populations remain mysterious (10,11). The deletion-containing genomic RNAs carried by DIPs are commonly referred to as defective viral genomes (DVGs) (3).…”

Section: Introductionmentioning

confidence: 99%

Influenza A virus defective viral genomes are inefficiently packaged into virions relative to wild-type genomic RNAs

Alnaji

Reiser

Velthuis

et al. 2021

Preprint

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Deletion-containing viral genomes (DelVGs) are commonly produced during influenza A virus infection and have been implicated in influencing clinical infection outcomes. Despite their ubiquity, the specific molecular mechanisms that govern DelVG formation and their packaging into defective interfering particles (DIPs) remain poorly understood. Here, we utilized next-generation sequencing to analyze DelVGs that form de novo early during infection, prior to packaging. Analysis of these early DelVGs revealed that deletion formation occurs in clearly defined hotspots and is significantly associated with both direct sequence repeats and enrichment of adenosine and uridine bases. By comparing intracellular DelVGs with those packaged into extracellular virions, we discovered that DelVGs face a significant bottleneck during genome packaging relative to wild type genomic RNAs. Surprisingly, packaged DelVGs exhibited no signs of enrichment for specific deletion characteristics suggesting that all DelVGs are equally limited in packaging efficiency. Our data provide the first unbiased, high-resolution portrait of the diversity of DelVGs that are generated by the IAV replication machinery and shed light on the mechanisms that underly DelVG formation.

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Section: Introductionmentioning

confidence: 99%

Influenza A virus defective viral genomes are inefficiently packaged into virions relative to wild-type genomic RNAs

Alnaji

Reiser

Velthuis

et al. 2021

Preprint

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“…An approach that was previously suggested is the use of defective interfering (DI) particles (DIPs) as an antiviral agent (Alnaji and Brooke 2020 ; Dimmock et al 2008 ; Scott et al 2011a , b ; Smith et al 2016 ; Zhao et al 2018 ). DIPs are naturally occurring virus mutants that have been observed for most DNA and RNA viruses.…”

Section: Introductionmentioning

confidence: 99%

OP7, a novel influenza A virus defective interfering particle: production, purification, and animal experiments demonstrating antiviral potential

Hein

Kollmus

Marichal-Gallardo

et al. 2020

Appl Microbiol Biotechnol

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The novel influenza A virus (IAV) defective interfering particle “OP7” inhibits IAV replication in a co-infection and was previously suggested as a promising antiviral agent. Here, we report a batch-mode cell culture-based production process for OP7. In the present study, a seed virus containing standard virus (STV) and OP7 was used. The yield of OP7 strongly depended on the production multiplicity of infection. To inactivate infectious STV in the OP7 material, which may cause harm in a potential application, UV irradiation was used. The efficacy of OP7 in this material was preserved, as shown by an in vitro interference assay. Next, steric exclusion chromatography was used to purify and to concentrate (~ 13-fold) the UV-treated material. Finally, administration of produced OP7 material in mice did not show any toxic effects. Furthermore, all mice infected with a lethal dose of IAV survived the infection upon OP7 co-treatment. Thus, the feasibility of a production workflow for OP7 and its potential for antiviral treatment was demonstrated. Key points • OP7 efficacy strongly depended on the multiplicity of infection used for production • Purification by steric exclusion chromatography increased OP7 efficacy • OP7-treated mice were protected against a lethal infection with IAV

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“…However, the biological role of DIPs emerging during in vivo infection is not clearly defined. They might be a tolerable effect of rapid, but error-prone replication [15]. Otherwise, they might mitigate the disease enabling survival of the host thus favouring virus spread [12].…”

Section: Introductionmentioning

confidence: 99%

Low pathogenic avian influenza virus isolates with different levels of defective genome segments vary in pathogenicity and transmission efficiency

Świętoń

Tarasiuk

Śmietanka

2020

Vet Res

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Defective interfering particles (DIPs) of influenza virus are generated through incorporation of highly truncated forms of genome segments, mostly those coding polymerase complex proteins (PB2, PB1, PA). Such particles are able to replicate only in the presence of a virus with the complete genome, thus DIPs may alter the infection outcome by suppressing production of standard virus particles, but also by stimulating the immune response. In the present study we compared the clinical outcome, mortality and transmission in chickens and turkeys infected with the same infectious doses of H7N7 low pathogenic avian influenza virus containing different levels of defective gene segments (95/95(DVG-high) and 95/95(DVG-low)). No clinical signs, mortality or transmission were noted in SPF chickens inoculated with neither virus stock. Turkeys infected with 95/95(DVG-high) showed only slight clinical signs with no mortality, and the virus was transmitted only to birds in direct contact. In contrast, more severe disease, mortality and transmission to direct and indirect contact birds was observed in turkeys infected with 95/95(DVG-low). Apathy, lower water and food intake, respiratory system disorders and a total mortality of 60% were noted. Shedding patterns in contact turkeys indicated more efficient within-and between-host spread of the virus than in 95/95(DVG-high) group. Sequencing of virus genomes showed no mutations that could account for the observed differences in pathogenicity. The results suggest that the abundance of DIPs in the inoculum was the factor responsible for the mild course of infection and disrupted virus transmission.

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Influenza virus DI particles: Defective interfering or delightfully interesting?

Cited by 41 publications

References 25 publications

Influenza A virus defective viral genomes are inefficiently packaged into virions relative to wild-type genomic RNAs

Influenza A virus defective viral genomes are inefficiently packaged into virions relative to wild-type genomic RNAs

OP7, a novel influenza A virus defective interfering particle: production, purification, and animal experiments demonstrating antiviral potential

Low pathogenic avian influenza virus isolates with different levels of defective genome segments vary in pathogenicity and transmission efficiency

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