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Viruses, Volume 9, Issue 8 (August 2017)

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Open AccessArticle Vaccination with Recombinant Baculovirus Expressing Ranavirus Major Capsid Protein Induces Protective Immunity in Chinese Giant Salamander, Andrias davidianus
Viruses 2017, 9(8), 195; doi:10.3390/v9080195
Received: 13 June 2017 / Revised: 20 July 2017 / Accepted: 21 July 2017 / Published: 25 July 2017
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Abstract
The Chinese giant salamander iridovirus (CGSIV), belonging to the genus Ranavirus in the family Iridoviridae, is the causative agent of an emerging infectious disease causing high mortality of more than 90% and economic losses in Chinese giant salamanders in China. In this
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The Chinese giant salamander iridovirus (CGSIV), belonging to the genus Ranavirus in the family Iridoviridae, is the causative agent of an emerging infectious disease causing high mortality of more than 90% and economic losses in Chinese giant salamanders in China. In this study, a recombinant baculovirus-based vaccine expressing the CGSIV major capsid protein (MCP) was developed and its protective immunity in Chinese giant salamanders was evaluated. The recombinant Autographa californica nucleopolyhedrosis virus (AcNPV), expressing CGSIV MCP, designated as AcNPV-MCP, was generated with the highest titers of 1 × 108 plaque forming units/mL (PFU/mL) and confirmed by Western blot and indirect immunofluorescence (IIF) assays. Western blot analysis revealed that the expressed MCP reacted with mouse anti-MCP monoclonal antibodies at the band of about 53 kDa. The results of IIF indicated that the MCP was expressed in the infected Spodoptera frugiperda 9 (Sf9) cells with the recombinant baculovirus, and the Chinese giant salamander muscle cells also transduced with the AcNPV-MCP. Immunization with the recombinant baculovirus of AcNPV-MCP elicited robust specific humoral immune responses detected by ELISA and neutralization assays and potent cellular immune responses in Chinese giant salamanders. Importantly, the effective immunization conferred highly protective immunity for Chinese giant salamanders against CGSIV challenge and produced a relative percent of survival rate of 84%. Thus, the recombinant baculovirus expressing CGSIV MCP can induce significant immune responses involving both humoral and cell-mediated immunity in Chinese giant salamanders and might represent a potential baculovirus based vaccine candidate for Chinese giant salamanders against CGSIV. Full article
(This article belongs to the Section Antivirals & Vaccines)
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Open AccessArticle Perspectives on the Evolution of Porcine Parvovirus
Viruses 2017, 9(8), 196; doi:10.3390/v9080196
Received: 13 June 2017 / Revised: 19 July 2017 / Accepted: 24 July 2017 / Published: 26 July 2017
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Abstract
Porcine parvovirus (PPV) is one of the main causes of porcine reproductive failure. It is important for swine industries to understand the recent trends in PPV evolution. Previous data show that PPV has two genetic lineages originating in Germany. In this study, two
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Porcine parvovirus (PPV) is one of the main causes of porcine reproductive failure. It is important for swine industries to understand the recent trends in PPV evolution. Previous data show that PPV has two genetic lineages originating in Germany. In this study, two more genetic lineages were defined, one of which was distinctly Asian. Additionally, amino acid substitutions in European strains and Asian strains showed distinct differences in several regions of the VP2 gene. The VP1 gene of the recent PPV isolate (T142_South Korea) was identical to that of Kresse strain isolated in the USA in 1985, indicating that modern PPV strains now resemble the original strains (Kresse and NADL-2). In this study, we compared strains isolated in the 20th century to recent isolates and confirmed the trend that modern strains are becoming more similar to previous strains. Full article
(This article belongs to the Special Issue Protoparvoviruses: Friends or Foes?)
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Open AccessArticle The Mechanisms for Within-Host Influenza Virus Control Affect Model-Based Assessment and Prediction of Antiviral Treatment
Viruses 2017, 9(8), 197; doi:10.3390/v9080197
Received: 30 June 2017 / Revised: 18 July 2017 / Accepted: 24 July 2017 / Published: 26 July 2017
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Abstract
Models of within-host influenza viral dynamics have contributed to an improved understanding of viral dynamics and antiviral effects over the past decade. Existing models can be classified into two broad types based on the mechanism of viral control: models utilising target cell depletion
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Models of within-host influenza viral dynamics have contributed to an improved understanding of viral dynamics and antiviral effects over the past decade. Existing models can be classified into two broad types based on the mechanism of viral control: models utilising target cell depletion to limit the progress of infection and models which rely on timely activation of innate and adaptive immune responses to control the infection. In this paper, we compare how two exemplar models based on these different mechanisms behave and investigate how the mechanistic difference affects the assessment and prediction of antiviral treatment. We find that the assumed mechanism for viral control strongly influences the predicted outcomes of treatment. Furthermore, we observe that for the target cell-limited model the assumed drug efficacy strongly influences the predicted treatment outcomes. The area under the viral load curve is identified as the most reliable predictor of drug efficacy, and is robust to model selection. Moreover, with support from previous clinical studies, we suggest that the target cell-limited model is more suitable for modelling in vitro assays or infection in some immunocompromised/immunosuppressed patients while the immune response model is preferred for predicting the infection/antiviral effect in immunocompetent animals/patients. Full article
(This article belongs to the Special Issue Mathematical Modeling of Viral Infections)
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Open AccessArticle Infectious Bronchitis Virus Infection Induces Apoptosis during Replication in Chicken Macrophage HD11 Cells
Viruses 2017, 9(8), 198; doi:10.3390/v9080198
Received: 18 April 2017 / Revised: 16 July 2017 / Accepted: 21 July 2017 / Published: 26 July 2017
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Abstract
Avian infectious bronchitis has caused huge economic losses in the poultry industry. Previous studies have reported that infectious bronchitis virus (IBV) infection can produce cytopathic effects (CPE) and apoptosis in some mammalian cells and primary cells. However, there is little research on IBV-induced
[...] Read more.
