Speaker
Description
Defective interfering particles (DIPs) are considered promising antiviral agents because they can strongly inhibit viral infections \cite{1}. OP7, an influenza virus DIP with numerous point mutations, has demonstrated greater efficacy than other DIPs in animal models \cite{2,3}. However, the impact of OP7 on human cells that induce an innate immune response (IIR) has not yet been evaluated.
In this study, we examined the coinfection of influenza A virus (IAV) and OP7 in human lung cells in vitro to evaluate the impact of the IIR and identify possible application windows for patients. Using experimental and computational methods, we studied coinfection dynamics under different infection conditions. Based on experimental data, we developed a mathematical model that describes intracellular virus replication, the IIR, and infection spread between cells.
We found that both low and high doses of OP7 significantly enhanced the IIR and reduced virus titers. The mathematical model closely described virus dynamics for all tested conditions. Model simulations predicted a therapeutic application window of up to 12 hours. Further, the model predicted that the IIR plays an important role at a low multiplicity of infection (MOI) but has a minor impact in high MOI settings. Subsequent experiments confirmed these predictions.
In summary, we developed a mathematical model that allows for a thorough analysis of IAV and OP7 coinfections and supports the development of antiviral applications.
Bibliography
@article{1,
title = {Defective {Interfering} {Influenza} {Virus} {RNAs}: {Time} {To} {Reevaluate} {Their} {Clinical} {Potential} as {Broad}-{Spectrum} {Antivirals}?},
volume = {88},
issn = {0022-538X, 1098-5514},
shorttitle = {Defective {Interfering} {Influenza} {Virus} {RNAs}},
url = {https://journals.asm.org/doi/10.1128/JVI.03193-13},
doi = {10.1128/JVI.03193-13},
abstract = {ABSTRACT
Defective interfering (DI) RNAs are highly deleted forms of the infectious genome that are made by most families of RNA viruses. DI RNAs retain replication and packaging signals, are synthesized preferentially over infectious genomes, and are packaged as DI virus particles which can be transmitted to susceptible cells. Their ability to interfere with the replication of infectious virus in cell culture and their potential as antivirals in the clinic have long been known. However, until now, no realistic formulation has been described. In this review, we consider the early evidence of antiviral activity by DI viruses and, using the example of DI influenza A virus, outline developments that have led to the production of a cloned DI RNA that is highly active in preclinical studies not only against different subtypes of influenza A virus but also against heterologous respiratory viruses. These data suggest the timeliness of reassessing the potential of DI viruses as a novel class of antivirals that may have general applicability.},
language = {en},
number = {10},
urldate = {2026-02-23},
journal = {Journal of Virology},
author = {Dimmock, Nigel J. and Easton, Andrew J.},
editor = {Goff, S. P.},
month = may,
year = {2014},
pages = {5217--5227},
}
@article{2,
title = {A {Novel} {Type} of {Influenza} {A} {Virus}-{Derived} {Defective} {Interfering} {Particle} with {Nucleotide} {Substitutions} in {Its} {Genome}},
volume = {93},
issn = {0022-538X, 1098-5514},
url = {https://journals.asm.org/doi/10.1128/JVI.01786-18},
doi = {10.1128/JVI.01786-18},
abstract = {Defective interfering particles (DIPs) typically contain a highly deleted form of the viral genome, rendering them defective in virus replication. Yet upon complementation through coinfection with fully infectious standard virus (STV), interference with the viral life cycle can be observed, leading to suppressed STV replication and the release of mainly noninfectious DIPs. Interestingly, recent research indicates that DIPs may serve as an antiviral agent. Here we report the discovery of a yet-unknown type of influenza A virus-derived DIP (termed “OP7” virus) that contains numerous point mutations instead of large deletions in its genome. Furthermore, the underlying principles that render OP7 virions interfering and apparently defective seem to differ from those of conventional DIPs. In conclusion, we believe that OP7 virus might be a promising candidate for antiviral therapy. Moreover, it exerts strong effects, both on virus replication and on the host cell response, and may have been overlooked in other IAV preparations.
,
ABSTRACT
Defective interfering particles (DIPs) replicate at the expense of coinfecting, fully infectious homologous virus. Typically, they contain a highly deleted form of the viral genome. Utilizing single-cell analysis, here we report the discovery of a yet-unknown DIP type, derived from influenza A viruses (IAVs), termed OP7 virus. Instead of deletions, the genomic viral RNA (vRNA) of segment 7 (S7) carried 37 point mutations compared to the reference sequence, affecting promoter regions, encoded proteins, and genome packaging signals. Coinfection experiments demonstrated strong interference of OP7 virus with IAV replication, manifested by a dramatic decrease in the infectivity of released virions. Moreover, an overproportional quantity of S7 in relation to other genome segments was observed, both intracellularly and in the released virus population. Concurrently, OP7 virions lacked a large fraction of other vRNA segments, which appears to constitute its defect in virus replication. OP7 virus might serve as a promising candidate for antiviral therapy. Furthermore, this novel form of DIP may also be present in other IAV preparations.
IMPORTANCE
Defective interfering particles (DIPs) typically contain a highly deleted form of the viral genome, rendering them defective in virus replication. Yet upon complementation through coinfection with fully infectious standard virus (STV), interference with the viral life cycle can be observed, leading to suppressed STV replication and the release of mainly noninfectious DIPs. Interestingly, recent research indicates that DIPs may serve as an antiviral agent. Here we report the discovery of a yet-unknown type of influenza A virus-derived DIP (termed “OP7” virus) that contains numerous point mutations instead of large deletions in its genome. Furthermore, the underlying principles that render OP7 virions interfering and apparently defective seem to differ from those of conventional DIPs. In conclusion, we believe that OP7 virus might be a promising candidate for antiviral therapy. Moreover, it exerts strong effects, both on virus replication and on the host cell response, and may have been overlooked in other IAV preparations.},
language = {en},
number = {4},
urldate = {2026-02-23},
journal = {Journal of Virology},
author = {Kupke, Sascha Young and Riedel, Dietmar and Frensing, Timo and Zmora, Pawel and Reichl, Udo},
editor = {García-Sastre, Adolfo},
month = feb,
year = {2019},
pages = {e01786--18},
}
@article{3,
title = {Broad-{Spectrum} {Antiviral} {Activity} of {Influenza} {A} {Defective} {Interfering} {Particles} against {Respiratory} {Syncytial}, {Yellow} {Fever}, and {Zika} {Virus} {Replication} {In} {Vitro}},
volume = {15},
issn = {1999-4915},
url = {https://www.mdpi.com/1999-4915/15/9/1872},
doi = {10.3390/v15091872},
abstract = {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.},
language = {en},
number = {9},
urldate = {2026-02-23},
journal = {Viruses},
author = {Pelz, Lars and Piagnani, Elena and Marsall, Patrick and Wynserski, Nancy and Hein, Marc Dominique and Marichal-Gallardo, Pavel and Kupke, Sascha Young and Reichl, Udo},
month = sep,
year = {2023},
pages = {1872},
}
