Viruses

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Open AccessArticle

Characterisation of Structural Proteins from Chronic Bee Paralysis Virus (CBPV) Using Mass Spectrometry

by Aurore Chevin, Bruno Coutard, Philippe Blanchard, Anne-Sophie Dabert-Gay, Magali Ribière-Chabert and Richard Thiéry

Viruses 2015, 7(6), 3329-3344; https://doi.org/10.3390/v7062774 - 23 Jun 2015

Cited by 10 | Viewed by 8022

Abstract

Chronic bee paralysis virus (CBPV) is the etiological agent of chronic paralysis, an infectious and contagious disease in adult honeybees. CBPV is a positive single-stranded RNA virus which contains two major viral RNA fragments. RNA 1 (3674 nt) and RNA 2 (2305 nt) [...] Read more.

Chronic bee paralysis virus (CBPV) is the etiological agent of chronic paralysis, an infectious and contagious disease in adult honeybees. CBPV is a positive single-stranded RNA virus which contains two major viral RNA fragments. RNA 1 (3674 nt) and RNA 2 (2305 nt) encode three and four putative open reading frames (ORFs), respectively. RNA 1 is thought to encode the viral RNA-dependent RNA polymerase (RdRp) since the amino acid sequence derived from ORF 3 shares similarities with the RdRP of families Nodaviridae and Tombusviridae. The genomic organization of CBPV and in silico analyses have suggested that RNA 1 encodes non-structural proteins, while RNA 2 encodes structural proteins, which are probably encoded by ORFs 2 and 3. In this study, purified CBPV particles were used to characterize virion proteins by mass spectrometry. Several polypeptides corresponding to proteins encoded by ORF 2 and 3 on RNA 2 were detected. Their role in the formation of the viral capsid is discussed. Full article

(This article belongs to the Special Issue Honeybee Viruses)

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Open AccessArticle

Phylodynamics of H5N1 Highly Pathogenic Avian Influenza in Europe, 2005–2010: Potential for Molecular Surveillance of New Outbreaks

by Mohammad A. Alkhamis, Brian R. Moore and Andres M. Perez

Viruses 2015, 7(6), 3310-3328; https://doi.org/10.3390/v7062773 - 23 Jun 2015

Cited by 17 | Viewed by 6816

Abstract

Previous Bayesian phylogeographic studies of H5N1 highly pathogenic avian influenza viruses (HPAIVs) explored the origin and spread of the epidemic from China into Russia, indicating that HPAIV circulated in Russia prior to its detection there in 2005. In this study, we extend this [...] Read more.

Previous Bayesian phylogeographic studies of H5N1 highly pathogenic avian influenza viruses (HPAIVs) explored the origin and spread of the epidemic from China into Russia, indicating that HPAIV circulated in Russia prior to its detection there in 2005. In this study, we extend this research to explore the evolution and spread of HPAIV within Europe during the 2005–2010 epidemic, using all available sequences of the hemagglutinin (HA) and neuraminidase (NA) gene regions that were collected in Europe and Russia during the outbreak. We use discrete-trait phylodynamic models within a Bayesian statistical framework to explore the evolution of HPAIV. Our results indicate that the genetic diversity and effective population size of HPAIV peaked between mid-2005 and early 2006, followed by drastic decline in 2007, which coincides with the end of the epidemic in Europe. Our results also suggest that domestic birds were the most likely source of the spread of the virus from Russia into Europe. Additionally, estimates of viral dispersal routes indicate that Russia, Romania, and Germany were key epicenters of these outbreaks. Our study quantifies the dynamics of a major European HPAIV pandemic and substantiates the ability of phylodynamic models to improve molecular surveillance of novel AIVs. Full article

(This article belongs to the Section Animal Viruses)

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Open AccessArticle

Honey Bee Infecting Lake Sinai Viruses

by Katie F. Daughenbaugh, Madison Martin, Laura M. Brutscher, Ian Cavigli, Emma Garcia, Matt Lavin and Michelle L. Flenniken

Viruses 2015, 7(6), 3285-3309; https://doi.org/10.3390/v7062772 - 23 Jun 2015

Cited by 77 | Viewed by 15794

Abstract

Honey bees are critical pollinators of important agricultural crops. Recently, high annual losses of honey bee colonies have prompted further investigation of honey bee infecting viruses. To better characterize the recently discovered and very prevalent Lake Sinai virus (LSV) group, we sequenced currently [...] Read more.

Honey bees are critical pollinators of important agricultural crops. Recently, high annual losses of honey bee colonies have prompted further investigation of honey bee infecting viruses. To better characterize the recently discovered and very prevalent Lake Sinai virus (LSV) group, we sequenced currently circulating LSVs, performed phylogenetic analysis, and obtained images of LSV2. Sequence analysis resulted in extension of the LSV1 and LSV2 genomes, the first detection of LSV4 in the US, and the discovery of LSV6 and LSV7. We detected LSV1 and LSV2 in the Varroa destructor mite, and determined that a large proportion of LSV2 is found in the honey bee gut, suggesting that vector-mediated, food-associated, and/or fecal-oral routes may be important for LSV dissemination. Pathogen-specific quantitative PCR data, obtained from samples collected during a small-scale monitoring project, revealed that LSV2, LSV1, Black queen cell virus (BQCV), and Nosema ceranae were more abundant in weak colonies than strong colonies within this sample cohort. Together, these results enhance our current understanding of LSVs and illustrate the importance of future studies aimed at investigating the role of LSVs and other pathogens on honey bee health at both the individual and colony levels. Full article

(This article belongs to the Special Issue Honeybee Viruses)

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Open AccessReview

Viral Membrane Channels: Role and Function in the Virus Life Cycle

by ChingWooen Sze and Yee-Joo Tan

Viruses 2015, 7(6), 3261-3284; https://doi.org/10.3390/v7062771 - 23 Jun 2015

Cited by 27 | Viewed by 7539

Abstract

Viroporins are small, hydrophobic trans-membrane viral proteins that oligomerize to form hydrophilic pores in the host cell membranes. These proteins are crucial for the pathogenicity and replication of viruses as they aid in various stages of the viral life cycle, from genome uncoating [...] Read more.

Viroporins are small, hydrophobic trans-membrane viral proteins that oligomerize to form hydrophilic pores in the host cell membranes. These proteins are crucial for the pathogenicity and replication of viruses as they aid in various stages of the viral life cycle, from genome uncoating to viral release. In addition, the ion channel activity of viroporin causes disruption in the cellular ion homeostasis, in particular the calcium ion. Fluctuation in the calcium level triggers the activation of the host defensive programmed cell death pathways as well as the inflammasome, which in turn are being subverted for the viruses’ replication benefits. This review article summarizes recent developments in the functional investigation of viroporins from various viruses and their contributions to viral replication and virulence. Full article

(This article belongs to the Special Issue Viroporins)

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Open AccessArticle

Characterization of Equine Infectious Anemia Virus Integration in the Horse Genome

by Qiang Liu, Xue-Feng Wang, Jian Ma, Xi-Jun He, Xiao-Jun Wang and Jian-Hua Zhou

Viruses 2015, 7(6), 3241-3260; https://doi.org/10.3390/v7062769 - 19 Jun 2015

Cited by 8 | Viewed by 6782

Abstract

Human immunodeficiency virus (HIV)-1 has a unique integration profile in the human genome relative to murine and avian retroviruses. Equine infectious anemia virus (EIAV) is another well-studied lentivirus that can also be used as a promising retro-transfection vector, but its integration into its [...] Read more.