Avian infectious bronchitis has caused huge economic losses in the poultry industry. Previous studies have reported that infectious bronchitis virus (IBV) infection can produce cytopathic effects (CPE) and apoptosis in some mammalian cells and primary cells. However, there is little research on IBV-induced immune cell apoptosis. In this study, chicken macrophage HD11 cells were established as a cellular model that is permissive to IBV infection. Then, IBV-induced apoptosis was observed through a cell viability assay, morphological changes, and flow cytometry. The activity of caspases, the inhibitory efficacy of caspase-inhibitors and the expression of apoptotic genes further suggested the activation of apoptosis through both intrinsic and extrinsic pathways in IBV-infected HD11 cells. Additionally, ammonium chloride (NH4Cl) pretreated HD11 cells blocked IBV from entering cells and inhibited IBV-induced apoptosis. UV-inactivated IBV also lost the ability of apoptosis induction. IBV replication was increased by blocking caspase activation. This study presents a chicken macrophage cell line that will enable further analysis of IBV infection and offers novel insights into the mechanisms of IBV-induced apoptosis in immune cells. Full article
(This article belongs to the Special Issue Viral Infection and Apoptosis)
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Open AccessArticle HBV Drug Resistance Substitutions Existed before the Clinical Approval of Nucleos(t)ide Analogues: A Bioinformatic Analysis by GenBank Data Mining
Viruses 2017, 9(8), 199; doi:10.3390/v9080199
Received: 24 May 2017 / Revised: 21 July 2017 / Accepted: 24 July 2017 / Published: 27 July 2017
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Abstract
Naturally occurring nucleos(t)ide analogue resistance (NUCr) substitution frequencies in the reverse transcriptase (RT) of the hepatitis B virus (HBV) were studied extensively after the clinical approval of nucleos(t)ide analogues (NUCs; year of approval 1998). We aimed to study NUCr substitutions in HBV RT
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Naturally occurring nucleos(t)ide analogue resistance (NUCr) substitution frequencies in the reverse transcriptase (RT) of the hepatitis B virus (HBV) were studied extensively after the clinical approval of nucleos(t)ide analogues (NUCs; year of approval 1998). We aimed to study NUCr substitutions in HBV RT sequences obtained before 1998 and better understand the evolution of RT sequences without NUC pressures. Our strategy was to retrieve HBV sequences from GenBank deposited before 1998. The initial search used the keywords “hepatitis B virus” or “HBV” and 1139 sequences were found. Data analyses included information extraction: sequence quality control and amino acid substitution analysis on 8 primary NUCr and 3 secondary substitution codons. Three hundred and ninety-four RT-containing sequences of 8 genotypes from 25 countries in 4 continents were selected. Twenty-seven (6.9%) sequences were found to harbor substitutions at NUCr-related codons. Secondary substitutions (rtL80V and rtV173G/A/L) occurred more frequently than primary NUCr substitutions (rtI169L; rtA181G; T184A/S; rtS202T/R; rtM204L and rtM250K). Typical amino acid substitutions associated with NUCr were of rtL80V, rtV173L and rtT184A/S. We confirm the presence of naturally occurring typical HBV NUCr substitutions with very low frequencies, and secondary substitutions are more likely to occur than primary NUCr substitutions without the selective pressure of NUCs. Full article
(This article belongs to the Section Antivirals & Vaccines)
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Open AccessArticle Characterization of Two Historic Smallpox Specimens from a Czech Museum
Viruses 2017, 9(8), 200; doi:10.3390/v9080200
Received: 26 June 2017 / Revised: 22 July 2017 / Accepted: 25 July 2017 / Published: 27 July 2017
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Abstract
Although smallpox has been known for centuries, the oldest available variola virus strains were isolated in the early 1940s. At that time, large regions of the world were already smallpox-free. Therefore, genetic information of these strains can represent only the very last fraction
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Although smallpox has been known for centuries, the oldest available variola virus strains were isolated in the early 1940s. At that time, large regions of the world were already smallpox-free. Therefore, genetic information of these strains can represent only the very last fraction of a long evolutionary process. Based on the genomes of 48 strains, two clades are differentiated: Clade 1 includes variants of variola major, and clade 2 includes West African and variola minor (Alastrim) strains. Recently, the genome of an almost 400-year-old Lithuanian mummy was determined, which fell basal to all currently sequenced strains of variola virus on phylogenetic trees. Here, we determined two complete variola virus genomes from human tissues kept in a museum in Prague dating back 60 and 160 years, respectively. Moreover, mass spectrometry-based proteomic, chemical, and microscopic examinations were performed. The 60-year-old specimen was most likely an importation from India, a country with endemic smallpox at that time. The genome of the 160-year-old specimen is related to clade 2 West African and variola minor strains. This sequence likely represents a new endemic European variant of variola virus circulating in the midst of the 19th century in Europe. Full article
(This article belongs to the Special Issue Smallpox and Emerging Zoonotic Orthopoxviruses: What Is Coming Next?)
