Abstract
BackgroundViruses can fall prey to their defective interfering (DI) particles. When viruses are cultured by serial passage on susceptible host cells, the presence of virus-like DI particles can cause virus populations to rise and fall, reflecting predator-prey interactions between DI and virus particles. The levels of virus and DI particles in each population passage can be determined experimentally by plaque and yield-reduction assays, respectively.ResultsTo better understand DI and virus particle interactions we measured vesicular stomatitis virus and DI particle production during serial-passage culture on BHK cells. When the multiplicity of infection (MOI, or ratio of infectious virus particles to cells) was fixed, virus yields followed a pattern of progressive decline, with higher MOI driving earlier and faster drops in virus level. These patterns of virus decline were consistent with predictions from a mathematical model based on single-passage behavior of cells co-infected with virus and DI particles. By contrast, the production of virus during fixed-volume passages exhibited irregular fluctuations that could not be described by either the steady-state or regular oscillatory dynamics of the model. However, these irregularities were, to a significant degree, reproduced when measured host-cell levels were incorporated into the model, revealing a high sensitivity of virus and DI particle populations to fluctuations in available cell resources.ConclusionsThis study shows how the development of mathematical models, when guided by quantitative experiments, can provide new insight into the dynamic behavior of virus populations.
Highlights
Viruses can fall prey to their defective interfering (DI) particles
Fixed-volume versus fixed-multiplicity of infection (MOI) passaging Over the course of 13 fixed-volume passages levels of virus production from cell monolayers dropped more than 10-fold, and passage-to-passage titers of virus fluctuated up to 100-fold (Fig. 1a), producing drops and recoveries in virus yield that are indicative of infections containing mixtures of virus and its defective interfering particles [5,32]
When passages were performed with fixed MOI, rather than fixed volume, more regular and rapid declines in virus productivity occurred at higher MOI passages (Fig. 1b), providing evidence that DI particles accumulate in populations more rapidly during passage at high MOI
Summary
Viruses can fall prey to their defective interfering (DI) particles. When viruses are cultured by serial passage on susceptible host cells, the presence of virus-like DI particles can cause virus populations to rise and fall, reflecting predator-prey interactions between DI and virus particles. The use of site-specific mutagenesis or reverse genetics to precisely create desired genomic defects, or introduce new functions, opens applications for DI particles as vaccines or prophylactics [10,11] Their ability to activate innate immunity can alter the susceptibility of host cells to infection by standard virus [12,13]. Mixtures of different DI particles can complement their own defects and thereby productively infect cells in the absence of standard virus [14,15,16] This example provides an intriguing mechanism for viral infections to spread and persist in the absence of a single agent that can be isolated and cultured. The ability of DI particles to adapt their degree of interference in response to mutation and selection of their co-infecting virus [18] may provide insights for the design of anti-viral strategies that resist escape [19,20]
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