Human immunodeficiency virus (HIV)-1 has a unique integration profile in the human genome relative to murine and avian retroviruses. Equine infectious anemia virus (EIAV) is another well-studied lentivirus that can also be used as a promising retro-transfection vector, but its integration into its native host has not been characterized. In this study, we mapped 477 integration sites of the EIAV strain EIAV_FDDV13 in fetal equine dermal (FED) cells during in vitro infection. Published integration sites of EIAV and HIV-1 in the human genome were also analyzed as references. Our results demonstrated that EIAV_FDDV13 tended to integrate into genes and AT-rich regions, and it avoided integrating into transcription start sites (TSS), which is consistent with EIAV and HIV-1 integration in the human genome. Notably, the integration of EIAV_FDDV13 favored long interspersed elements (LINEs) and DNA transposons in the horse genome, whereas the integration of HIV-1 favored short interspersed elements (SINEs) in the human genome. The chromosomal environment near LINEs or DNA transposons potentially influences viral transcription and may be related to the unique EIAV latency states in equids. The data on EIAV integration in its natural host will facilitate studies on lentiviral infection and lentivirus-based therapeutic vectors. Full article

(This article belongs to the Section Animal Viruses)

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Open AccessReview

RNA Viruses and RNAi: Quasispecies Implications for Viral Escape

by John B. Presloid and Isabel S. Novella

Viruses 2015, 7(6), 3226-3240; https://doi.org/10.3390/v7062768 - 19 Jun 2015

Cited by 26 | Viewed by 6649

Abstract

Due to high mutation rates, populations of RNA viruses exist as a collection of closely related mutants known as a quasispecies. A consequence of error-prone replication is the potential for rapid adaptation of RNA viruses when a selective pressure is applied, including host [...] Read more.

Due to high mutation rates, populations of RNA viruses exist as a collection of closely related mutants known as a quasispecies. A consequence of error-prone replication is the potential for rapid adaptation of RNA viruses when a selective pressure is applied, including host immune systems and antiviral drugs. RNA interference (RNAi) acts to inhibit protein synthesis by targeting specific mRNAs for degradation and this process has been developed to target RNA viruses, exhibiting their potential as a therapeutic against infections. However, viruses containing mutations conferring resistance to RNAi were isolated in nearly all cases, underlining the problems of rapid viral evolution. Thus, while promising, the use of RNAi in treating or preventing viral diseases remains fraught with the typical complications that result from high specificity of the target, as seen in other antiviral regimens. Full article

(This article belongs to the Special Issue Gene Technology and Resistance to Viruses - Reviews)

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Open AccessReview

Exosomes and Their Role in the Life Cycle and Pathogenesis of RNA Viruses

by Harendra Singh Chahar, Xiaoyong Bao and Antonella Casola

Viruses 2015, 7(6), 3204-3225; https://doi.org/10.3390/v7062770 - 19 Jun 2015

Cited by 183 | Viewed by 20851

Abstract

Exosomes are membrane-enclosed vesicles actively released into the extracellular space, whose content reflect the physiological/pathological state of the cells they originate from. These vesicles participate in cell-to-cell communication and transfer of biologically active proteins, lipids, and RNAs. Their role in viral infections is [...] Read more.

Exosomes are membrane-enclosed vesicles actively released into the extracellular space, whose content reflect the physiological/pathological state of the cells they originate from. These vesicles participate in cell-to-cell communication and transfer of biologically active proteins, lipids, and RNAs. Their role in viral infections is just beginning to be appreciated. RNA viruses are an important class of pathogens and affect millions of people worldwide. Recent studies on Human Immunodeficiency Virus (HIV), Hepatitis C Virus (HCV), human T-cell lymphotropic virus (HTLV), and Dengue Virus (DENV) have demonstrated that exosomes released from infected cells harbor and deliver many regulatory factors including viral RNA and proteins, viral and cellular miRNA, and other host functional genetic elements to neighboring cells, helping to establish productive infections and modulating cellular responses. Exosomes can either spread or limit an infection depending on the type of pathogen and target cells, and can be exploited as candidates for development of antiviral or vaccine treatments. This review summarizes recent progress made in understanding the role of exosomes in RNA virus infections with an emphasis on their potential contribution to pathogenesis. Full article

(This article belongs to the Special Issue Viruses and Exosomes)

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Open AccessCorrection

Correction: Hollingworth, R.; Grand, R.J. Modulation of DNA Damage and Repair Pathways by Human Tumour Viruses. Viruses 2015, 7, 2542-2591

by Robert Hollingworth and Roger J. Grand

Viruses 2015, 7(6), 3201-3203; https://doi.org/10.3390/v7062767 - 19 Jun 2015

Cited by 1 | Viewed by 4339

Abstract

We have noted a number of errors in the references of this manuscript.[...] Full article

(This article belongs to the Special Issue Tumour Viruses)

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Open AccessReview

Coordinated DNA Replication by the Bacteriophage T4 Replisome

by Erin Noble, Michelle M. Spiering and Stephen J. Benkovic

Viruses 2015, 7(6), 3186-3200; https://doi.org/10.3390/v7062766 - 19 Jun 2015

Cited by 14 | Viewed by 14884

Abstract

The T4 bacteriophage encodes eight proteins, which are sufficient to carry out coordinated leading and lagging strand DNA synthesis. These purified proteins have been used to reconstitute DNA synthesis in vitro and are a well-characterized model system. Recent work on the T4 replisome [...] Read more.

