Robust kinetics of an RNA virus: Transcription rates are set by genome levels

Timm, Collin M.; Gupta, Ankur; Yin, John

doi:10.1002/bit.25578

Cited by 14 publications

(15 citation statements)

References 28 publications

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“…Diverse viruses might evoke different dynamics of IFN expression. The k 1, related to viral replication, and k 2 , related to viral ability to initiate anti-viral signal are closely related to virus type [ 37 – 40 ]. Our analysis revealed that the increase in value of k 1 or k 2 resulted in earlier onset of the IFNβ M and IFNλ1 M ( Fig 2D and 2E ) as well as greater values of SD ( Fig 2F and 2G ), indicating that diverse virus types significantly affected variability in IFN induction among multiple cells.…”

Section: Resultsmentioning

confidence: 99%

Integrated modeling and analysis of intracellular and intercellular mechanisms in shaping the interferon response to viral infection

et al. 2017

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The interferons (IFNs) responses to viral infection are heterogeneous, while the underlying mechanisms for variability among cells are still not clear. In this study, we developed a hybrid model to systematically identify the sources of IFN induction heterogeneity. The experiment-integrated simulation demonstrated that the viral dose/type, the diversity in transcriptional factors activation and the intercellular paracrine signaling could strikingly shape the heterogeneity of IFN expression. We further determined that the IFNβ and IFNλ1 induced diverse dynamics of IFN-stimulated genes (ISGs) production. Collectively, our findings revealed the intracellular and intercellular mechanisms contributing to cell-to-cell variation in IFN induction, and further demonstrated the significant effects of IFN heterogeneity on antagonizing viruses.

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Section: Resultsmentioning

confidence: 99%

Integrated modeling and analysis of intracellular and intercellular mechanisms in shaping the interferon response to viral infection

et al. 2017

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“…Importantly, multiple infection with identical viral genomes can also alter infection outcomes. Such cooperation was documented for VSV and HIV, where rates of transcription and replication were enhanced with increasing multiplicity of infection (MOI) 23, 24 . Similarly, faster kinetics of virus production were seen at high MOI for poliovirus and IAV 19, 25 .…”

Section: Introductionmentioning

confidence: 92%

Collective interactions augment influenza A virus replication in a host-dependent manner

Phipps

Ganti

Jacobs

et al. 2019

Preprint

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22implicated the PA gene segment as a major driver of this phenotype and quantification of viral 33RNA synthesis indicated that both replication and transcription were affected. These findings 34 indicate that multiple distinct mechanisms underlie IAV reliance on multiple infection and 35 underscore the importance of virus-virus interactions in IAV infection, evolution and emergence. 36Importantly, multiple infection with identical viral genomes can also alter infection 58 outcomes. Such cooperation was documented for VSV and HIV, where rates of transcription and 59 replication were enhanced with increasing multiplicity of infection (MOI) 23,24 . Similarly, faster 60 kinetics of virus production were seen at high MOI for poliovirus and IAV 19,25 . In these instances, 61 it is thought that increased copy number of infecting viral genomes provides a kinetic benefit 62 important in the race to establish infection before innate antiviral responses take hold. Indeed, it 63 has been suggested that multiple infection may be particularly relevant for facilitating viral growth 64 under adverse conditions, such as antiviral drug treatment 3,26 . 65For IAV, an important adverse condition to consider is that of a novel host environment. 66IAVs occupy a broad host range, including multiple species of wild waterfowl, poultry, swine, 67 humans and other mammals 27,28 . Host barriers to infection typically confine a given lineage to 68 circulation in one species or a small number of related species 29,30 . Spillovers occur occasionally, 69 however, and can seed novel lineages. When a novel IAV lineage is established in humans, the 70 result is a pandemic of major public health consequence 31,32 . The likelihood of successful cross-71 species transfer of IAV is determined largely by the presence, absence, and compatibility of host 72 factors on which the virus relies to complete its life cycle, and on the viruses' ability to overcome 73 antiviral defenses in the novel host [33][34][35] . 74Our objective herein was to assess the degree to which IAV relies on the delivery of 75 multiple viral genomes to a cell to ensure production of progeny. In particular, we sought to 76 determine whether this phenotype varies with host species. We therefore examined the 77 multiplicity dependence of one human and a panel of avian-origin viruses in multiple host systems. 78Results from all virus/cell combinations tested confirm prior reports that cells multiply-infected with 79 IAV produce more viral progeny than singly-infected cells. Importantly, however, the extent to 80 which viral progeny production is concentrated within the multiply-infected fraction of a cell 81 population varies greatly with virus-host context. Two poultry-adapted H9N2 viruses (A/guinea 82 fowl/HK/WF10/99 (GFHK99) and A/quail/HK/A28945/88 (QaHK88)) exhibit an acute dependence 83 on multiple infection in mammalian systems that is greatly diminished in natural host systems. 84This strong dependence on multiple infection is not seen for the human strain, influenza 85 ...

