Novel OP7 Virus as an Antiviral Agent

Motivation

The influenza A virus (IAV) is an important human pathogen as IAV epidemics occur annually and lead to a substantial morbidity and mortality. Occasionally, more severe pandemics can occur as well. Previously, defective interfering particles (DIPs) were suggested as an effective prophylactic and therapeutic antiviral agent. DIPs typically harbor a large internal deletion in one of their eight IAV genomic viral RNA (vRNA) segments. As a result of their defective, interfering and antivirally acting phenotype, the administration of DIPs to mice and ferrets resulted in a protection from an otherwise lethal challenges of IAV. Therefore, they are of growing interest for clinical application in humans. Recently, we discovered a novel type of DIP, termed “OP7” virus, using single-cell analysis of IAV replication. Instead of a large internal deletion, OP7 virus contains various nucleotide substitutions in its segment 7 (S7) vRNA.

Figure 1. Genomic structure of OP7 virus. The infectious IAV particle (A) contains eight individual vRNA segments.  Conventional DIPs (B) harbour a large internal deletion (C) in one of their segments. FL, full-length; DI, defective interfering. In contrast, OP7 virions (D) show a large number of point mutations in S7 vRNA (E), affecting different functional regions. Red lines indicate nucleotide substitutions. Adapted from [4].

In vitro co-infections in animal cell cultures demonstrated strong interference of OP7 virus with replication of IAV, as shown by a dramatic reduction in the release of infectious virions. The interference was directed not only against an ordinary laboratory strain (i.e. H1N1 A/PR/8/34), but also against other relevant human IAV strains. Specifically, interference with an epidemic (H3N2 A/Hong Kong/4801/2014) and pandemic (H1N1 A/California/7/2009) strain was shown. Both strains were previously suggested by the WHO as vaccine strains until ~2016-2018. These results suggest that OP7 virions may even be utilized as universal antivirals on an annual basis (as proposed for conventional DIPs). OP7 virions were shown to also interfere with IAV propagation in human cell lines. Further, we observed an unspecific stimulation of innate immunity upon OP7 virus infection, which may even further enhance its antiviral effect. Together, OP7 virions might be a very promising candidate for antiviral therapy.

Aim of the project

First of all, we strive for a better understanding of the molecular mechanisms of the interference of OP7 virus with wild-type IAV. Moreover, we conduct research on high-yield cell culture-based production of OP7 virus. In particular, we consider process intensification strategies, and will explore options for cell line engineering. Next, we will conduct animal experiments in mice to test the produced OP7 material. Finally, we may transition our animal experiments to ferrets and macaques.

References

Dimmock and Easton
Cloned Defective Interfering Influenza RNA and a Possible Pan-Specific Treatment of Respiratory Virus Diseases
2015, Viruses 7:3768-3788
Nigel J. Dimmock, Edward W. Rainsford, Paul D. Scott, Anthony C. Marriott
Influenza Virus Protecting RNA: an Effective Prophylactic and Therapeutic Antiviral
2008, Journal of Virology. 82:8570-8578
Nigel J. Dimmock, Brian K. Dove, Paul D. Scott, Bo Meng, Irene Taylor, Linda Cheung, Bassam Hallis, Anthony C. Marriott, Miles W. Carroll, and Andrew J. Easton
Cloned Defective Interfering Influenza Virus Protects Ferrets from Pandemic 2009 Influenza A Virus and Allows Protective Immunity to Be Established
2012, PLoS One 7:e49394
Kupke, S. Y.; Riedel, D.; Frensing, T.; Zmora, P.; Reichl, U.: A Novel Type of Influenza A Virus-Derived Defective Interfering Particle with Nucleotide Substitutions in Its Genome. Journal of Virology 93 (4), 01786-18 (2019)
Heldt, F. S.; Kupke, S. Y.; Dorl, S.; Frensing, T.; Reichl, U.: Single-cell analysis and stochastic modelling unveil large cell-to-cell variability in influenza A virus infection. Nature Communications 6, 8938 (2015)
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