Cycles, chaos, and evolution in virus cultures: a model of defective interfering particles.

Abstract

Defective interfering particles (DIP) are spontaneous deletion mutants of viruses that replicate at the expense of the parent virus. DIP have complex effects on the growth of viruses in vitro, including the establishment of persistent infection, cyclical variation in virus titer, eradication of replicating virus, and rapid evolution of the virus. We show here that a simple mathematical model, based only on experimental observations, can explain all ofthe major effects ofDIP on the population dynamics of virus growth. The The interaction between DIP, wild-type virus, and the host cell population provides an interesting system within which a three-way game is played out. The evolutionary implications of this situation were touched on by Nee and Maynard Smith (4) and have been considered more recently by Szathmary (5, 6).We have been interested in the effects ofDIP in modulating virus growth and persistence during infections (7). In particular, it is regularly observed that successive passaging of virus in culture at high multiplicity of infection (moi) 8685The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Rapid titer determination using quantitative real-time PCR

“…One concern with PCRbased titer methods is an inability to detect defective interfering particles or other inhibitors within the vector supernate. [17][18][19] Nevertheless, titer estimation reflected the biologic titers in this assay, suggesting the contribution of defective particles and inhibitors on titer is similar in the vectors tested in this study. We have noted this to be the case with vector produced in the GP+envAM12 cell line 13 and vector generated in the gibbon ape leukemia virus-derived producer cell line PG13.…”

Error threshold in RNA quasispecies models with complementation

“…Complementation between different viral genomes by means of trans interactions between different virus genotypes has been shown to be of importance in the dynamics of viral replication and cell infection, as shown in some theoretical studies [27][28][29]. Previous modeling attempts of viral complementation, including interaction between DIPs and full viral genomes, focused in the ecological interactions [25][26][27] or population genetics [24] of the different genotypes and the host cell.…”

“…Previous modeling attempts of viral complementation, including interaction between DIPs and full viral genomes, focused in the ecological interactions [25][26][27] or population genetics [24] of the different genotypes and the host cell. The main difference between these previous analyses and this work, is that here we studied two simple quasispecies models considering complementation during the replication of master (wild-type) and mutant genomes and the effect of such trans interactions on the error-threshold.…”

“…For instance, studying the dynamics of defective interfering particles (DIPs) as an extreme case of complementation [25][26][27][28][29]. DIPs are mutant viruses that lack most of the viral genome and cannot complete the infectious cycle by themselves [30,31] (see also [32] for a review).…”

“…Later, Kirkwood et al [27] developed a differential equations model to analyze a system formed by host cells, wild-type virions and DIPs. Such a model was able to explain several dynamic behaviors found in experiments, especially the fluctuations in virus titers on successive passages.…”