The T4 bacteriophage encodes eight proteins, which are sufficient to carry out coordinated leading and lagging strand DNA synthesis. These purified proteins have been used to reconstitute DNA synthesis in vitro and are a well-characterized model system. Recent work on the T4 replisome has yielded more detailed insight into the dynamics and coordination of proteins at the replication fork. Since the leading and lagging strands are synthesized in opposite directions, coordination of DNA synthesis as well as priming and unwinding is accomplished by several protein complexes. These protein complexes serve to link catalytic activities and physically tether proteins to the replication fork. Essential to both leading and lagging strand synthesis is the formation of a holoenzyme complex composed of the polymerase and a processivity clamp. The two holoenzymes form a dimer allowing the lagging strand polymerase to be retained within the replisome after completion of each Okazaki fragment. The helicase and primase also form a complex known as the primosome, which unwinds the duplex DNA while also synthesizing primers on the lagging strand. Future studies will likely focus on defining the orientations and architecture of protein complexes at the replication fork. Full article

(This article belongs to the Special Issue Viral Replication Complexes: Structures, Functions, Applications and Inhibitors)

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Open AccessArticle

The Effect of Oral Administration of dsRNA on Viral Replication and Mortality in Bombus terrestris

by Niels Piot, Simon Snoeck, Maarten Vanlede, Guy Smagghe and Ivan Meeus

Viruses 2015, 7(6), 3172-3185; https://doi.org/10.3390/v7062765 - 18 Jun 2015

Cited by 44 | Viewed by 7955

Abstract

Israeli acute paralysis virus (IAPV), a single-stranded RNA virus, has a worldwide distribution and affects honeybees as well as other important pollinators. IAPV infection in honeybees has been successfully repressed by exploiting the RNA interference (RNAi) pathway of the insect’s innate immune response [...] Read more.

Israeli acute paralysis virus (IAPV), a single-stranded RNA virus, has a worldwide distribution and affects honeybees as well as other important pollinators. IAPV infection in honeybees has been successfully repressed by exploiting the RNA interference (RNAi) pathway of the insect’s innate immune response with virus-specific double stranded RNA (dsRNA). Here we investigated the effect of IAPV infection in the bumblebee Bombus terrestris and its tissue tropism. B. terrestris is a common pollinator of wild flowers in Europe and is used for biological pollination in agriculture. Infection experiments demonstrated a similar pathology and tissue tropism in bumblebees as reported for honeybees. The effect of oral administration of virus-specific dsRNA was examined and resulted in an effective silencing of the virus, irrespective of the length. Interestingly, we observed that non-specific dsRNA was also efficient against IAPV. However further study is needed to clarify the precise mechanism behind this effect. Finally we believe that our data are indicative of the possibility to use dsRNA for a broad range viral protection in bumblebees. Full article

(This article belongs to the Special Issue Honeybee Viruses)

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Open AccessArticle

Antiviral Potential of a Novel Compound CW-33 against Enterovirus A71 via Inhibition of Viral 2A Protease

by Ching-Ying Wang, An-Cheng Huang, Mann-Jen Hour, Su-Hua Huang, Szu-Hao Kung, Chao-Hsien Chen, I-Chieh Chen, Yuan-Shiun Chang, Jin-Cherng Lien and Cheng-Wen Lin

Viruses 2015, 7(6), 3155-3171; https://doi.org/10.3390/v7062764 - 17 Jun 2015

Cited by 16 | Viewed by 7194

Abstract

Enterovirus A71 (EV-A71) in the Picornaviridae family causes hand-foot-and-mouth disease, aseptic meningitis, severe central nervous system disease, even death. EV-A71 2A protease cleaves Type I interferon (IFN)-α/β receptor 1 (IFNAR1) to block IFN-induced Jak/STAT signaling. This study investigated anti-EV-A7l activity and synergistic mechanism(s) [...] Read more.

Enterovirus A71 (EV-A71) in the Picornaviridae family causes hand-foot-and-mouth disease, aseptic meningitis, severe central nervous system disease, even death. EV-A71 2A protease cleaves Type I interferon (IFN)-α/β receptor 1 (IFNAR1) to block IFN-induced Jak/STAT signaling. This study investigated anti-EV-A7l activity and synergistic mechanism(s) of a novel furoquinoline alkaloid compound CW-33 alone and in combination with IFN-β Anti-EV-A71 activities of CW-33 alone and in combination with IFN-β were evaluated by inhibitory assays of virus-induced apoptosis, plaque formation, and virus yield. CW-33 showed antiviral activities with an IC₅₀ of near 200 µM in EV-A71 plaque reduction and virus yield inhibition assays. While, anti-EV-A71 activities of CW-33 combined with 100 U/mL IFN-β exhibited a synergistic potency with an IC₅₀ of approximate 1 µM in plaque reduction and virus yield inhibition assays. Molecular docking revealed CW-33 binding to EV-A71 2A protease active sites, correlating with an inhibitory effect of CW33 on in vitro enzymatic activity of recombinant 2A protease IC₅₀ = 53.1 µM). Western blotting demonstrated CW-33 specifically inhibiting 2A protease-mediated cleavage of IFNAR1. CW-33 also recovered Type I IFN-induced Tyk2 and STAT1 phosphorylation as well as 2',5'-OAS upregulation in EV-A71 infected cells. The results demonstrated CW-33 inhibiting viral 2A protease activity to reduce Type I IFN antagonism of EV-A71. Therefore, CW-33 combined with a low-dose of Type I IFN could be applied in developing alternative approaches to treat EV-A71 infection. Full article

(This article belongs to the Section Viral Immunology, Vaccines, and Antivirals)

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Open AccessArticle

Evaluation of Signature Erosion in Ebola Virus Due to Genomic Drift and Its Impact on the Performance of Diagnostic Assays

by Shanmuga Sozhamannan, Mitchell Y. Holland, Adrienne T. Hall, Daniel A. Negrón, Mychal Ivancich, Jeffrey W. Koehler, Timothy D. Minogue, Catherine E. Campbell, Walter J. Berger, George W. Christopher, Bruce G. Goodwin and Michael A. Smith

Viruses 2015, 7(6), 3130-3154; https://doi.org/10.3390/v7062763 - 17 Jun 2015

Cited by 33 | Viewed by 10393

Abstract

Genome sequence analyses of the 2014 Ebola Virus (EBOV) isolates revealed a potential problem with the diagnostic assays currently in use; i.e., drifting genomic profiles of the virus may affect the sensitivity or even produce false-negative results. We evaluated signature erosion in ebolavirus [...] Read more.

Genome sequence analyses of the 2014 Ebola Virus (EBOV) isolates revealed a potential problem with the diagnostic assays currently in use; i.e., drifting genomic profiles of the virus may affect the sensitivity or even produce false-negative results. We evaluated signature erosion in ebolavirus molecular assays using an in silico approach and found frequent potential false-negative and false-positive results. We further empirically evaluated many EBOV assays, under real time PCR conditions using EBOV Kikwit (1995) and Makona (2014) RNA templates. These results revealed differences in performance between assays but were comparable between the old and new EBOV templates. Using a whole genome approach and a novel algorithm, termed BioVelocity, we identified new signatures that are unique to each of EBOV, Sudan virus (SUDV), and Reston virus (RESTV). Interestingly, many of the current assay signatures do not fall within these regions, indicating a potential drawback in the past assay design strategies. The new signatures identified in this study may be evaluated with real-time reverse transcription PCR (rRT-PCR) assay development and validation. In addition, we discuss regulatory implications and timely availability to impact a rapidly evolving outbreak using existing but perhaps less than optimal assays versus redesign these assays for addressing genomic changes. Full article

(This article belongs to the Collection Advances in Ebolavirus, Marburgvirus, and Cuevavirus Research)

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Open AccessReview

Important Role of the IL-32 Inflammatory Network in the Host Response against Viral Infection

by Yaqin Zhou and Ying Zhu

Viruses 2015, 7(6), 3116-3129; https://doi.org/10.3390/v7062762 - 16 Jun 2015

Cited by 23 | Viewed by 8004

Abstract

The pro-inflammatory cytokine interleukin (IL)-32 has gained much attention recently because of its important role in the inflammatory network. Since the discovery of IL-32 in 2005, our appreciation for its diverse roles continues to grow. Recent studies have discovered the antiviral effects induced [...] Read more.

