scholarly journals Genetic recombination of poliovirus facilitates subversion of host barriers to infection

2018 ◽  
Author(s):  
Ashley Acevedo ◽  
Andrew Woodman ◽  
Jamie J. Arnold ◽  
Ming Te Yeh ◽  
David Evans ◽  
...  
Keyword(s):  
Virus Replication ◽  
Genetic Recombination ◽  
Rna Virus ◽  
Small Population ◽  
Viral Fitness ◽  
Primary Role ◽  
Rna Recombination ◽  
Viral Mutant ◽  
The Impact

AbstractThe contribution of RNA recombination to viral fitness and pathogenesis is poorly defined. Here, we isolate a recombination-deficient, poliovirus variant and find that, while recombination is detrimental to virus replication in tissue culture, recombination is important for pathogenesis in infected animals. Notably, recombination-defective virus exhibits severe attenuation following intravenous inoculation that is associated with a significant reduction in population size during intra-host spread. Because the impact of high mutational loads manifests most strongly at small population sizes, our data suggest that the repair of mutagenized genomes is an essential function of recombination and that this function may drive the long-term maintenance of recombination in viral species despite its associated fitness costs.Significance StatementRNA recombination is a widespread but poorly understood feature of RNA virus replication. For poliovirus, recombination is involved in the emergence of neurovirulent circulating vaccine-derived poliovirus, which has hampered global poliovirus eradication efforts. This emergence illustrates the power of recombination to drive major adaptive change; however, it remains unclear if these adaptive events represent the primary role of recombination in virus survival. Here, we identify a viral mutant with a reduced rate of recombination and find that recombination also plays a central role in the spread of virus within animal hosts. These results highlight a novel approach for improving the safety of live attenuated vaccines and further our understanding of the role of recombination in virus pathogenesis and evolution.

scholarly journals The Proteasomal Rpn11 Metalloprotease Suppresses Tombusvirus RNA Recombination and Promotes Viral Replication via Facilitating Assembly of the Viral Replicase Complex

2014 ◽  
Vol 89 (5) ◽  
pp. 2750-2763 ◽  
Author(s):  
K. Reddisiva Prasanth ◽  
Daniel Barajas ◽  
Peter D. Nagy
Keyword(s):  
Viral Replication ◽  
Genetic Recombination ◽  
Rna Virus ◽  
Viral Rna ◽  
Rna Recombination ◽  
Viral Recombination ◽  
Antiviral Responses ◽  
New Hosts

ABSTRACTRNA viruses co-opt a large number of cellular proteins that affect virus replication and, in some cases, viral genetic recombination. RNA recombination helps viruses in an evolutionary arms race with the host's antiviral responses and adaptation of viruses to new hosts. Tombusviruses and a yeast model host are used to identify cellular factors affecting RNA virus replication and RNA recombination. In this study, we have examined the role of the conserved Rpn11p metalloprotease subunit of the proteasome, which couples deubiquitination and degradation of proteasome substrates, in tombusvirus replication and recombination inSaccharomyces cerevisiaeand plants. Depletion or mutations of Rpn11p lead to the rapid formation of viral RNA recombinants in combination with reduced levels of viral RNA replication in yeast orin vitrobased on cell extracts. Rpn11p interacts with the viral replication proteins and is recruited to the viral replicase complex (VRC). Analysis of the multifunctional Rpn11p has revealed that the primary role of Rpn11p is to act as a “matchmaker” that brings the viral p92polreplication protein and the DDX3-like Ded1p/RH20 DEAD box helicases into VRCs. Overexpression of Ded1p can complement the defect observed inrpn11mutant yeast by reducing TBSV recombination. This suggests that Rpn11p can suppress tombusvirus recombination via facilitating the recruitment of the cellular Ded1p helicase, which is a strong suppressor of viral recombination, into VRCs. Overall, this work demonstrates that the co-opted Rpn11p, which is involved in the assembly of the functional proteasome, also functions in the proper assembly of the tombusvirus VRCs.IMPORTANCERNA viruses evolve rapidly due to genetic changes based on mutations and RNA recombination. Viral genetic recombination helps viruses in an evolutionary arms race with the host's antiviral responses and facilitates adaptation of viruses to new hosts. Cellular factors affect viral RNA recombination, although the role of the host in virus evolution is still understudied. In this study, we used a plant RNA virus, tombusvirus, to examine the role of a cellular proteasomal protein, called Rpn11, in tombusvirus recombination in a yeast model host, in plants, andin vitro. We found that the cellular Rpn11 is subverted for tombusvirus replication and Rpn11 has a proteasome-independent function in facilitating viral replication. When the Rpn11 level is knocked down or a mutated Rpn11 is expressed, then tombusvirus RNA goes through rapid viral recombination and evolution. Taken together, the results show that the co-opted cellular Rpn11 is a critical host factor for tombusviruses by regulating viral replication and genetic recombination.

