title: 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.
authors.affiliation: Otto von Guericke University, Universitaetsplatz 2, 39106 Magdeburg, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Laske
authors.affiliation: Max Planck Institute for Dynamics of Complex Technical Systems, Sandtorstr. 1, 39106 Magdeburg, Germany.
authors.forename: Frank Stefan
authors.initials: FS
authors.lastname: Heldt
authors.affiliation: Max Planck Institute for Dynamics of Complex Technical Systems, Sandtorstr. 1, 39106 Magdeburg, Germany.
authors.forename: Helene
authors.initials: H
authors.lastname: Hoffmann
authors.affiliation: Otto von Guericke University, Universitaetsplatz 2, 39106 Magdeburg, Germany; Max Planck Institute for Dynamics of Complex Technical Systems, Sandtorstr. 1, 39106 Magdeburg, Germany. Electronic address: frensing@mpi-magdeburg.mpg.de.
authors.forename: Timo
authors.initials: T
authors.lastname: Frensing
authors.affiliation: Otto von Guericke University, Universitaetsplatz 2, 39106 Magdeburg, Germany; Max Planck Institute for Dynamics of Complex Technical Systems, Sandtorstr. 1, 39106 Magdeburg, Germany.
authors.forename: Udo
authors.initials: U
authors.lastname: Reichl
mesh_terms: D003673:Defective Viruses / Q000235:genetics / Q000254:growth & development*; D009980:Influenza A virus / Q000235:genetics / Q000254:growth & development*; D008962:Models, Theoretical; D012367:RNA, Viral / Q000235:genetics* / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D012367:RNA, Viral
keywords: Defective interfering particles; Influenza A virus; Interference mechanism; Mathematical model; Replication advantage