The pro-inflammatory cytokine interleukin (IL)-32 has gained much attention recently because of its important role in the inflammatory network. Since the discovery of IL-32 in 2005, our appreciation for its diverse roles continues to grow. Recent studies have discovered the antiviral effects induced by IL-32 and its associated regulatory mechanisms. The interactions between IL-32 and various cytokines including cyclooxygenase 2 (COX-2), inducible nitric oxide synthase (iNOS), interferon (IFN)-λ1, interleukin (IL)-6, and soluble IL-6 receptor have been described. This review aims to integrate these new findings into explicit concepts and raises the intriguing possibility of IL-32 as a therapeutic target. Full article

(This article belongs to the Special Issue Gene Technology and Resistance to Viruses - Reviews)

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Open AccessReview

Overview on Sobemoviruses and a Proposal for the Creation of the Family Sobemoviridae

by Merike Sõmera, Cecilia Sarmiento and Erkki Truve

Viruses 2015, 7(6), 3076-3115; https://doi.org/10.3390/v7062761 - 15 Jun 2015

Cited by 58 | Viewed by 9953

Abstract

The genus Sobemovirus, unassigned to any family, consists of viruses with single-stranded plus-oriented single-component RNA genomes and small icosahedral particles. Currently, 14 species within the genus have been recognized by the International Committee on Taxonomy of Viruses (ICTV) but several new species are [...] Read more.

The genus Sobemovirus, unassigned to any family, consists of viruses with single-stranded plus-oriented single-component RNA genomes and small icosahedral particles. Currently, 14 species within the genus have been recognized by the International Committee on Taxonomy of Viruses (ICTV) but several new species are to be recognized in the near future. Sobemovirus genomes are compact with a conserved structure of open reading frames and with short untranslated regions. Several sobemoviruses are important pathogens. Moreover, over the last decade sobemoviruses have become important model systems to study plant virus evolution. In the current review we give an overview of the structure and expression of sobemovirus genomes, processing and functions of individual proteins, particle structure, pathology and phylogenesis of sobemoviruses as well as of satellite RNAs present together with these viruses. Based on a phylogenetic analysis we propose that a new family Sobemoviridae should be recognized including the genera Sobemovirus and Polemovirus. Finally, we outline the future perspectives and needs for the research focusing on sobemoviruses. Full article

(This article belongs to the Section Viruses of Plants, Fungi and Protozoa)

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Open AccessReview

HIV Rev Assembly on the Rev Response Element (RRE): A Structural Perspective

by Jason W. Rausch and Stuart F. J. Le Grice

Viruses 2015, 7(6), 3053-3075; https://doi.org/10.3390/v7062760 - 12 Jun 2015

Cited by 55 | Viewed by 11412

Abstract

HIV-1 Rev is an ~13 kD accessory protein expressed during the early stage of virus replication. After translation, Rev enters the nucleus and binds the Rev response element (RRE), a ~350 nucleotide, highly structured element embedded in the env gene in unspliced and [...] Read more.

HIV-1 Rev is an ~13 kD accessory protein expressed during the early stage of virus replication. After translation, Rev enters the nucleus and binds the Rev response element (RRE), a ~350 nucleotide, highly structured element embedded in the env gene in unspliced and singly spliced viral RNA transcripts. Rev-RNA assemblies subsequently recruit Crm1 and other cellular proteins to form larger complexes that are exported from the nucleus. Once in the cytoplasm, the complexes dissociate and unspliced and singly-spliced viral RNAs are packaged into nascent virions or translated into viral structural proteins and enzymes, respectively. Rev binding to the RRE is a complex process, as multiple copies of the protein assemble on the RNA in a coordinated fashion via a series of Rev-Rev and Rev-RNA interactions. Our understanding of the nature of these interactions has been greatly advanced by recent studies using X-ray crystallography, small angle X-ray scattering (SAXS) and single particle electron microscopy as well as biochemical and genetic methodologies. These advances are discussed in detail in this review, along with perspectives on development of antiviral therapies targeting the HIV-1 RRE. Full article

(This article belongs to the Special Issue Viral Replication Complexes: Structures, Functions, Applications and Inhibitors)

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Open AccessArticle

IFITMs from Mycobacteria Confer Resistance to Influenza Virus When Expressed in Human Cells

by William J. Melvin, Temet M. McMichael, Nicholas M. Chesarino, Jocelyn C. Hach and Jacob S. Yount

Viruses 2015, 7(6), 3035-3052; https://doi.org/10.3390/v7062759 - 12 Jun 2015

Cited by 19 | Viewed by 7051

Abstract

Interferon induced transmembrane proteins (IFITMs) found in vertebrates restrict infections by specific viruses. IFITM3 is known to be essential for restriction of influenza virus infections in both mice and humans. Vertebrate IFITMs are hypothesized to have derived from a horizontal gene transfer from [...] Read more.

Interferon induced transmembrane proteins (IFITMs) found in vertebrates restrict infections by specific viruses. IFITM3 is known to be essential for restriction of influenza virus infections in both mice and humans. Vertebrate IFITMs are hypothesized to have derived from a horizontal gene transfer from bacteria to a primitive unicellular eukaryote. Since bacterial IFITMs share minimal amino acid identity with human IFITM3, we hypothesized that examination of bacterial IFITMs in human cells would provide insight into the essential characteristics necessary for antiviral activity of IFITMs. We examined IFITMs from Mycobacterium avium and Mycobacterium abscessus for potential antiviral activity. Both of these IFITMs conferred a moderate level of resistance to influenza virus in human cells, identifying them as functional homologues of IFITM3. Analysis of sequence elements shared by bacterial IFITMs and IFITM3 identified two hydrophobic domains, putative S-palmitoylation sites, and conserved phenylalanine residues associated with IFITM3 interactions, which are all necessary for IFITM3 antiviral activity. We observed that, like IFITM3, bacterial IFITMs were S-palmitoylated, albeit to a lesser degree. We also demonstrated the ability of a bacterial IFITM to co-immunoprecipitate with IFITM3 suggesting formation of a complex, and also visualized strong co-localization of bacterial IFITMs with IFITM3. However, the mycobacterial IFITMs lack the endocytic-targeting motif conserved in vertebrate IFITM3. As such, these bacterial proteins, when expressed alone, had diminished colocalization with cathepsin B-positive endolysosomal compartments that are the primary site of IFITM3-dependent influenza virus restriction. Though the precise evolutionary origin of vertebrate IFITMs is not known, our results support a model whereby transfer of a bacterial IFITM gene to eukaryotic cells may have provided a selective advantage against viral infection that was refined through the course of vertebrate evolution to include more robust signals for S-palmitoylation and localization to sites of endocytic virus trafficking. Full article

