The secrets of “OP7”, an influenza DIP: mathematical model, impact of mutations and antiviral mechanisms

DanielRüdiger

Max Planck Institute Magdeburg

"The secrets of “OP7”, an influenza DIP: mathematical model, impact of mutations and antiviral mechanisms"

Defective interfering particles (DIPs) are mutated, replication-incompetent virions that can inhibit their corresponding standard virus (STV). Previous studies have shown the effectiveness of DIPs against various virus species, highlighting them as promising broad-spectrum antivirals. OP7, an influenza DIP with 37 nucleotide substitutions in its segment 7 (S7) vRNA, has been found to suppress STV replication more effectively than conventional DIPs. However, the effects of these mutations on the replication of OP7 and its mechanism of interference with the STV remained unclear. In this study, we investigated the infection dynamics during a coinfection of influenza STV and OP7 in cell culture. We monitored the dynamics of viral RNAs, assessed viral protein levels, and determined virus titers. With these experimental results, we developed a mathematical model to simulate the coinfection of STV and OP7. Subsequently, we used this model to explore various hypotheses about the impact of mutations on virus replication and to predict the suppression of STV by OP7 in passaging experiments. In vitro experiments show that S7-OP7 surpasses the levels of all STV genome segments. Model simulations suggest this is induced by a significantly increased rate of replication, attributed to mutations in S7-OP7 inducing a “superpromoter”. Additionally, simulations predicted a notable reduction in viral mRNA transcription for S7-OP7, which was later validated experimentally. Moreover, we deduce that the M1 protein derived from S7-OP7 mRNA is likely defective. Lastly, the model accurately predicts the spread of OP7 and the suppression of STV in infected cell cultures over multiple passages under various initial conditions. In summary, we developed a mathematical model that enables a thorough examination of STV and OP7 coinfection, improves our understanding of DIP interference mechanisms, and supports the development of antiviral therapies.
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