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Open AccessArticle Importance of Autophagy in Mediating Human Immunodeficiency Virus (HIV) and Morphine-Induced Metabolic Dysfunction and Inflammation in Human Astrocytes
Viruses 2017, 9(8), 201; doi:10.3390/v9080201
Received: 9 June 2017 / Revised: 24 July 2017 / Accepted: 24 July 2017 / Published: 28 July 2017
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Abstract
Under physiological conditions, the function of astrocytes in providing brain metabolic support is compromised under pathophysiological conditions caused by human immunodeficiency virus (HIV) and opioids. Herein, we examined the role of autophagy, a lysosomal degradation pathway important for cellular homeostasis and survival, as
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Under physiological conditions, the function of astrocytes in providing brain metabolic support is compromised under pathophysiological conditions caused by human immunodeficiency virus (HIV) and opioids. Herein, we examined the role of autophagy, a lysosomal degradation pathway important for cellular homeostasis and survival, as a potential regulatory mechanism during pathophysiological conditions in primary human astrocytes. Blocking autophagy with small interfering RNA (siRNA) targeting BECN1, but not the Autophagy-related 5 (ATG5) gene, caused a significant decrease in HIV and morphine-induced intracellular calcium release. On the contrary, inducing autophagy pharmacologically with rapamycin further enhanced calcium release and significantly reverted HIV and morphine-decreased glutamate uptake. Furthermore, siBeclin1 caused an increase in HIV-induced nitric oxide (NO) release, while viral-induced NO in astrocytes exposed to rapamycin was decreased. HIV replication was significantly attenuated in astrocytes transfected with siRNA while significantly induced in astrocytes exposed to rapamycin. Silencing with siBeclin1, but not siATG5, caused a significant decrease in HIV and morphine-induced interleukin (IL)-8 and tumor necrosis factor alpha (TNF-α) release, while secretion of IL-8 was significantly induced with rapamycin. Mechanistically, the effects of siBeclin1 in decreasing HIV-induced calcium release, viral replication, and viral-induced cytokine secretion were associated with a decrease in activation of the nuclear factor kappa B (NF-κB) pathway. Full article
(This article belongs to the Special Issue Viruses and Autophagy)
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Open AccessArticle A Motif in the F Homomorph of Rabbit Haemorrhagic Disease Virus Polymerase Is Important for the Subcellular Localisation of the Protein and Its Ability to Induce Redistribution of Golgi Membranes
Viruses 2017, 9(8), 202; doi:10.3390/v9080202
Received: 22 June 2017 / Revised: 21 July 2017 / Accepted: 21 July 2017 / Published: 1 August 2017
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Abstract
Rabbit haemorrhagic disease virus (RHDV) is a calicivirus that infects and frequently kills rabbits. Previously, we showed that the RHDV RNA-dependent RNA polymerase (RdRp) is associated with distinct, but yet uncharacterised subcellular structures and is capable of inducing a redistribution of Golgi membranes.
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Rabbit haemorrhagic disease virus (RHDV) is a calicivirus that infects and frequently kills rabbits. Previously, we showed that the RHDV RNA-dependent RNA polymerase (RdRp) is associated with distinct, but yet uncharacterised subcellular structures and is capable of inducing a redistribution of Golgi membranes. In this study, we identified a partially hidden hydrophobic motif that determines the subcellular localisation of recombinant RHDV RdRp in transfected cells. This novel motif, 189LLWGCDVGVAVCAAAVFHNICY210, is located within the F homomorph, between the conserved F3 and A motifs of the core RdRp domain. Amino acid substitutions that decrease the hydrophobicity of this motif reduced the ability of the protein to accumulate in multiple subcellular foci and to induce a rearrangement of the Golgi network. Furthermore, preliminary molecular dynamics simulations suggest that the RHDV RdRp could align with the negatively charged surfaces of biological membranes and undergo a conformational change involving the F homomorph. These changes would expose the newly identified hydrophobic motif so it could immerse itself into the outer leaflet of intracellular membranes. Full article
(This article belongs to the Section Animal Viruses)
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Open AccessArticle Evaluation of Taterapox Virus in Small Animals
Viruses 2017, 9(8), 203; doi:10.3390/v9080203
Received: 8 July 2017 / Revised: 20 July 2017 / Accepted: 24 July 2017 / Published: 1 August 2017
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Abstract
Taterapox virus (TATV), which was isolated from an African gerbil (Tatera kempi) in 1975, is the most closely related virus to variola; however, only the original report has examined its virology. We have evaluated the tropism of TATV in vivo in
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Taterapox virus (TATV), which was isolated from an African gerbil (Tatera kempi) in 1975, is the most closely related virus to variola; however, only the original report has examined its virology. We have evaluated the tropism of TATV in vivo in small animals. We found that TATV does not infect Graphiurus kelleni, a species of African dormouse, but does induce seroconversion in the Mongolian gerbil (Meriones unguiculatus) and in mice; however, in wild-type mice and gerbils, the virus produces an unapparent infection. Following intranasal and footpad inoculations with 1 × 106 plaque forming units (PFU) of TATV, immunocompromised stat1−/− mice showed signs of disease but did not die; however, SCID mice were susceptible to intranasal and footpad infections with 100% mortality observed by Day 35 and Day 54, respectively. We show that death is unlikely to be a result of the virus mutating to have increased virulence and that SCID mice are capable of transmitting TATV to C57BL/6 and C57BL/6 stat1−/− animals; however, transmission did not occur from TATV inoculated wild-type or stat1−/− mice. Comparisons with ectromelia (the etiological agent of mousepox) suggest that TATV behaves differently both at the site of inoculation and in the immune response that it triggers. Full article
(This article belongs to the Special Issue Smallpox and Emerging Zoonotic Orthopoxviruses: What Is Coming Next?)