(This article belongs to the Special Issue Advances in Gene Technology and Resistance to Viruses)

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Open AccessArticle

A Thermophilic Phage Endolysin Fusion to a Clostridium perfringens-Specific Cell Wall Binding Domain Creates an Anti-Clostridium Antimicrobial with Improved Thermostability

by Steven M. Swift, Bruce S. Seal, Johnna K. Garrish, Brian B. Oakley, Kelli Hiett, Hung-Yueh Yeh, Rebekah Woolsey, Kathleen M. Schegg, John Eric Line and David M. Donovan

Viruses 2015, 7(6), 3019-3034; https://doi.org/10.3390/v7062758 - 12 Jun 2015

Cited by 48 | Viewed by 9133

Abstract

Clostridium perfringens is the third leading cause of human foodborne bacterial disease and is the presumptive etiologic agent of necrotic enteritis among chickens. Treatment of poultry with antibiotics is becoming less acceptable. Endolysin enzymes are potential replacements for antibiotics. Many enzymes are added [...] Read more.

Clostridium perfringens is the third leading cause of human foodborne bacterial disease and is the presumptive etiologic agent of necrotic enteritis among chickens. Treatment of poultry with antibiotics is becoming less acceptable. Endolysin enzymes are potential replacements for antibiotics. Many enzymes are added to animal feed during production and are subjected to high-heat stress during feed processing. To produce a thermostabile endolysin for treating poultry, an E. coli codon-optimized gene was synthesized that fused the N-acetylmuramoyl-L-alanine amidase domain from the endolysin of the thermophilic bacteriophage ɸGVE2 to the cell-wall binding domain (CWB) from the endolysin of the C. perfringens-specific bacteriophage ɸCP26F. The resulting protein, PlyGVE2CpCWB, lysed C. perfringens in liquid and solid cultures. PlyGVE2CpCWB was most active at pH 8, had peak activity at 10 mM NaCl, 40% activity at 150 mM NaCl and was still 16% active at 600 mM NaCl. The protein was able to withstand temperatures up to 50° C and still lyse C. perfringens. Herein, we report the construction and characterization of a thermostable chimeric endolysin that could potentially be utilized as a feed additive to control the bacterium during poultry production. Full article

(This article belongs to the Special Issue 21st Evergreen International Phage Biology Meeting - Emerging Research)

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Open AccessReview

APOBEC3 Interference during Replication of Viral Genomes

by Luc Willems and Nicolas Albert Gillet

Viruses 2015, 7(6), 2999-3018; https://doi.org/10.3390/v7062757 - 11 Jun 2015

Cited by 30 | Viewed by 10511

Abstract

Co-evolution of viruses and their hosts has reached a fragile and dynamic equilibrium that allows viral persistence, replication and transmission. In response, infected hosts have developed strategies of defense that counteract the deleterious effects of viral infections. In particular, single-strand DNA editing by [...] Read more.

Co-evolution of viruses and their hosts has reached a fragile and dynamic equilibrium that allows viral persistence, replication and transmission. In response, infected hosts have developed strategies of defense that counteract the deleterious effects of viral infections. In particular, single-strand DNA editing by Apolipoprotein B Editing Catalytic subunits proteins 3 (APOBEC3s) is a well-conserved mechanism of mammalian innate immunity that mutates and inactivates viral genomes. In this review, we describe the mechanisms of APOBEC3 editing during viral replication, the viral strategies that prevent APOBEC3 activity and the consequences of APOBEC3 modulation on viral fitness and host genome integrity. Understanding the mechanisms involved reveals new prospects for therapeutic intervention. Full article

(This article belongs to the Special Issue Viral Replication Complexes: Structures, Functions, Applications and Inhibitors)

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Open AccessArticle

Recombinant Immunomodulating Lentogenic or Mesogenic Oncolytic Newcastle Disease Virus for Treatment of Pancreatic Adenocarcinoma

by Pascal Buijs, Stefan Van Nieuwkoop, Vincent Vaes, Ron Fouchier, Casper Van Eijck and Bernadette Van den Hoogen

Viruses 2015, 7(6), 2980-2998; https://doi.org/10.3390/v7062756 - 11 Jun 2015

Cited by 34 | Viewed by 9369

Abstract

Oncolytic Newcastle disease virus (NDV) might be a promising new therapeutic agent for the treatment of pancreatic cancer. We evaluated recombinant NDVs (rNDVs) expressing interferon (rNDV-hIFNβ-F\(_{\rm{0}}\)) or an IFN antagonistic protein (rNDV-NS1-F\(_{\rm{0}}\)), as well as rNDV with increased virulence (rNDV-F\(_{\rm{3aa}}\)) for oncolytic efficacy [...] Read more.

Oncolytic Newcastle disease virus (NDV) might be a promising new therapeutic agent for the treatment of pancreatic cancer. We evaluated recombinant NDVs (rNDVs) expressing interferon (rNDV-hIFNβ-F\(_{\rm{0}}\)) or an IFN antagonistic protein (rNDV-NS1-F\(_{\rm{0}}\)), as well as rNDV with increased virulence (rNDV-F\(_{\rm{3aa}}\)) for oncolytic efficacy in human pancreatic adenocarcinoma cells. Expression of additional proteins did not hamper virus replication or cytotoxic effects on itself. However, expression of interferon, but not NS1, resulted in loss of multicycle replication. Conversely, increasing the virulence (rNDV-F\(_{\rm{3aa}}\)) resulted in enhanced replication of the virus. Type I interferon was produced in high amounts by all tumor cells inoculated with rNDV-hIFNβ -F\(_{\rm{0}}\), while inoculation with rNDV-NS1-F\(_{\rm{0}}\) resulted in a complete block of interferon production in most cells. Inoculation of human pancreatic adenocarcinoma cells with rNDV-F\(_{\rm{3aa}}\) caused markedly more cytotoxicity compared to rNDV-F\(_{\rm{0}}\), while inoculation with rNDV-hIFNβ -F\(_{\rm{0}}\) and rNDV-NS1-F\(_{\rm{0}}\) induced cytotoxic effects comparable to those induced by the parental rNDV-F\(_{\rm{0}}\). Evaluation in vivo using mice bearing subcutaneous pancreatic cancer xenografts revealed that only intratumoral injection with rNDV-F\(_{\rm{3aa}}\) resulted in regression of tumors. We conclude that although lentogenic rNDVs harboring proteins that modulate the type I interferon pathway proteins do have an oncolytic effect, a more virulent mesogenic rNDV might be needed to improve oncolytic efficacy. Full article

(This article belongs to the Special Issue Oncolytic Viruses)

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Open AccessArticle

Lentiviral Vector Mediated Claudin1 Silencing Inhibits Epithelial to Mesenchymal Transition in Breast Cancer Cells

by Xianqi Zhao, Yanan Zou, Qingqing Gu, Guannan Zhao, Horace Gray, Lawrence M. Pfeffer and Junming Yue

Viruses 2015, 7(6), 2965-2979; https://doi.org/10.3390/v7062755 - 10 Jun 2015

Cited by 27 | Viewed by 7156

Abstract

Breast cancer has a high incidence and mortality rate worldwide. Several viral vectors including lentiviral, adenoviral and adeno-associated viral vectors have been used in gene therapy for various forms of human cancer, and have shown promising effects in controlling tumor development. Claudin1 (CLDN1) [...] Read more.

