Viral Modeling and Simulation
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Influenza Viruses and mRNA Splicing: Doing More with Less

During their nuclear replication stage, influenza viruses hijack the host splicing machinery to process some of their RNA segments, the M and NS segments. In this review, we provide an overview of the current knowledge gathered on this interplay between influenza viruses and the cellular spliceosome, with a particular focus on influenza A viruses (IAV). These viruses have developed accurate regulation mechanisms to reassign the host spliceosome to alter host cellular expression and enable an optimal expression of specific spliced viral products throughout infection. Moreover, IAV segments undergoing splicing display high levels of similarity with human consensus splice sites and their viral transcripts show noteworthy secondary structures. Sequence alignments and consensus analyses, along with recently published studies, suggest both conservation and evolution of viral splice site sequences and structure for improved adaptation to the host. Altogether, these results emphasize the ability of IAV to be well adapted to the host’s splicing machinery, and further investigations may contribute to a better understanding of splicing regulation with regard to viral replication, host range, and pathogenesis

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Nice review of RNA splicing in influenza virus.

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Complete and Incomplete Genome Packaging of Influenza A and B Viruses

Complete and Incomplete Genome Packaging of Influenza A and B Viruses | Viral Modeling and Simulation | Scoop.it
The genomes of influenza A and B viruses comprise eight segmented, single-stranded, negative-sense viral RNAs (vRNAs). Although segmentation of the virus genome complicates the packaging of infectious progeny into virions, it provides an evolutionary benefit in that it allows viruses to exchange vRNAs with other strains. Influenza A viruses are believed to package their eight different vRNAs in a specific manner. However, several studies have shown that many viruses are noninfectious and fail to package at least one vRNA. Therefore, the genome-packaging mechanism is not fully understood. In this study, we used electron microscopy to count the number of ribonucleoproteins (RNPs) inside the virions of different influenza A and B virus strains. All eight strains examined displayed eight RNPs arranged in a “7+1” configuration in which a central RNP was surrounded by seven RNPs. Three-dimensional analysis of the virions showed that at least 80% of the virions packaged all eight RNPs; however, some virions packaged only five to seven RNPs, with the exact proportion depending on the strain examined. These results directly demonstrate that most viruses package eight RNPs, but some do indeed package fewer. Our findings support the selective genome-packaging model and demonstrate the variability in the number of RNPs incorporated by virions, suggesting that the genome-packaging mechanism of influenza viruses is more flexible than previously thought.


Via Ed Rybicki
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Virus Explorer | HHMI BioInteractive

Virus Explorer | HHMI BioInteractive | Viral Modeling and Simulation | Scoop.it
RT @UpbmAsso: #virus en modèles #3D: influenza, HIV, rabies, zika, papillomavirus (HPV), Ebola
https://t.co/0ax3iAlfO7 https://t.co/OD99Ym…
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Infectio: a Generic Framework for Computational Simulation of Virus Transmission between Cells

Viruses spread between cells, tissues, and organisms by cell-free and cell-cell mechanisms, depending on the cell type, the nature of the virus, or the phase of the infection cycle. The mode of viral transmission has a large impact on disease development
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Influenza virus intracellular replication dynamics, release kinetics, and particle morphology during propagation in MDCK cells

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Labeling of virus components for advanced, quantitative imaging analyses. - PubMed - NCBI

FEBS Lett. 2016 Mar 14. doi: 10.1002/1873-3468.12131. [Epub ahead of print] REVIEW
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A network model for Ebola spreading

A network model for Ebola spreading | Viral Modeling and Simulation | Scoop.it
The availability of accurate models for the spreading of infectious diseases has opened a new era in management and containment of epidemics. Models are extensively used to plan for and execute vaccination campaigns, to evaluate the risk of international spreadings and the feasibility of travel bans, and to inform prophylaxis campaigns. Even when no specific therapeutical protocol is available, as for the Ebola Virus Disease (EVD), models of epidemic spreading can provide useful insight to steer interventions in the field and to forecast the trend of the epidemic. Here, we propose a novel mathematical model to describe EVD spreading based on activity driven networks (ADNs). Our approach overcomes the simplifying assumption of homogeneous mixing, which is central to most of the mathematically tractable models of EVD spreading. In our ADN-based model, each individual is not bound to contact every other, and its network of contacts varies in time as a function of an activity potential. Our model contemplates the possibility of non-ideal and time-varying intervention policies, which are critical to accurately describe EVD spreading in afflicted countries. The model is calibrated from field data of the 2014 April-to-December spreading in Liberia. We use the model as a predictive tool, to emulate the dynamics of EVD in Liberia and offer a one-year projection, until December 2015. Our predictions agree with the current vision expressed by professionals in the field, who consider EVD in Liberia at its final stage. The model is also used to perform a what-if analysis to assess the efficacy of timely intervention policies. In particular, we show that an earlier application of the same intervention policy would have greatly reduced the number of EVD cases, the duration of the outbreak, and the infrastructures needed for the implementation of the intervention.
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Fusion-related host proteins are actively regulated by NA during influenza infection as revealed by quantitative proteomics analysis. - PubMed - NCBI