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Open AccessCommunication Rous Sarcoma Virus RNA Stability Element Inhibits Deadenylation of mRNAs with Long 3′UTRs
Viruses 2017, 9(8), 204; doi:10.3390/v9080204
Received: 5 June 2017 / Revised: 14 July 2017 / Accepted: 26 July 2017 / Published: 1 August 2017
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Abstract
All retroviruses use their full-length primary transcript as the major mRNA for Group-specific antigen (Gag) capsid proteins. This results in a long 3′ untranslated region (UTR) downstream of the termination codon. In the case of Rous sarcoma virus (RSV), there is a 7
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All retroviruses use their full-length primary transcript as the major mRNA for Group-specific antigen (Gag) capsid proteins. This results in a long 3′ untranslated region (UTR) downstream of the termination codon. In the case of Rous sarcoma virus (RSV), there is a 7 kb 3′UTR downstream of the gag terminator, containing the pol, env, and src genes. mRNAs containing long 3′UTRs, like those with premature termination codons, are frequently recognized by the cellular nonsense-mediated mRNA decay (NMD) machinery and targeted for degradation. To prevent this, RSV has evolved an RNA stability element (RSE) in the RNA immediately downstream of the gag termination codon. This 400-nt RNA sequence stabilizes premature termination codons (PTCs) in gag. It also stabilizes globin mRNAs with long 3′UTRs, when placed downstream of the termination codon. It is not clear how the RSE stabilizes the mRNA and prevents decay. We show here that the presence of RSE inhibits deadenylation severely. In addition, the RSE also impairs decapping (DCP2) and 5′-3′ exonucleolytic (XRN1) function in knockdown experiments in human cells. Full article
(This article belongs to the Special Issue Viral Interactions with Host RNA Decay Pathways)
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Open AccessArticle A Multiplex RT-PCR Assay to Detect and Discriminate Porcine Reproductive and Respiratory Syndrome Viruses in Clinical Specimens
Viruses 2017, 9(8), 205; doi:10.3390/v9080205
Received: 15 May 2017 / Revised: 26 July 2017 / Accepted: 28 July 2017 / Published: 1 August 2017
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Abstract
Outbreaks of highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) have led to large economic losses in China. The attenuated vaccine (HP-PRRSV JXA1-R) was used to control HP-PRRSV. However, in recent years, co-infection with classical PRRSV (C-PRRSV), HP-PRRSV, and/or HP-PRRSV JXA1-R has
[...] Read more.
Outbreaks of highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) have led to large economic losses in China. The attenuated vaccine (HP-PRRSV JXA1-R) was used to control HP-PRRSV. However, in recent years, co-infection with classical PRRSV (C-PRRSV), HP-PRRSV, and/or HP-PRRSV JXA1-R has been increasing in China, resulting in a significant impact on PRRSV diagnostics and management. To facilitate rapid discrimination of HP-PRRSV JXA1-R from HP-PRRSV and C-PRRSV, a multiplex RT-PCR assay for the visual detection of HP-PRRSV JXA1-R, HP-PRRSV, and C-PRRSV was established and evaluated with reference PRRSV strains and clinical samples. Primer specificities were evaluated with RNA/DNA extracted from 10 viral strains, and our results revealed that the primers had a high specificity for PRRSV. The assay sensitivity was 24 copies/μL for PRRSVs. A total of 516 serum samples were identified, of which 12.21% (63/516) were HP-PRRSV-positive, 2.33% (12/516) were HP-PRRSV JXA1-R-positive, and 1.16% (6/516) were C-PRRSV-positive, respectively, which was completely consistent with the sequencing method. The high specificity, sensitivity, and reliability of the multiplex RT-PCR assay described in this study indicate that it is useful for the rapid and differential diagnosis of HP-PRRSV JXA1-R, HP-PRRSV, and C-PRRSV. Full article
(This article belongs to the Section Antivirals & Vaccines)
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Open AccessArticle The Susceptibilities of Respiratory Syncytial Virus to Nucleolin Receptor Blocking and Antibody Neutralization are Dependent upon the Method of Virus Purification
Viruses 2017, 9(8), 207; doi:10.3390/v9080207
Received: 23 June 2017 / Revised: 25 July 2017 / Accepted: 27 July 2017 / Published: 3 August 2017
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Abstract
Respiratory Syncytial Virus (RSV) that is propagated in cell culture is purified from cellular contaminants that can confound experimental results. A number of different purification methods have been described, including methods that utilize fast protein liquid chromatography (FPLC) and gradient ultracentrifugation. Thus, the
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Respiratory Syncytial Virus (RSV) that is propagated in cell culture is purified from cellular contaminants that can confound experimental results. A number of different purification methods have been described, including methods that utilize fast protein liquid chromatography (FPLC) and gradient ultracentrifugation. Thus, the constituents and experimental responses of RSV stocks purified by ultracentrifugation in sucrose and by FPLC were analyzed and compared by infectivity assay, Coomassie stain, Western blot, mass spectrometry, immuno-transmission electron microscopy (TEM), and ImageStream flow cytometry. The FPLC-purified RSV had more albumin contamination, but there was less evidence of host-derived exosomes when compared to ultracentrifugation-purified RSV as detected by Western blot and mass spectrometry for the exosome markers superoxide dismutase [Cu-Zn] (SOD1) and the tetraspanin CD63. Although the purified virus stocks were equally susceptible to nucleolin-receptor blocking by the DNA aptamer AS1411, the FPLC-purified RSV was significantly less susceptible to anti-RSV polyclonal antibody neutralization; there was 69% inhibition (p = 0.02) of the sucrose ultracentrifugation-purified RSV, 38% inhibition (p = 0.03) of the unpurified RSV, but statistically ineffective neutralization in the FPLC-purified RSV (22% inhibition; p = 0.30). The amount of RSV neutralization of the purified RSV stocks was correlated with anti-RSV antibody occupancy on RSV particles observed by immuno-TEM. RSV purified by different methods alters the stock composition and morphological characteristics of virions that can lead to different experimental responses. Full article