Breast cancer has a high incidence and mortality rate worldwide. Several viral vectors including lentiviral, adenoviral and adeno-associated viral vectors have been used in gene therapy for various forms of human cancer, and have shown promising effects in controlling tumor development. Claudin1 (CLDN1) is a member of the tetraspan transmembrane protein family that plays a major role in tight junctions and is associated with tumor metastasis. However, the role of CLDN1 in breast cancer is largely unexplored. In this study, we tested the therapeutic potential of silencing CLDN1 expression in two breast cancer (MDA-MB-231 and MCF7) cell lines using lentiviral vector mediated RNA interference. We found that a CLDN1 short hairpin (shRNA) construct efficiently silenced CLDN1 expression in both breast cancer cell lines, and CLDN1 knockdown resulted in reduced cell proliferation, survival, migration and invasion. Furthermore, silencing CLDN1 inhibited epithelial to mesenchymal transition (EMT) by upregulating the epithelial cell marker, E-cadherin, and downregulating mesenchymal markers, smooth muscle cell alpha-actin (SMA) and Snai2. Our data demonstrated that lentiviral vector mediated CLDN1 RNA interference has great potential in breast cancer gene therapy by inhibiting EMT and controlling tumor cell growth. Full article

(This article belongs to the Special Issue Gene Therapy with Emphasis on RNA Interference)

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Open AccessArticle

The Chikungunya Virus Capsid Protein Contains Linear B Cell Epitopes in the N- and C-Terminal Regions that are Dependent on an Intact C-Terminus for Antibody Recognition

by Lucas Y. H. Goh, Jody Hobson-Peters, Natalie A. Prow, Kelly Baker, Thisun B. H. Piyasena, Carmel T. Taylor, Ashok Rana, Marcus L. Hastie, Jeff J. Gorman and Roy A. Hall

Viruses 2015, 7(6), 2943-2964; https://doi.org/10.3390/v7062754 - 8 Jun 2015

Cited by 14 | Viewed by 9179

Abstract

Chikungunya virus (CHIKV) is an arthropod-borne agent that causes severe arthritic disease in humans and is considered a serious health threat in areas where competent mosquito vectors are prevalent. CHIKV has recently been responsible for several millions of cases of disease, involving over [...] Read more.

Chikungunya virus (CHIKV) is an arthropod-borne agent that causes severe arthritic disease in humans and is considered a serious health threat in areas where competent mosquito vectors are prevalent. CHIKV has recently been responsible for several millions of cases of disease, involving over 40 countries. The recent re-emergence of CHIKV and its potential threat to human health has stimulated interest in better understanding of the biology and pathogenesis of the virus, and requirement for improved treatment, prevention and control measures. In this study, we mapped the binding sites of a panel of eleven monoclonal antibodies (mAbs) previously generated towards the capsid protein (CP) of CHIKV. Using N- and C-terminally truncated recombinant forms of the CHIKV CP, two putative binding regions, between residues 1–35 and 140–210, were identified. Competitive binding also revealed that five of the CP-specific mAbs recognized a series of overlapping epitopes in the latter domain. We also identified a smaller, N-terminally truncated product of native CP that may represent an alternative translation product of the CHIKV 26S RNA and have potential functional significance during CHIKV replication. Our data also provides evidence that the C-terminus of CP is required for authentic antigenic structure of CP. This study shows that these anti-CP mAbs will be valuable research tools for further investigating the structure and function of the CHIKV CP. Full article

(This article belongs to the Section Animal Viruses)

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Open AccessReview

The Roles of Syncytin-Like Proteins in Ruminant Placentation

by Yuki Nakaya and Takayuki Miyazawa

Viruses 2015, 7(6), 2928-2942; https://doi.org/10.3390/v7062753 - 5 Jun 2015

Cited by 18 | Viewed by 10450

Abstract

Recent developments in genome sequencing techniques have led to the identification of huge numbers of endogenous retroviruses (ERV) in various mammals. ERVs, which occupy 8%–13% of mammalian genomes, are believed to affect mammalian evolution and biological diversity. Although the functional significance of most [...] Read more.

Recent developments in genome sequencing techniques have led to the identification of huge numbers of endogenous retroviruses (ERV) in various mammals. ERVs, which occupy 8%–13% of mammalian genomes, are believed to affect mammalian evolution and biological diversity. Although the functional significance of most ERVs remains to be elucidated, several ERVs are thought to have pivotal roles in host physiology. We and other groups recently identified ERV envelope proteins (e.g., Fematrin-1, Syncytin-Rum1, endogenous Jaagsiekte sheep retrovirus Env) that may determine the morphogenesis of the unique fused trophoblast cells, termed trinucleate cells and syncytial plaques, found in ruminant placentas; however, there are still a number of outstanding issues with regard to the role of ERVs that remain to be resolved. Here, we review what is known about how these ERVs have contributed to the development of ruminant-specific trophoblast cells. Full article

(This article belongs to the Special Issue Endogenous Viruses)

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Open AccessArticle

Activation of DNA Damage Response Pathways during Lytic Replication of KSHV

by Robert Hollingworth, George L. Skalka, Grant S. Stewart, Andrew D. Hislop, David J. Blackbourn and Roger J. Grand

Viruses 2015, 7(6), 2908-2927; https://doi.org/10.3390/v7062752 - 5 Jun 2015

Cited by 39 | Viewed by 8915

Abstract

Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of several human malignancies. Human tumour viruses such as KSHV are known to interact with the DNA damage response (DDR), the molecular pathways that recognise and repair lesions in cellular DNA. Here it is demonstrated [...] Read more.

Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of several human malignancies. Human tumour viruses such as KSHV are known to interact with the DNA damage response (DDR), the molecular pathways that recognise and repair lesions in cellular DNA. Here it is demonstrated that lytic reactivation of KSHV leads to activation of the ATM and DNA-PK DDR kinases resulting in phosphorylation of multiple downstream substrates. Inhibition of ATM results in the reduction of overall levels of viral replication while inhibition of DNA-PK increases activation of ATM and leads to earlier viral release. There is no activation of the ATR-CHK1 pathway following lytic replication and CHK1 phosphorylation is inhibited at later times during the lytic cycle. Despite evidence of double-strand breaks and phosphorylation of H2AX, 53BP1 foci are not consistently observed in cells containing lytic virus although RPA32 and MRE11 localise to sites of viral DNA synthesis. Activation of the DDR following KSHV lytic reactivation does not result in a G1 cell cycle block and cells are able to proceed to S-phase during the lytic cycle. KSHV appears then to selectively activate DDR pathways, modulate cell cycle progression and recruit DDR proteins to sites of viral replication during the lytic cycle. Full article

(This article belongs to the Special Issue Tumour Viruses)

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Open AccessArticle

Contribution of the Major ND10 Proteins PML, hDaxx and Sp100 to the Regulation of Human Cytomegalovirus Latency and Lytic Replication in the Monocytic Cell Line THP-1

by Nadine Wagenknecht, Nina Reuter, Myriam Scherer, Anna Reichel, Regina Müller and Thomas Stamminger

Viruses 2015, 7(6), 2884-2907; https://doi.org/10.3390/v7062751 - 5 Jun 2015

Cited by 60 | Viewed by 9543

Abstract

Promyelocytic leukemia nuclear bodies, also termed nuclear domain 10 (ND10), have emerged as nuclear protein accumulations mediating an intrinsic cellular defense against viral infections via chromatin-based mechanisms, however, their contribution to the control of herpesviral latency is still controversial. In this study, we [...] Read more.

Promyelocytic leukemia nuclear bodies, also termed nuclear domain 10 (ND10), have emerged as nuclear protein accumulations mediating an intrinsic cellular defense against viral infections via chromatin-based mechanisms, however, their contribution to the control of herpesviral latency is still controversial. In this study, we utilized the monocytic cell line THP-1 as an in vitro latency model for human cytomegalovirus infection (HCMV). Characterization of THP-1 cells by immunofluorescence andWestern blot analysis confirmed the expression of all major ND10 components. THP-1 cells with a stable, individual knockdown of PML, hDaxx or Sp100 were generated. Importantly, depletion of the major ND10 proteins did not prevent the terminal cellular differentiation of THP-1 monocytes. After construction of a recombinant, endotheliotropic human cytomegalovirus expressing IE2-EYFP, we investigated whether the depletion of ND10 proteins affects the onset of viral IE gene expression. While after infection of differentiated, THP-1-derived macrophages as well as during differentiation-induced reactivation from latency an increase in the number of IE-expressing cells was readily detectable in the absence of the major ND10 proteins, no effect was observed in non-differentiated monocytes. We conclude that PML, hDaxx and Sp100 primarily act as cellular restriction factors during lytic HCMV replication and during the dynamic process of reactivation but do not serve as key determinants for the establishment of HCMV latency. Full article

(This article belongs to the Section Animal Viruses)

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Open AccessReview

Protein-Protein Interactions of Viroporins in Coronaviruses and Paramyxoviruses: New Targets for Antivirals?

by Jaume Torres, Wahyu Surya, Yan Li and Ding Xiang Liu

Viruses 2015, 7(6), 2858-2883; https://doi.org/10.3390/v7062750 - 4 Jun 2015

Cited by 19 | Viewed by 9730

Abstract

Viroporins are members of a rapidly growing family of channel-forming small polypeptides found in viruses. The present review will be focused on recent structural and protein-protein interaction information involving two viroporins found in enveloped viruses that target the respiratory tract; (i) the envelope [...] Read more.

Viroporins are members of a rapidly growing family of channel-forming small polypeptides found in viruses. The present review will be focused on recent structural and protein-protein interaction information involving two viroporins found in enveloped viruses that target the respiratory tract; (i) the envelope protein in coronaviruses and (ii) the small hydrophobic protein in paramyxoviruses. Deletion of these two viroporins leads to viral attenuation in vivo, whereas data from cell culture shows involvement in the regulation of stress and inflammation. The channel activity and structure of some representative members of these viroporins have been recently characterized in some detail. In addition, searches for protein-protein interactions using yeast-two hybrid techniques have shed light on possible functional roles for their exposed cytoplasmic domains. A deeper analysis of these interactions should not only provide a more complete overview of the multiple functions of these viroporins, but also suggest novel strategies that target protein-protein interactions as much needed antivirals. These should complement current efforts to block viroporin channel activity. Full article

(This article belongs to the Special Issue Viroporins)

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Open AccessReview

The Emerging Roles of Viroporins in ER Stress Response and Autophagy Induction during Virus Infection

by To Sing Fung, Jaume Torres and Ding Xiang Liu

Viruses 2015, 7(6), 2834-2857; https://doi.org/10.3390/v7062749 - 4 Jun 2015

Cited by 49 | Viewed by 12036

Abstract

Viroporins are small hydrophobic viral proteins that oligomerize to form aqueous pores on cellular membranes. Studies in recent years have demonstrated that viroporins serve important functions during virus replication and contribute to viral pathogenicity. A number of viroporins have also been shown to [...] Read more.

Viroporins are small hydrophobic viral proteins that oligomerize to form aqueous pores on cellular membranes. Studies in recent years have demonstrated that viroporins serve important functions during virus replication and contribute to viral pathogenicity. A number of viroporins have also been shown to localize to the endoplasmic reticulum (ER) and/or its associated membranous organelles. In fact, replication of most RNA viruses is closely linked to the ER, and has been found to cause ER stress in the infected cells. On the other hand, autophagy is an evolutionarily conserved “self-eating” mechanism that is also observed in cells infected with RNA viruses. Both ER stress and autophagy are also known to modulate a wide variety of signaling pathways including pro-inflammatory and innate immune response, thereby constituting a major aspect of host-virus interactions. In this review, the potential involvement of viroporins in virus-induced ER stress and autophagy will be discussed. Full article

(This article belongs to the Special Issue Viroporins)

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Open AccessArticle

Hydrogen Peroxide Induce Human Cytomegalovirus Replication through the Activation of p38-MAPK Signaling Pathway

by Jun Xiao, Jiang Deng, Liping Lv, Qiong Kang, Ping Ma, Fan Yan, Xin Song, Bo Gao, Yanyu Zhang and Jinbo Xu

Viruses 2015, 7(6), 2816-2833; https://doi.org/10.3390/v7062748 - 4 Jun 2015

Cited by 25 | Viewed by 9605

Abstract

Human cytomegalovirus (HCMV) is a major risk factor in transplantation and AIDS patients, which induces high morbidity and mortality. These patients infected with HCMV experience an imbalance of redox homeostasis that cause accumulation of reactive oxygen species (ROS) at the cellular level. H2O2, [...] Read more.