PLoS One. 2014 Aug 25;9(8):e105947. doi: 10.1371/journal.pone.0105947. eCollection 2014. Research Support, Non-U.S. Gov't
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An in-host model of HIV incorporating latent infection and viral mutation


Via Mel Melendrez-Vallard
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Minimal within-host dengue models highlight the specific roles of the immune response in primary and secondary dengue infections

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Geometry of the Gene Expression Space of Individual Cells

Geometry of the Gene Expression Space of Individual Cells | Viral Modeling and Simulation | Scoop.it
Author Summary In the past, biological experiments usually pooled together millions of cells, masking the differences between individual cells. Current technology takes a big step forward by measuring gene expression from individual cells. Interpreting this data is challenging because we need to understand how cells are arranged in a high dimensional gene expression space. Here we test recent theory that suggests that cells facing multiple tasks should be arranged in simple low dimensional po
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Alteration of Protein Levels during Influenza Virus H1N1 Infection in Host Cells: A Proteomic Survey of Host and Virus Reveals Differential Dynamics

Alteration of Protein Levels during Influenza Virus H1N1 Infection in Host Cells: A Proteomic Survey of Host and Virus Reveals Differential Dynamics | Viral Modeling and Simulation | Scoop.it
We studied the dynamics of the proteome of influenza virus A/PR/8/34 (H1N1) infected Madin-Darby canine kidney cells up to 12 hours post infection by mass spectrometry based quantitative proteomics using the approach of stable isotope labeling by amino acids in cell culture (SILAC). We identified 1311 cell proteins and, apart from the proton channel M2, all major virus proteins. Based on their abundance two groups of virus proteins could be distinguished being in line with the function of the proteins in genesis and formation of new virions. Further, the data indicate a correlation between the amount of proteins synthesized and their previously determined copy number inside the viral particle. We employed bioinformatic approaches such as functional clustering, gene ontology, and pathway (KEGG) enrichment tests to uncover co-regulated cellular protein sets, assigned the individual subsets to their biological function, and determined their interrelation within the progression of viral infection. For the first time we are able to describe dynamic changes of the cellular and, of note, the viral proteome in a time dependent manner simultaneously. Through cluster analysis, time dependent patterns of protein abundances revealed highly dynamic up- and/or down-regulation processes. Taken together our study provides strong evidence that virus infection has a major impact on the cell status at the protein level.
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Structural analysis of the roles of influenza A virus membrane-associated proteins in assembly and morphology.

IMPORTANCE Influenza A virus is a major respiratory pathogen. It assembles membrane-enveloped virus particles whose shapes vary from spherical to filamentous. Here we have studied the roles of individual viral proteins in mediating virus assembly and in determining virus shape. To do this, we used a range of electron microscopy techniques to obtain and compare 2D and 3D images of virus particles and virus-like particles during and after assembly. The virus-like particles were produced using different combinations of viral proteins. Among our results, we found that co-expression of one or both of the viral surface proteins (hemagglutinin and neuraminidase), together with the viral membrane associated proteins encoded in the M segment, results in assembly and release of filamentous virus-like particles in a manner very similar to the budding and release of influenza virions. These data provide novel insights into the roles played by individual viral proteins in influenza A virus assembly.

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Single-Molecule FISH Reveals Non-selective Packaging of Rift Valley Fever Virus Genome Segments

Author Summary The bunyavirus family is one of the largest virus families on Earth, of which several members cause severe disease in humans, animals or plants. Little is known about the mechanisms that facilitate the production of infectious bunyavirus virions, which should contain at least one copy of the small (S), medium (M) and large (L) genome segment. In this study, we investigated the genome packaging process of the Rift Valley fever virus (RVFV) by visualizing individual genome segments inside infected cells and virions. Experiments performed with wild-type virus, two- and four-segmented variants, and a variant with a codon-shuffled M segment showed that the production of infectious virions is a non-selective process and is unlikely to involve the formation of a supramolecular viral RNA complex. These observations have broad implications for understanding the bunyavirus replication cycle and may facilitate the development of new vaccines and the identification of novel antiviral targets.
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T cells bully influenza virus into submission | Virology News

Australian researchers are at the forefront of developing a vaccine which could lead to lifelong immunity against the influenza virus. | Virology News
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Dissecting Virus Infectious Cycles by Cryo-Electron Microscopy

In response to events such as receptor binding and endocytic triggers, viruses undergo large-scale, dynamic conformational changes necessary for cell entry and genome delivery. In later stages of the infectious cycle, replication machinery must read and synthesize nucleic acid strands to generate new copies of genetic material, and structural proteins must assemble and package the appropriate contents in order to produce new infectious particles. Structural elucidation of these events is key to understanding them and their inhibition by antiviral agents such as neutralizing antibodies and drugs. Electron microscopy is a versatile technique that offers the ability to resolve three-dimensional structures of individual viral proteins and whole virions in multiple functional states, even in cells at different stages of infection (Fig 1). Here we focus on the use of transmission electron microscopy of frozen-hydrated specimens, i.e., cryo-electron microscopy (cryo-EM). A major advantage of cryo-EM over other structural approaches is that samples of a broad range of sizes can be imaged under near-physiological conditions with native hydration intact. This approach does not require the specimen to be fixed, stained, or coaxed into a crystalline lattice. This versatility has enabled cryo-EM to expand the envelope of structural virology and opened new avenues for understanding the molecular and cellular processes of virus infection and pathogenesis.