(This article belongs to the Section Antivirals & Vaccines)
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Open AccessArticle Characterization of Monoclonal Antibodies against HA Protein of H1N1 Swine Influenza Virus and Protective Efficacy against H1 Viruses in Mice
Viruses 2017, 9(8), 209; doi:10.3390/v9080209
Received: 26 June 2017 / Revised: 30 July 2017 / Accepted: 3 August 2017 / Published: 8 August 2017
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Abstract
H1N1 swine influenza viruses (SIV) are prevalent in pigs globally, and occasionally emerge in humans, which raises concern about their pandemic threats. To stimulate hemagglutination (HA) of A/Swine/Guangdong/LM/2004 (H1N1) (SW/GD/04) antibody response, eukaryotic expression plasmid pCI-neo-HA was constructed and used as an immunogen
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H1N1 swine influenza viruses (SIV) are prevalent in pigs globally, and occasionally emerge in humans, which raises concern about their pandemic threats. To stimulate hemagglutination (HA) of A/Swine/Guangdong/LM/2004 (H1N1) (SW/GD/04) antibody response, eukaryotic expression plasmid pCI-neo-HA was constructed and used as an immunogen to prepare monoclonal antibodies (mAbs). Five mAbs (designed 8C4, 8C6, 9D6, 8A4, and 8B1) against HA protein were obtained and characterized. Western blot showed that the 70 kDa HA protein could be detected by all mAbs in MDCK cells infected with SW/GD/04. Three mAbs—8C4, 8C6, and 9D6—have hemagglutination inhibition (HI) and neutralization test (NT) activities, and 8C6 induces the highest HI and NT titers. The protection efficacy of 8C6 was investigated in BALB/c mice challenged with homologous or heterologous strains of the H1 subtype SIV. The results indicate that mAb 8C6 protected the mice from viral infections, especially the homologous strain, which was clearly demonstrated by the body weight changes and reduction of viral load. Thus, our findings document for the first time that mAb 8C6 might be of potential therapeutic value for H1 subtype SIV infection. Full article
(This article belongs to the Section Antivirals & Vaccines)
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Open AccessArticle Viral Ubiquitin Ligase Stimulates Selective Host MicroRNA Expression by Targeting ZEB Transcriptional Repressors
Viruses 2017, 9(8), 210; doi:10.3390/v9080210
Received: 10 July 2017 / Revised: 31 July 2017 / Accepted: 2 August 2017 / Published: 7 August 2017
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Abstract
Infection with herpes simplex virus-1 (HSV-1) brings numerous changes in cellular gene expression. Levels of most host mRNAs are reduced, limiting synthesis of host proteins, especially those involved in antiviral defenses. The impact of HSV-1 on host microRNAs (miRNAs), an extensive network of
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Infection with herpes simplex virus-1 (HSV-1) brings numerous changes in cellular gene expression. Levels of most host mRNAs are reduced, limiting synthesis of host proteins, especially those involved in antiviral defenses. The impact of HSV-1 on host microRNAs (miRNAs), an extensive network of short non-coding RNAs that regulate mRNA stability/translation, remains largely unexplored. Here we show that transcription of the miR-183 cluster (miR-183, miR-96, and miR-182) is selectively induced by HSV-1 during productive infection of primary fibroblasts and neurons. ICP0, a viral E3 ubiquitin ligase expressed as an immediate-early protein, is both necessary and sufficient for this induction. Nuclear exclusion of ICP0 or removal of the RING (really interesting new gene) finger domain that is required for E3 ligase activity prevents induction. ICP0 promotes the degradation of numerous host proteins and for the most part, the downstream consequences are unknown. Induction of the miR-183 cluster can be mimicked by depletion of host transcriptional repressors zinc finger E-box binding homeobox 1 (ZEB1)/-crystallin enhancer binding factor 1 (δEF1) and zinc finger E-box binding homeobox 2 (ZEB2)/Smad-interacting protein 1 (SIP1), which we establish as new substrates for ICP0-mediated degradation. Thus, HSV-1 selectively stimulates expression of the miR-183 cluster by ICP0-mediated degradation of ZEB transcriptional repressors. Full article
(This article belongs to the Section Animal Viruses)
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Open AccessArticle Characterization of Naturally Occurring NS5A and NS5B Polymorphisms in Patients Infected with HCV Genotype 3a Treated with Direct-Acting Antiviral Agents
Viruses 2017, 9(8), 212; doi:10.3390/v9080212
Received: 28 June 2017 / Revised: 27 July 2017 / Accepted: 31 July 2017 / Published: 7 August 2017
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Abstract