scholarly journals Formation of plant RNA virus replication complexes on membranes: role of an endoplasmic reticulum-targeted viral protein

1997 ◽  
Vol 16 (13) ◽  
pp. 4049-4059 ◽  
Author(s):  
Mary C. Schaad ◽  
Patricia E. Jensen ◽  
James C. Carrington
Keyword(s):  
Endoplasmic Reticulum ◽  
Virus Replication ◽  
Viral Protein ◽  
Rna Virus

Biophysical determinants of mutational robustness in a viral molecular fitness landscape

2017 ◽  
Author(s):  
Manasi A. Pethe ◽  
Aliza B. Rubenstein ◽  
Dmitri Zorine ◽  
Sagar D. Khare
Keyword(s):  
Fitness Landscape ◽  
Rna Virus ◽  
Fitness Landscapes ◽  
Viral Fitness ◽  
Mutational Robustness ◽  
Hcv Protease ◽  
Viral Polyprotein ◽  
Biophysical Interactions ◽  
Proteins And Peptides

Biophysical interactions between proteins and peptides are key determinants of genotype-fitness landscapes, but an understanding of how molecular structure and residue-level energetics at protein-peptide interfaces shape functional landscapes remains elusive. Combining information from yeast-based library screening, next-generation sequencing and structure-based modeling, we report comprehensive sequence-energetics-function mapping of the specificity landscape of the Hepatitis C Virus (HCV) NS3/4A protease, whose function — site-specific cleavages of the viral polyprotein — is a key determinant of viral fitness. We elucidate the cleavability of 3.2 million substrate variants by the HCV protease and find extensive clustering of cleavable and uncleavable motifs in sequence space indicating mutational robustness, and thereby providing a plausible molecular mechanism to buffer the effects of low replicative fidelity of this RNA virus. Specificity landscapes of known drug-resistant variants are similarly clustered. Our results highlight the key and constraining role of molecular-level energetics in shaping plateau-like fitness landscapes from quasispecies theory.

The Impact of Conflict Judgments between Developers and Testers in Software Development

2013 ◽  
Vol 24 (4) ◽  
pp. 26-50 ◽  
Author(s):  
Xihui Zhang ◽  
Jasbir S. Dhaliwal ◽  
Mark L. Gillenson ◽  
Thomas F. Stafford
Keyword(s):  
Job Satisfaction ◽  
Software Development ◽  
Software Quality ◽  
Theory And Practice ◽  
Primary Role ◽  
Software Development Process ◽  
Research Model ◽  
Quality Testing ◽  
The Impact

The primary role of testers is to verify and validate the software produced by developers to ensure its quality. Testing is designed to catch problems in the software and report them for correction, so it is a conflict-laden, confrontational, and judgmental process. This “audit” role of testing is inherently adversarial, ensuring the development of components of interpersonal conflict judgments between developers and testers. Prior research indicates that such conflict is likely to be negatively associated with software quality and job satisfaction, producing negative judgments about the artifact production process and about the job itself. This study addresses the question: How do judgments of conflict between developers and testers impact the software development process? The authors develop and empirically test a research model which proposes that the conflict judgment targets of both the tasks and the persons who perform them will have direct impact on both software quality and job satisfaction judgments. Results of testing this model indicate that interpersonal judgments arising from conflict, as well as judgments made by testers and developers about the conflict targets of tasks and persons negatively influence subsequent software quality and job satisfaction judgments. Implications for theory and practice are discussed.

