Cell culture-based production of defective interfering particles for influenza antiviral therapy

Wasik, Milena A.; Eichwald, Luca; Genzel, Yvonne; Reichl, Udo

doi:10.1007/s00253-017-8660-3

Cited by 31 publications

(38 citation statements)

References 31 publications

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“…Due to the ability of in vitro derived DIPs to interfere with replication of full virus particles and induce immune response, their potential application as antiviral and immunostimulatory agents has been studied extensively in recent years [ 12 – 14 ]. However, the biological role of DIPs emerging during in vivo infection is not clearly defined.…”

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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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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“…If we cannot guarantee that a fast-growing virus will suppress growth of a slow-growing virus, then this strategy might be risky. For example, some have suggested using defective interfering particles (DIPs) as a possible method for blocking infections [51][52][53][54][55]. DIPs cannot replicate on their own, but have a high growth rate when fully-functioning virus is present.…”

Section: Discussionmentioning

confidence: 99%

Effect of stochasticity on coinfection dynamics of respiratory viruses

2019

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Background Respiratory viral infections are a leading cause of mortality worldwide. As many as 40% of patients hospitalized with influenza-like illness are reported to be infected with more than one type of virus. However, it is not clear whether these infections are more severe than single viral infections. Mathematical models can be used to help us understand the dynamics of respiratory viral coinfections and their impact on the severity of the illness. Most models of viral infections use ordinary differential equations (ODE) that reproduce the average behavior of the infection, however, they might be inaccurate in predicting certain events because of the stochastic nature of viral replication cycle. Stochastic simulations of single virus infections have shown that there is an extinction probability that depends on the size of the initial viral inoculum and parameters that describe virus-cell interactions. Thus the coinfection dynamics predicted by the ODE might be difficult to observe in reality. Results In this work, a continuous-time Markov chain (CTMC) model is formulated to investigate probabilistic outcomes of coinfections. This CTMC model is based on our previous coinfection model, expressed in terms of a system of ordinary differential equations. Using the Gillespie method for stochastic simulation, we examine whether stochastic effects early in the infection can alter which virus dominates the infection. Conclusions We derive extinction probabilities for each virus individually as well as for the infection as a whole. We find that unlike the prediction of the ODE model, for similar initial growth rates stochasticity allows for a slower growing virus to out-compete a faster growing virus. Electronic supplementary material The online version of this article (10.1186/s12859-019-2793-6) contains supplementary material, which is available to authorized users.

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“…It has previously been reported that 244 DI (UUG) virus, which is obtained as a mixture of WT and 244 DI (UUG) viruses after UV-irradiation, can inhibit WT virus propagation. 20 To investigate whether the purely clonal 244 DI (UUG) virus also suppresses WT virus replication, MDCK cells were coinfected with 244 DI (UUG) and WT viruses and the virus titers determined at 48 hpi by plaque assay using MDCK cells. In these experiments, the MOI of WT virus was consistently set to 0.0001, whereas that of coinfected 244 DI (UUG) virus ranged from 0.001 to 1.…”

Section: Purely Clonal 244 DI (Uug) Virus Prevents Replication Of Wmentioning

confidence: 99%

Generation of a purely clonal defective interfering influenza virus

Yamagata

Muramoto

Miyamoto

et al. 2019

Microbiology and Immunology

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Defective interfering (DI) influenza viruses carry a large deletion in a gene segment that interferes with the replication of infectious virus; thus, such viruses have potential for antiviral therapy. However, because DI viruses cannot replicate autonomously without the aid of an infectious helper virus, clonal DI virus stocks that are not contaminated with helper virus have not yet been generated. To overcome this problem, we used reverse genetics to generate a clonal DI virus with a PB2 DI gene, amplified the clonal DI virus using a cell line stably expressing the PB2 protein, and confirmed its ability to interfere with infectious virus replication in vitro. Thus, our approach is suitable for obtaining purely clonal DI viruses, will contribute to the understanding of DI virus interference mechanisms and can be used to develop DI virus‐based antivirals.

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Cell culture-based production of defective interfering particles for influenza antiviral therapy

Cited by 31 publications

References 31 publications

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

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

Effect of stochasticity on coinfection dynamics of respiratory viruses

Generation of a purely clonal defective interfering influenza virus

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