Hepatitis C virus (HCV) genotype (GT)3 is associated with increased risk of steatosis, development of cirrhosis and hepatocellular carcinoma. Limited data are available regarding genetic variability and use of direct-acting antiviral agents in these patients. non-structural protein 5A (NS5A) and non-structural protein 5B
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Hepatitis C virus (HCV) genotype (GT)3 is associated with increased risk of steatosis, development of cirrhosis and hepatocellular carcinoma. Limited data are available regarding genetic variability and use of direct-acting antiviral agents in these patients. non-structural protein 5A (NS5A) and non-structural protein 5B (NS5B) sequencing was performed on 45 HCV GT3-infected Italian patients subsequently treated with sofosbuvir ± daclatasvir (SOF ± DCV). Novel GT3a polymorphisms were observed by Sanger sequencing in three NS5A (T79S, T107K, and T107S) and three NS5B (G166R, Q180K, and C274W) baseline sequences in patients who achieved sustained virological response (SVR). Baseline NS5A resistance-associated substitutions A30K and Y93H were detected in 9.5% of patients; one patient with A30K did not achieve SVR. Phylogenetic analyses of sequences showed no distinct clustering. Genetic heterogeneity of NS5A and NS5B was evaluated using ultra-deep pyrosequencing (UDPS) in samples longitudinally collected in patients not achieving SVR. Some novel NS5A and NS5B polymorphisms detected at baseline may not impact treatment outcome, as they were not enriched in post-failure samples. In contrast, the novel L31F NS5A variant emerged in one treatment failure, and I184T, G188D and N310S, located on the same NS5B haplotype, became predominant after failure. These findings suggest a potential impact of these novel substitutions on the treatment outcome; however, their significance requires further investigation. Full article
(This article belongs to the Section Antivirals & Vaccines)
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Open AccessArticle An Inactivated Novel Genotype Fowl Adenovirus 4 Protects Chickens against the Hydropericardium Syndrome That Recently Emerged in China
Viruses 2017, 9(8), 216; doi:10.3390/v9080216
Received: 10 June 2017 / Revised: 2 August 2017 / Accepted: 6 August 2017 / Published: 8 August 2017
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Abstract
Since 2015, China has experienced outbreaks of severe hydropericardium syndrome (HPS), associated with a novel genotype and hypervirulent fowl adenovirus serotype 4 (FAdV-4) infection, with a prevalence in various provinces of the country. This has resulted in huge economic losses in the poultry
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Since 2015, China has experienced outbreaks of severe hydropericardium syndrome (HPS), associated with a novel genotype and hypervirulent fowl adenovirus serotype 4 (FAdV-4) infection, with a prevalence in various provinces of the country. This has resulted in huge economic losses in the poultry industry. The novel FAdV-4 showed new genome characters, such as the natural deletion of open reading frame (ORF) 19 and ORF 27 (1966 bp), and high pathogenicity toward chickens. These are coupled with severe hydropericardium, inclusion body hepatitis, and mortality rates ranging from 30% to 90%. Although several inactivated and subunit vaccines against the traditional FAdV-4 have been developed, no commercial vaccine against the emerged disease caused by the novel strain has been available until now. The potential risks of infection with this novel hypervirulent FAdV-4 urgently require an effective vaccine. Thus, an inactivated oil-emulsion FAdV-4 vaccine formulated with the novel genotype virus was developed in this study. The vaccine provided a high level of antibody, preferential T helper 2 (Th2) (interleukin-4 secretion) not Th1 (interferon-γ secretion) response, and full protection against a lethal dose of the novel hypervirulent FAdV-4. Therefore, the novel genotype FAdV-4 vaccine is proposed as an attractive candidate to prevent and reduce the spread of HPS in the poultry industry of China. Full article
(This article belongs to the Section Antivirals & Vaccines)
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Open AccessArticle The Potential for Reassortment between Oropouche and Schmallenberg Orthobunyaviruses
Viruses 2017, 9(8), 220; doi:10.3390/v9080220
Received: 1 July 2017 / Revised: 3 August 2017 / Accepted: 6 August 2017 / Published: 11 August 2017
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Abstract
A number of viruses within the Peribunyaviridae family are naturally occurring reassortants, a common phenomenon for segmented viruses. Using a minigenome-reporter and virus-like particle (VLP) production assay, we have accessed the potential of Oropouche virus (OROV), Schmallenberg virus (SBV), and other orthobunyaviruses within
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A number of viruses within the Peribunyaviridae family are naturally occurring reassortants, a common phenomenon for segmented viruses. Using a minigenome-reporter and virus-like particle (VLP) production assay, we have accessed the potential of Oropouche virus (OROV), Schmallenberg virus (SBV), and other orthobunyaviruses within the Simbu serogroup to reassort. We found that the untranslated region (UTR) in the medium segment is a potential contributing factor for reassortment by the tested viruses. We demonstrate that for promoter activity to occur it was essential that the viral RNA polymerase (L) and nucleocapsid (N) proteins were from the same virus, reinforcing the hypothesis that the large and small segments that encode these proteins segregate together during genome reassortment. Our results indicate that, given the right epidemiological setting, reassortment between SBV and OROV would potentially be feasible and could contribute to the emergence of a new Simbu virus. Full article
