Reprint of “Modeling the intracellular replication of influenza A virus in the presence of defective interfering RNAs

Abstract

Like many other viral pathogens, influenza A viruses can form defective interfering particles (DIPs). These particles carry a large internal deletion in at least one of their genome segments. Thus, their replication depends on the co-infection of cells by standard viruses (STVs), which supply the viral protein(s) encoded by the defective segment. However, DIPs also interfere with STV replication at the molecular level and, despite considerable research efforts, the mechanism of this interference remains largely elusive. Here, we present a mechanistic mathematical model for the intracellular replication of DIPs. In this model, we account for the common hypothesis that defective interfering RNAs (DI RNAs) possess a replication advantage over full-length (FL) RNAs due to their reduced length. By this means, the model captures experimental data from yield reduction assays and from studies testing different co-infection timings. In addition, our model predicts that one important aspect of interference is the competition for viral proteins, namely the heterotrimeric viral RNA-dependent RNA polymerase (RdRp) and the viral nucleoprotein (NP), which are needed for encapsidation of naked viral RNA. Moreover, we find that there may be an optimum for both the DI RNA synthesis rate and the time point of successive co-infection of a cell by DIPs and STVs. Comparing simulations for the growth of DIPs with a deletion in different genome segments suggests that DI RNAs derived from segments which encode for the polymerase subunits are more competitive than others. Overall, our model, thus, helps to elucidate the interference mechanism of DI RNAs and provides a novel hypothesis why DI RNAs derived from the polymerase-encoding segments are more abundant in DIP preparations.

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

“…Second, since influenza viral RNA exists and replicates in the form of RNPs, DVG competes with RdRps and NPs to encapsulate its own vRNA (−) and replicate, reducing the proportion of RNPs obtained by STV vRNA (−). Third, DVG RNPs can also compete with the RNPs, structural proteins, and glycoproteins of other STV segments to package DIPs [14,46]. Theoretically, the presence of DIPs can reduce the effective amount of STVs, resulting in lower infectious virus yield.…”

Experimental and mathematical insights on the interactions between poliovirus and a defective interfering genome

“…Laske and colleagues introduce a very detailed kinetic model of the dynamic of influenza with its DIs. [ 30 ]. While similar intracellular kinetic models exist for poliovirus [ 31 ], their application for the biological scope of this paper brings an unnecessary burden from the point of view of computation and parameter estimation.…”