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Supra-epigenomic impact of the human JC polyomavirus

ABSTRACT: Human and animal viruses possess remarkable capabilities in hijacking host processes to facilitate viral infection. Viruses use various strategies to target antiviral response mechanisms while promoting cellular phenotypic states that benefit viral replication. Viruses that replicate and assemble in the nucleus, including human pathogenic DNA viruses, need to balance maximal use of the host DNA replication machinery while at the same time avoid damage to the nucleus before generating a large number of viruses that will support the spread of infection. We have identified a novel mechanism of virus interference with the cell nucleus that involves virus-mediated modulation of nuclear mechanical properties. One of the most widespread human viruses, the JC polyomavirus, interferes with nuclear architecture to form virus-occupied space and substantially reduces the rigidity of the infected human cell nucleus. The JC virus's impact on nuclear rigidity is mediated by the viral nonstructural protein, Agnoprotein (Agno). The Agno interference with nuclear mechanics is governed by structurally diverse mimics of host proteins that support chromatin interaction with the key chromatin regulator, heterochromatin protein 1 alpha (HP1α), and is critical for JC virus infection in vitro. The ability to control chromatin organization and thus nuclear mechanics reveals a previously unknown virus strategy of hijacking the mechanism controlling nuclear physical properties to maximize virus production within the nucleus.

ORGANISM(S): Homo sapiens

PROVIDER: GSE271609 | GEO | 2024/12/31

REPOSITORIES: GEO

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Project description:Heldt2012 - Influenza Virus Replication The model describes the life cycle of influenza A virus in a mammalian cell including the following steps: attachment of parental virions to the cell membrane, receptor-mediated endocytosis, fusion of the virus envelope with the endosomal membrane, nuclear import of vRNPs, viral transcription and replication, translation of the structural viral proteins, nuclear export of progeny vRNPs and budding of new virions. It also explicitly accounts for the stabilization of cRNA by viral polymerases and NP and the inhibition of vRNP activity by M1 protein binding. In short, the model focuses on the molecular mechanism that controls viral transcription and replication. This model is described in the article: Modeling the intracellular dynamics of influenza virus replication to understand the control of viral RNA synthesis. Heldt FS, Frensing T, Reichl U. J Virol. Abstract: Influenza viruses transcribe and replicate their negative-sense RNA genome inside the nucleus of host cells via three viral RNA species. In the course of an infection, these RNAs show distinct dynamics, suggesting that differential regulation takes place. To investigate this regulation in a systematic way, we developed a mathematical model of influenza virus infection at the level of a single mammalian cell. It accounts for key steps of the viral life cycle, from virus entry to progeny virion release, while focusing in particular on the molecular mechanisms that control viral transcription and replication. We therefore explicitly consider the nuclear export of viral genome copies (vRNPs) and a recent hypothesis proposing that replicative intermediates (cRNA) are stabilized by the viral polymerase complex and the nucleoprotein (NP). Together, both mechanisms allow the model to capture a variety of published data sets at an unprecedented level of detail. Our findings provide theoretical support for an early regulation of replication by cRNA stabilization. However, they also suggest that the matrix protein 1 (M1) controls viral RNA levels in the late phase of infection as part of its role during the nuclear export of viral genome copies. Moreover, simulations show an accumulation of viral proteins and RNA toward the end of infection, indicating that transport processes or budding limits virion release. Thus, our mathematical model provides an ideal platform for a systematic and quantitative evaluation of influenza virus replication and its complex regulation. With the current parameter set, the model reproduces an infection at a multiplicity of infection (MOI) of 10. Figure 2A of the paper is reproduced here, with parameters kDegRnp and kSynP changed to zeros. Initial conditions and parameter changes that were used to obtain specific figures in the article can be found in Table A2. The model has the correct value for kAttLo as 4.55e-04. The value of this parameter mentioned as 4.55e-02 in Table 1 of the paper is incorrect. This is checked with the author. This model is hosted on BioModels Database and identified by: MODEL1307270000 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Supra-epigenomic impact of the human JC polyomavirus

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