(This article belongs to the Section Animal Viruses)
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Open AccessArticle Inhibitors of Deubiquitinating Enzymes Block HIV-1 Replication and Augment the Presentation of Gag-Derived MHC-I Epitopes
Viruses 2017, 9(8), 222; doi:10.3390/v9080222
Received: 2 June 2017 / Revised: 4 August 2017 / Accepted: 8 August 2017 / Published: 12 August 2017
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Abstract
In recent years it has been well established that two major constituent parts of the ubiquitin proteasome system (UPS)—the proteasome holoenzymes and a number of ubiquitin ligases—play a crucial role, not only in virus replication but also in the regulation of the immunogenicity
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In recent years it has been well established that two major constituent parts of the ubiquitin proteasome system (UPS)—the proteasome holoenzymes and a number of ubiquitin ligases—play a crucial role, not only in virus replication but also in the regulation of the immunogenicity of human immunodeficiency virus type 1 (HIV-1). However, the role in HIV-1 replication of the third major component, the deubiquitinating enzymes (DUBs), has remained largely unknown. In this study, we show that the DUB-inhibitors (DIs) P22077 and PR-619, specific for the DUBs USP7 and USP47, impair Gag processing and thereby reduce the infectivity of released virions without affecting viral protease activity. Furthermore, the replication capacity of X4- and R5-tropic HIV-1NL4-3 in human lymphatic tissue is decreased upon treatment with these inhibitors without affecting cell viability. Most strikingly, combinatory treatment with DIs and proteasome inhibitors synergistically blocks virus replication at concentrations where mono-treatment was ineffective, indicating that DIs can boost the therapeutic effect of proteasome inhibitors. In addition, P22077 and PR-619 increase the polyubiquitination of Gag and thus its entry into the UPS and the major histocompatibility complex (MHC)-I pathway. In summary, our data point towards a model in which specific inhibitors of DUBs not only interfere with virus spread but also increase the immune recognition of HIV-1 expressing cells. Full article
(This article belongs to the Special Issue Viruses and the Proteasome)
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Open AccessArticle Effects of the HN Antigenic Difference between the Vaccine Strain and the Challenge Strain of Newcastle Disease Virus on Virus Shedding and Transmission
Viruses 2017, 9(8), 225; doi:10.3390/v9080225
Received: 5 July 2017 / Revised: 31 July 2017 / Accepted: 3 August 2017 / Published: 15 August 2017
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Abstract
Newcastle disease (ND) leading to heavy economic losses to the poultry industry worldwide is caused by Newcastle disease virus (NDV). Even though intensive vaccination programs have been implemented in many countries, virulent NDV can still be frequently isolated in well-vaccinated flocks. We compared
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Newcastle disease (ND) leading to heavy economic losses to the poultry industry worldwide is caused by Newcastle disease virus (NDV). Even though intensive vaccination programs have been implemented in many countries, virulent NDV can still be frequently isolated in well-vaccinated flocks. We compared the protection efficiency of LaSota and two sub-genotype VIId vaccines, NDV/AI4 and NDV O/AI4, in which NDV O/AI4 was constructed by replacing the hemagglutinin–neuraminidase (HN) gene of the vaccine strain NDV/AI4 with that from the variant NDV strain JS-14-12-Ch by the cross hemagglutination inhibition test and immune protection test. The number of birds shedding the virus and the titer of the shedding virus from the challenged birds were tested to evaluate the protection efficiency in the immune protection test. The cross hemagglutination inhibition and neutralization tests between JS-14-12-Ch and the three vaccines displayed a significant antigenic difference between JS-14-12-Ch and LaSota or NDV/AI4, but not between JS-14-12-Ch and NDV O/AI4. The results of the immune protection test showed that NDV O/AI4 could provide improved protection as determined by a significant decrease in both the number of birds shedding the virus and the titer of the shedding virus from the challenged birds. The results in this study indicated that the antigenic similarity between the vaccine strain and the challenge strain is important in reducing the shedding of virulent virus in which the congruence of the NDV HN protein may play a critical role. Full article
(This article belongs to the Section Animal Viruses)
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Open AccessArticle Reliable Detection of Herpes Simplex Virus Sequence Variation by High-Throughput Resequencing
Viruses 2017, 9(8), 226; doi:10.3390/v9080226
Received: 3 May 2017 / Revised: 14 July 2017 / Accepted: 9 August 2017 / Published: 16 August 2017
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Abstract
High-throughput sequencing (HTS) has resulted in data for a number of herpes simplex virus (HSV) laboratory strains and clinical isolates. The knowledge of these sequences has been critical for investigating viral pathogenicity. However, the assembly of complete herpesviral genomes, including HSV, is complicated
[...] Read more.