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“…Processes that affect the latent time include primary transcription, which entails using the viral RNA polymerase associated with the entering viral genome to make viral mRNA, synthesis of viral proteins, replication of viral genomes, secondary transcription, and further viral protein synthesis. Recent measures and kinetic modeling of VSV early infection suggest that cellular resources for primary transcription and protein synthesis are not limiting (42), making these initial steps unlikely targets for interference by defective genomes. However, during secondary transcription and translation, as essential components for genome replication are synthesized, diversion of these resources to DIP genome replication, rather than viral genomic replication, reduces available levels of genomic template for production of viral mRNA and subsequent synthesis of viral proteins (6,7,37,73).…”

Section: Chosen Modelmentioning

confidence: 99%

“…Vesicular stomatitis virus (VSV), grown on diverse cell cultures, has served for more than 50 years as a model for the study of DIPs (5,39). Moreover, quantitative mathematical and computational models have been developed to describe the kinetics of VSV replication in cells (40)(41)(42), its intracellular interaction with DIPs (43,44), and its population dynamics (29).…”

mentioning

confidence: 99%

High-Throughput Single-Cell Kinetics of Virus Infections in the Presence of Defective Interfering Particles

Akpinar

Timm

Yin

2016

J Virol

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T he infection of a cell by a virus produces a mixture of viable and noninfectious progeny particles (1-3). A common class of noninfectious particles has defective genomes, often carrying deletions in essential genes that disable their ability to productively infect cells. However, in coinfections with viable or helper virus, the genomes of these defective particles compete with the viral replication machinery and packaging processes, interfering with infectious virus production in vitro (4, 5), and often reducing virulence in vivo (6, 7). These so-called defective interfering particles (DIPs) have for many decades been observed in laboratory cultures of virtually every class of DNA and RNA virus (4,8). More recently, DIPs have been isolated and characterized from patients infected with influenza virus (9), individuals infected with dengue virus (10, 11), and birds infected with West Nile virus (12). Moreover, sequencing of patient and natural isolates has contributed to a growing list of diverse viral genomes that carry deletions in essential genes or regulatory sequences, including hepatitis C virus (HCV) (13), polyomavirus BK (14), hepatitis B virus (15), human papillomavirus type 16 (16), and baculovirus (17). Notably, for hepatitis C virus, trans-complementation studies showed that defective HCV genomes could be encapsidated and released from cells as infectious virus-like particles (13)

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Robust kinetics of an RNA virus: Transcription rates are set by genome levels

Cited by 14 publications

References 28 publications

Integrated modeling and analysis of intracellular and intercellular mechanisms in shaping the interferon response to viral infection

Integrated modeling and analysis of intracellular and intercellular mechanisms in shaping the interferon response to viral infection

Collective interactions augment influenza A virus replication in a host-dependent manner

High-Throughput Single-Cell Kinetics of Virus Infections in the Presence of Defective Interfering Particles

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