Human cytomegalovirus (HCMV) is a major risk factor in transplantation and AIDS patients, which induces high morbidity and mortality. These patients infected with HCMV experience an imbalance of redox homeostasis that cause accumulation of reactive oxygen species (ROS) at the cellular level. H2O2, the most common reactive oxygen species, is the main byproduct of oxidative metabolism. However, the function of H2O2 on HCMV infection is not yet fully understood and the effect and mechanism of N-acetylcysteine (NAC) on H2O2-stimulated HCMV replication is unclear. We, therefore, examined the effect of NAC on H2O2-induced HCMV production in human foreskin fibroblast cells. In the present study, we found that H2O2 enhanced HCMV lytic replication through promoting major immediate early (MIE) promoter activity and immediate early (IE) gene transcription. Conversely, NAC inhibited H2O2-upregulated viral IE gene expression and viral replication. The suppressive effect of NAC on CMV in an acute CMV-infected mouse model also showed a relationship between antioxidants and viral lytic replication. Intriguingly, the enhancement of HCMV replication via supplementation with H2O2 was accompanied with the activation of the p38 mitogen-activated protein kinase pathway. Similar to NAC, the p38 inhibitor SB203580 inhibited H2O2-induced p38 phosphorylation and HCMV upregulation, while upregulation of inducible ROS was unaffected. These results directly relate HCMV replication to H2O2, suggesting that treatment with antioxidants may be an attractive preventive and therapeutic strategy for HCMV. Full article

(This article belongs to the Special Issue Viral Replication Complexes: Structures, Functions, Applications and Inhibitors)

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Open AccessReview

Dynamics of Virus-Receptor Interactions in Virus Binding, Signaling, and Endocytosis

by Steeve Boulant, Megan Stanifer and Pierre-Yves Lozach

Viruses 2015, 7(6), 2794-2815; https://doi.org/10.3390/v7062747 - 2 Jun 2015

Cited by 135 | Viewed by 21880

Abstract

During viral infection the first challenge that viruses have to overcome is gaining access to the intracellular compartment. The infection process starts when the virus contacts the surface of the host cell. A complex series of events ensues, including diffusion at the host [...] Read more.

During viral infection the first challenge that viruses have to overcome is gaining access to the intracellular compartment. The infection process starts when the virus contacts the surface of the host cell. A complex series of events ensues, including diffusion at the host cell membrane surface, binding to receptors, signaling, internalization, and delivery of the genetic information. The focus of this review is on the very initial steps of virus entry, from receptor binding to particle uptake into the host cell. We will discuss how viruses find their receptor, move to sub-membranous regions permissive for entry, and how they hijack the receptor-mediated signaling pathway to promote their internalization. Full article

(This article belongs to the Special Issue Viruses and Exosomes)

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Open AccessArticle

The Molecular Switch of Telomere Phages: High Binding Specificity of the PY54 Cro Lytic Repressor to a Single Operator Site

by Jens Andre Hammerl, Nicole Roschanski, Rudi Lurz, Reimar Johne, Erich Lanka and Stefan Hertwig

Viruses 2015, 7(6), 2771-2793; https://doi.org/10.3390/v7062746 - 2 Jun 2015

Cited by 6 | Viewed by 6405

Abstract

Temperate bacteriophages possess a molecular switch, which regulates the lytic and lysogenic growth. The genomes of the temperate telomere phages N15, PY54 and ɸKO2 harbor a primary immunity region (immB) comprising genes for the prophage repressor, the lytic repressor and a [...] Read more.

Temperate bacteriophages possess a molecular switch, which regulates the lytic and lysogenic growth. The genomes of the temperate telomere phages N15, PY54 and ɸKO2 harbor a primary immunity region (immB) comprising genes for the prophage repressor, the lytic repressor and a putative antiterminator. The roles of these products are thought to be similar to those of the lambda proteins CI, Cro and Q, respectively. Moreover, the gene order and the location of several operator sites in the prototype telomere phage N15 and in ɸKO2 are also reminiscent of lambda-like phages. By contrast, in silico analyses revealed the presence of only one operator (O\(_{\rm{R}}\)3) in PY54. The purified PY54 Cro protein was used for EMSA studies demonstrating that it exclusively binds to a 16-bp palindromic site (O\(_{\rm{R}}\)3) upstream of the prophage repressor gene. The O\(_{\rm{R}}\)3 operator sequences of PY54 and ɸKO2/N15 only differ by their peripheral base pairs, which are responsible for Cro specificity. PY54 cI and cro transcription is regulated by highly active promoters initiating the synthesis of a homogenious species of leaderless mRNA. The location of the PY54 Cro binding site and of the identified promoters suggests that the lytic repressor suppresses cI transcription but not its own synthesis. The results indicate an unexpected diversity of the growth regulation mechanisms in lambda-related phages. Full article

(This article belongs to the Special Issue 21st Evergreen International Phage Biology Meeting - Emerging Research)

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Open AccessArticle

HCV Core Protein Uses Multiple Mechanisms to Induce Oxidative Stress in Human Hepatoma Huh7 Cells

by Alexander V. Ivanov, Olga A. Smirnova, Irina Y. Petrushanko, Olga N. Ivanova, Inna L. Karpenko, Ekaterina Alekseeva, Irina Sominskaya, Alexander A. Makarov, Birke Bartosch, Sergey N. Kochetkov and Maria G. Isaguliants

Viruses 2015, 7(6), 2745-2770; https://doi.org/10.3390/v7062745 - 29 May 2015

Cited by 71 | Viewed by 8907

Abstract

Hepatitis C virus (HCV) infection is accompanied by the induction of oxidative stress, mediated by several virus proteins, the most prominent being the nucleocapsid protein (HCV core). Here, using the truncated forms of HCV core, we have delineated several mechanisms by which it [...] Read more.

Hepatitis C virus (HCV) infection is accompanied by the induction of oxidative stress, mediated by several virus proteins, the most prominent being the nucleocapsid protein (HCV core). Here, using the truncated forms of HCV core, we have delineated several mechanisms by which it induces the oxidative stress. The N-terminal 36 amino acids of HCV core induced TGFβ1-dependent expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases 1 and 4, both of which independently contributed to the production of reactive oxygen species (ROS). The same fragment also induced the expression of cyclo-oxygenase 2, which, however, made no input into ROS production. Amino acids 37–191 of HCV core up-regulated the transcription of a ROS generating enzyme cytochrome P450 2E1. Furthermore, the same fragment induced the expression of endoplasmic reticulum oxidoreductin 1α. The latter triggered efflux of Ca2+ from ER to mitochondria via mitochondrial Ca2+ uniporter, leading to generation of superoxide anions, and possibly also H2O2. Suppression of any of these pathways in cells expressing the full-length core protein led to a partial inhibition of ROS production. Thus, HCV core causes oxidative stress via several independent pathways, each mediated by a distinct region of the protein. Full article

(This article belongs to the Section Animal Viruses)

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