Via Ed Rybicki
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Time-Resolved Imaging of Single HIV-1 Uncoating In Vitro and in Living Cells

Author Summary HIV-1 genome and key enzymes required for establishing productive infection are encased in a cone-shaped shell made of the capsid protein (CA). After being released into the cytosol of target cells, the cone-shaped core complex undergoes a series of carefully orchestrated steps, including uncoating (loss of CA). HIV-1 uncoating remains poorly understood, due in part to the lack of direct assays enabling studies of this process in living cells. Here, we introduce a novel strategy for labeling the HIV-1 capsid without genetically modifying the CA protein. We designed a novel fluorescent cyclophilin A construct that binds the capsid with an extremely high avidity and (1) efficiently incorporates into virions without compromising infectivity; (2) remains bound to cores after viral fusion; and (3) is lost from post-fusion cores along with CA. The novel imaging assay provides new insights into the kinetics and spatial distribution of HIV-1 uncoating in living cells.
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Boolean Modeling of Cellular and Molecular Pathways Involved in Influenza Infection. - PubMed - NCBI

Comput Math Methods Med. 2016;2016:7686081. doi: 10.1155/2016/7686081. Epub 2016 Feb 14.
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Modelling the role of immunity in reversion of viral antigenic sites

Modelling the role of immunity in reversion of viral antigenic sites | Viral Modeling and Simulation | Scoop.it
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Cell-to-cell infection by HIV contributes over half of virus infection. - PubMed - NCBI

Cell-to-cell infection by HIV contributes over half of virus infection. - PubMed - NCBI | Viral Modeling and Simulation | Scoop.it
Elife. 2015 Oct 6;4. doi: 10.7554/eLife.08150.
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Molecular responses to the influenza A virus in chicken trachea-derived cells

Molecular responses to the influenza A virus in chicken trachea-derived cells | Viral Modeling and Simulation | Scoop.it
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The influenza A virus infects a broad range of species and spreads easily through the respiratory tract. Because of these characteristics, the influenza A virus has caused pandemic disease in humans and livestock. To investigate the early molecular responses after influenza A virus infection in chickens, we infected tracheal epithelial cells derived from 20-day-old chick embryos with influenza A virus (H1N1). The gene expression patterns of the infected tracheal epithelial cells were analyzed via DNA microarray at different time points (0, 6, 12, 24, and 36 hr) after viral infection. Differentially expressed genes were identified at 6, 12, 24, and 36 hours post infection. A total of 1,936, 2,168, 3,670 and 2,894 genes were upregulated (≥2-fold, P < 0.05), whereas 884, 592, 1,503 and 1,925 genes were downregulated at the respective time points (≤0.5-fold, P < 0.05). When the differentially expressed genes were functionally categorized, immune-related and defense response gene ontology terms were detected in 12, 24, or 36 hours post infection. Interestingly, in the defense response, most of the gallinacin (GAL) genes were rapidly induced within 24 hr post infection. Subsequently, we predicted transcription factor binding sites within promoters of the GAL gene family, and analyzed the gene expression pattern for the common GAL gene regulatory factors to identify the viral infection-induced immune mechanism. Our results might contribute to an understanding of early host responses and regulatory mechanisms for host defense peptide induction against viral infections in chicken.

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An unbiased proteomics approach to identify human cytomegalovirus RNA-associated proteins

An unbiased proteomics approach to identify human cytomegalovirus RNA-associated proteins | Viral Modeling and Simulation | Scoop.it
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Computational assignment of cell-cycle stage from single-cell transcriptome data

Computational assignment of cell-cycle stage from single-cell transcriptome data | Viral Modeling and Simulation | Scoop.it
The transcriptome of single cells can reveal important information about cellular states and heterogeneity within populations of cells. Recently, single-cell RNA-sequencing has facilitated expression profiling of large numbers of single cells in parallel. To fully exploit these data, it is critical that suitable computational approaches are developed. One key challenge, especially pertinent when considering dividing populations of cells, is to understand the cell-cycle stage of each captured cell. Here we describe and compare five established supervised machine learning methods and a custom-built predictor for allocating cells to their cell-cycle stage on the basis of their transcriptome. In particular, we assess the impact of different normalization strategies and the usage of prior knowledge on the predictive power of the classifiers. We tested the methods on previously published datasets and found that a PCA-based approach and the custom predictor performed best. Moreover, our analysis shows that the performance depends strongly on normalization and the usage of prior knowledge. Only by leveraging prior knowledge in form of cell-cycle annotated genes and by preprocessing the data using a rank-based normalization, is it possible to robustly capture the transcriptional cell
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