Defective Interfering Particles of Influenza Virus and Their Characteristics, Impacts, and Use in Vaccines and Antiviral Strategies: A Systematic Review

Wu, Min; Zhou, Entong; Sheng, Rui; Fu, Xiaoshu; Li, Jiemin; Jiang, Chunlai; Su, Weiheng

doi:10.3390/v14122773

Cited by 8 publications

(6 citation statements)

References 102 publications

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“…Influenza viral genome segments have known variation in their propensity to generate defective viral genomes. In particular, the polymerase complex genes (PB2, PB1, and PA) are known to generate most of the DelVGs in a given influenza infection (Saira, 2013; Wu, 2022). Thus, made linear mixed models for each segment, separating into strain specific models, if strain was found to be a significant predictor.…”

Section: Resultsmentioning

confidence: 99%

“…Only 1 – 30% of virions can propagate fully from cell to cell (Brooke, 2013; Brooke, 2017; Diefenbacher, 2018). While there are a variety of reasons why virions are not fully infectious—for example, SNPs or faulty protein expression—virions harboring genome segments with internal sequence deletions (Davis, 1980; Nayak, 1982; Saira, 2013) have been termed defective interfering particles (DIP) when their accumulation by de novo or exogenous means diminishes the productivity of Influenza A infections and leads to mild disease outcomes; a phenomenon termed defective interference (Dimmock, 2014; Manzoni, 2018; Vignuzi, 2019; Wu, 2022). These defective interfering particles do not produce the proteins necessary for a single DIP to complete an infection, leading to a non-propagative infection that relies on virus coinfection to disseminate (Yamagata, 2019).…”

Section: Introductionmentioning

confidence: 99%

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Influenza A defective viral genomes and non-infectious particles are increased by host PI3K inhibition via anti-cancer drug alpelisib

Agu,

José,

Ram

et al. 2024

Preprint

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RNA viruses produce abundant defective viral genomes during replication, setting the stage for interactions between viral genomes that alter the course of pathogenesis. Harnessing these interactions to develop antivirals has become a recent goal of intense research focus. Despite decades of research, the mechanisms that regulate the production and interactions of Influenza A defective viral genomes are still unclear. The role of the host is essentially unexplored; specifically, it remains unknown whether host metabolism can influence the formation of defective viral genomes and the particles that house them. To address this question, we manipulated host cell anabolic signaling activity and monitored the production of defective viral genomes and particles by A/H1N1 and A/H3N2 strains, using a combination of single-cell immunofluorescence quantification, third-generation long-read sequencing, and the cluster-forming assay, a method we developed to titer defective and fully-infectious particles simultaneously. Here we show that alpelisib (Piqray), a highly selective inhibitor of mammalian Class 1a phosphoinositide-3 kinase (PI3K) receptors, significantly changed the proportion of defective particles and viral genomes (specifically deletion-containing viral genomes) in a strain-specific manner, under conditions that minimize multiple cycles of replication. Alpelisib pre-treatment of cells led to an increase in defective particles in the A/H3N2 strain, while the A/H1N1 strain showed a decrease in total viral particles. In the same infections, we found that defective viral genomes of polymerase and antigenic segments increased in the A/H1N1 strain, while the total particles decreased suggesting defective interference. We also found that the average deletion size in polymerase complex viral genomes increased in both the A/H3N2 and A/H1N1 strains. The A/H1N1 strain, additionally showed a dose-dependent increase in total number of defective viral genomes. In sum, we provide evidence that host cell metabolism can increase the production of defective viral genomes and particles at an early stage of infection, shifting the makeup of the infection and potential interactions among virions. Given that Influenza A defective viral genomes can inhibit pathogenesis, our study presents a new line of investigation into metabolic states associated with less severe flu infection and the potential induction of these states with metabolic drugs.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Influenza A defective viral genomes and non-infectious particles are increased by host PI3K inhibition via anti-cancer drug alpelisib