scholarly journals Cell Cycle Perturbations Induced by Infection with the Coronavirus Infectious Bronchitis Virus and Their Effect on Virus Replication

2006 ◽  
Vol 80 (8) ◽  
pp. 4147-4156 ◽  
Author(s):  
Brian Dove ◽  
Gavin Brooks ◽  
Katrina Bicknell ◽  
Torsten Wurm ◽  
Julian A. Hiscox
Keyword(s):  
Cell Cycle ◽  
Virus Replication ◽  
Infectious Bronchitis Virus ◽  
Rna Virus ◽  
Positive Strand ◽  
Infectious Bronchitis ◽  
M Phase ◽  
Infected Cells ◽  
Positive Strand Rna ◽  
The Impact

ABSTRACT In eukaryotic cells, cell growth and division occur in a stepwise, orderly fashion described by a process known as the cell cycle. The relationship between positive-strand RNA viruses and the cell cycle and the concomitant effects on virus replication are not clearly understood. We have shown that infection of asynchronously replicating and synchronized replicating cells with the avian coronavirus infectious bronchitis virus (IBV), a positive-strand RNA virus, resulted in the accumulation of infected cells in the G2/M phase of the cell cycle. Analysis of various cell cycle-regulatory proteins and cellular morphology indicated that there was a down-regulation of cyclins D1 and D2 (G1 regulatory cyclins) and that a proportion of virus-infected cells underwent aberrant cytokinesis, in which the cells underwent nuclear, but not cytoplasmic, division. We assessed the impact of the perturbations on the cell cycle for virus-infected cells and found that IBV-infected G2/M-phase-synchronized cells exhibited increased viral protein production when released from the block when compared to cells synchronized in the G0 phase or asynchronously replicating cells. Our data suggested that IBV induces a G2/M phase arrest in infected cells to promote favorable conditions for viral replication.

scholarly journals RNA recombination in brome mosaic virus, a model plus strand RNA virus.

1998 ◽  
Vol 45 (4) ◽  
pp. 847-868 ◽  
Author(s):  
M Figlerowicz ◽  
J J Bujarski
Keyword(s):  
Mosaic Virus ◽  
Genetic Recombination ◽  
Rna Virus ◽  
Brome Mosaic Virus ◽  
Template Switching ◽  
Rna Recombination ◽  
Signal Sequences ◽  
Experimental Systems ◽  
Replicase Complex ◽  
Molecular Aspects

Studies on the molecular mechanism of genetic recombination in RNA viruses have progressed at the time when experimental systems of efficient recombination crossovers were established. The system of brome mosaic virus (BMV) represents one of the most useful and most advanced tools for investigation of the molecular aspects of the mechanism of RNA-RNA recombination events. By using engineered BMV RNA components, the occurrence of both homologous and nonhomologous crosses were demonstrated among the segments of the BMV RNA genome. Studies show that the two types of crossovers require different RNA signal sequences and that both types depend upon the participation of BMV replicase proteins. Mutations in the two BMV-encoded replicase polypeptides (proteins 1a and 2a) reveal that their different regions participate in homologous and in nonhomologous crossovers. Based on all these data, it is most likely that homologous and nonhomologous recombinant crosses do occur via two different types of template switching events (copy-choice mechanism) where viral replicase complex changes RNA templates during viral RNA replication at distinct signal sequences. In this review we discuss various aspects of the mechanism of RNA recombination in BMV and we emphasize future projections of this research.