Agu,

José,

Ram

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Studies of other virus infections such as dengue virus, Zika virus, yellow fever virus respiratory syncytial virus, and influenza A virus showed that DIP treatment of human target cells inhibited virus production via activation of cellular innate immunity, which included interferon-dependent antiviral responses. Future direction of DIP-integrating mathematical modeling should incorporate a broad spectrum of virus-host interaction processes in order to robustly quantify and predict the function which the DIPs could have in vaccines, modulation of viral disease, innate immune responses, virus persistence, and virus evolution [68,69]. Although the DIPs offer a novel approach to antiviral therapy, the efforts to translate the in vitro studies to in vivo models are still limited.…”

Section: Discussionmentioning

confidence: 99%

Exploring the Therapeutic Potential of Defective Interfering Particles in Reducing the Replication of SARS-CoV-2

Locke,

Grebennikov,

Sazonov

et al. 2024

Mathematics

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SARS-CoV-2 still presents a global threat to human health due to the continued emergence of new strains and waning immunity among vaccinated populations. Therefore, it is still relevant to investigate potential therapeutics, such as therapeutic interfering particles (TIPs). Mathematical and computational modeling are valuable tools to study viral infection dynamics for predictive analysis. Here, we expand on the previous work on SARS-CoV-2 intra-cellular replication dynamics to include defective interfering particles (DIPs) as potential therapeutic agents. We formulate a deterministic model that describes the replication of wild-type (WT) SARS-CoV-2 virus in the presence of DIPs. Sensitivity analysis of parameters to several model outputs is employed to inform us on those parameters to be carefully calibrated from experimental data. We then study the effects of co-infection on WT replication and how DIP dose perturbs the release of WT viral particles. Furthermore, we provide a stochastic formulation of the model that is compared to the deterministic one. These models could be further developed into population-level models or used to guide the development and dose of TIPs.

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“…One such option is the use of defective interfering particles (DIPs) [ 22 , 23 , 24 , 25 ]. DIPs are naturally arising viral mutants that are found in a variety of RNA viruses [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ], including influenza A viruses (IAV) [ 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ]. Conventional IAV DIPs have a large internal deletion in one of their eight viral RNA (vRNA) segments, leading to a defect in virus replication.…”

Section: Introductionmentioning

confidence: 99%

Broad-Spectrum Antiviral Activity of Influenza A Defective Interfering Particles against Respiratory Syncytial, Yellow Fever, and Zika Virus Replication In Vitro

Pelz,

Piagnani,

Marsall

et al. 2023

Viruses

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New broadly acting and readily available antiviral agents are needed to combat existing and emerging viruses. Defective interfering particles (DIPs) of influenza A virus (IAV) are regarded as promising options for the prevention and treatment of IAV infections. Interestingly, IAV DIPs also inhibit unrelated viral infections by stimulating antiviral innate immunity. Here, we tested the ability of IAV DIPs to suppress respiratory syncytial, yellow fever and Zika virus infections in vitro. In human lung (A549) cells, IAV DIP co-infection inhibited the replication and spread of all three viruses. In contrast, we observed no antiviral activity in Vero cells, which are deficient in the production of interferon (IFN), demonstrating its importance for the antiviral effect. Further, in A549 cells, we observed an enhanced type-I and type-III IFN response upon co-infection that appears to explain the antiviral potential of IAV DIPs. Finally, a lack of antiviral activity in the presence of the Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib was detected. This revealed a dependency of the antiviral activity on the JAK/signal transducers and activators of transcription (STAT) signaling pathway. Overall, this study supports the notion that IAV DIPs may be used as broad-spectrum antivirals to treat infections with a variety of IFN-sensitive viruses, particularly respiratory viruses.

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Defective Interfering Particles of Influenza Virus and Their Characteristics, Impacts, and Use in Vaccines and Antiviral Strategies: A Systematic Review

Cited by 8 publications

References 102 publications

Influenza A defective viral genomes and non-infectious particles are increased by host PI3K inhibition via anti-cancer drug alpelisib

Influenza A defective viral genomes and non-infectious particles are increased by host PI3K inhibition via anti-cancer drug alpelisib

Exploring the Therapeutic Potential of Defective Interfering Particles in Reducing the Replication of SARS-CoV-2

Broad-Spectrum Antiviral Activity of Influenza A Defective Interfering Particles against Respiratory Syncytial, Yellow Fever, and Zika Virus Replication In Vitro

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