The role of response as predictor of improved outcome in advanced pancreatic cancer (APC) patients (pts) treated with first-line Gemcitabine plus Nab-paclitaxel (GemNab).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16758-e16758
Author(s):  
Maria Bensi ◽  
Brunella Di Stefano ◽  
Cinzia Bagalà ◽  
Alexia Spring ◽  
Marta Chiaravalli ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Advanced Pancreatic Cancer ◽  
Small Population ◽  
Uncinate Process ◽  
Tumor Shrinkage ◽  
First Line ◽  
Homogeneous Population ◽  
The Impact ◽  
Improved Outcome

e16758 Background: GemNab is one of the first-line standard treatment (tx) of APC. To date, no predictive factors, both clinical and molecular, of benefit from this regimen exist. Two retrospective studies showed that early tumor shrinkage (ETS) can predict an improved outcome in APC pts receiving a first-line tx with FOLFIRINOX or GemNab. However, data regarding GemNab, limited to a small population of only 57 pts, seem to not confirm the association of ETS with a better outcome. Hence, we retrospectively analysed an homogeneous population of APC treated with first-line GemNab at our Institution, investigating the impact of several clinical factors, including response and ETS. Methods: APC pts receiving a first-line tx with GemNab were included in the analysis. The association of RECIST response and ETS with PFS and OS was evaluated. The following variables were collected: gender; age ( > vs ≤ 55 years and ≥ vs < 70 years ); baseline ECOG PS; Ca 19.9 baseline level (≥ vs < 200); anamnesis of diabetes; site of primary tumor (head/uncinate process vs body/tail); locally A vs metastatic (m) PC; synchronous vs metachronous; number of m sites (1 vs > 1); m sites (liver, peritoneum, lung, nodes); number of tx lines (1 vs > 1). Univariate and multivariate analyses for PFS and OS were performed. Results: A total of 184 APC pts receiving first-line GemNab at our Institution from February 2014 to May 2019 were included in the analysis. RR and ETS were assessed in 174 and 168 pts, respectively. RR was 30%, disease control rate (DCR) 63% and ETS was 24%. Responders had a significant better PFS (12.5 vs 5.7 months, p < 0.0001) and OS (25.1 vs 12.1 months, p < 0.0001). ETS was significantly associated with improved PFS (12.3 vs 6.2 months, p < 0.0001) and OS (24.0 vs 12.8 months, p < 0.0001). At the multivariate analysis a significant association with survival parameters was confirmed for RECIST response, but not for ETS. At the multivariate analysis, also metachronous disease and number of tx lines > 1 were independently associated with better OS. Conclusions: Despite its retrospective nature, this is one of the largest series of APC pts treated with first-line GemNab investigating the role of RECIST response and ETS in predicting outcome. On the basis of our results, RECIST response may be considered a positive prognostic factor, whereas ETS does not. In conclusion, achieving tumor shrinkage, not necessarily early, significantly delays PC progression and prolongs survival in pts treated with first-line GemNab.

scholarly journals Exosome Biogenesis and Biological Function in Response to Viral Infections

2018 ◽  
Vol 12 (1) ◽  
pp. 134-148 ◽  
Author(s):  
Brennetta J. Crenshaw ◽  
Linlin Gu ◽  
Brian Sims ◽  
Qiana L. Matthews
Keyword(s):  
Protein Trafficking ◽  
Viral Infections ◽  
Rna Virus ◽  
Cellular Protein ◽  
Molecular Characteristics ◽  
Exosome Biogenesis ◽  
Pathogen Response ◽  
Viral Hijacking ◽  
The Impact

Introduction: Exosomes are extracellular vesicles that originate as intraluminal vesicles during the process of multivescular body formation. Exosomes mediate intercellular transfer of functional proteins, lipids, and RNAs. The investigation into the formation and role of exosomes in viral infections is still being elucidated. Exosomes and several viruses share similar structural and molecular characteristics. Explanation: It has been documented that viral hijacking exploits the exosomal pathway and mimics cellular protein trafficking. Exosomes released from virus-infected cells contain a variety of viral and host cellular factors that are able to modify recipient host cell responses. Recent studies have demonstrated that exosomes are crucial components in the pathogenesis of virus infection. Exosomes also allow the host to produce effective immunity against pathogens by activating antiviral mechanisms and transporting antiviral factors between adjacent cells. Conclusion: Given the ever-growing roles and importance of exosomes in both host and pathogen response, this review will address the impact role of exosome biogenesis and composition after DNA, RNA virus, on Retrovirus infections. This review also will also address how exosomes can be used as therapeutic agents as well as a vaccine vehicles.

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