High-throughput sequencing (HTS) has resulted in data for a number of herpes simplex virus (HSV) laboratory strains and clinical isolates. The knowledge of these sequences has been critical for investigating viral pathogenicity. However, the assembly of complete herpesviral genomes, including HSV, is complicated due to the existence of large repeat regions and arrays of smaller reiterated sequences that are commonly found in these genomes. In addition, the inherent genetic variation in populations of isolates for viruses and other microorganisms presents an additional challenge to many existing HTS sequence assembly pipelines. Here, we evaluate two approaches for the identification of genetic variants in HSV1 strains using Illumina short read sequencing data. The first, a reference-based approach, identifies variants from reads aligned to a reference sequence and the second, a de novo assembly approach, identifies variants from reads aligned to de novo assembled consensus sequences. Of critical importance for both approaches is the reduction in the number of low complexity regions through the construction of a non-redundant reference genome. We compared variants identified in the two methods. Our results indicate that approximately 85% of variants are identified regardless of the approach. The reference-based approach to variant discovery captures an additional 15% representing variants divergent from the HSV1 reference possibly due to viral passage. Reference-based approaches are significantly less labor-intensive and identify variants across the genome where de novo assembly-based approaches are limited to regions where contigs have been successfully assembled. In addition, regions of poor quality assembly can lead to false variant identification in de novo consensus sequences. For viruses with a well-assembled reference genome, a reference-based approach is recommended. Full article
(This article belongs to the Section Animal Viruses)
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Open AccessArticle Deciphering Single Nucleotide Polymorphisms and Evolutionary Trends in Isolates of the Cydia pomonella granulovirus
Viruses 2017, 9(8), 227; doi:10.3390/v9080227 (registering DOI)
Received: 21 May 2017 / Revised: 6 August 2017 / Accepted: 9 August 2017 / Published: 18 August 2017
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Abstract
Six complete genome sequences of Cydia pomonella granulovirus (CpGV) isolates from Mexico (CpGV-M and CpGV-M1), England (CpGV-E2), Iran (CpGV-I07 and CpGV-I12), and Canada (CpGV-S) were aligned and analyzed for genetic diversity and evolutionary processes. The selected CpGV isolates represented recently identified phylogenetic lineages
[...] Read more.
Six complete genome sequences of Cydia pomonella granulovirus (CpGV) isolates from Mexico (CpGV-M and CpGV-M1), England (CpGV-E2), Iran (CpGV-I07 and CpGV-I12), and Canada (CpGV-S) were aligned and analyzed for genetic diversity and evolutionary processes. The selected CpGV isolates represented recently identified phylogenetic lineages of CpGV, namely, the genome groups A to E. The genomes ranged from 120,816 bp to 124,269 bp. Several common differences between CpGV-M, -E2, -I07, -I12 and -S to CpGV-M1, the first sequenced and published CpGV isolate, were highlighted. Phylogenetic analysis based on the aligned genome sequences grouped CpGV-M and CpGV-I12 as the most derived lineages, followed by CpGV-E2, CpGV-S and CpGV-I07, which represent the most basal lineages. All of the genomes shared a high degree of co-linearity, with a common setup of 137 (CpGV-I07) to 142 (CpGV-M and -I12) open reading frames with no translocations. An overall trend of increasing genome size and a decrease in GC content was observed, from the most basal lineage (CpGV-I07) to the most derived (CpGV-I12). A total number of 788 positions of single nucleotide polymorphisms (SNPs) were determined and used to create a genome-wide SNP map of CpGV. Of the total amount of SNPs, 534 positions were specific for exactly one of either isolate CpGV-M, -E2, -I07, -I12 or -S, which allowed the SNP-based detection and identification of all known CpGV isolates. Full article
(This article belongs to the Section Insect Viruses)
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Open AccessArticle Adaption of FMDV Asia-1 to Suspension Culture: Cell Resistance Is Overcome by Virus Capsid Alterations
Viruses 2017, 9(8), 231; doi:10.3390/v9080231 (registering DOI)
Received: 2 June 2017 / Revised: 7 August 2017 / Accepted: 14 August 2017 / Published: 18 August 2017
PDF Full-text (1135 KB) | Supplementary Files
Abstract
Foot-and-mouth disease virus (FMDV) causes a highly contagious disease with catastrophic economic impact for affected countries. BHK21 suspension cells are preferred for the industrial production of FMDV vaccine antigen, but not all virus strains can be successfully propagated in these cells. Serotype Asia-1
[...] Read more.
Foot-and-mouth disease virus (FMDV) causes a highly contagious disease with catastrophic economic impact for affected countries. BHK21 suspension cells are preferred for the industrial production of FMDV vaccine antigen, but not all virus strains can be successfully propagated in these cells. Serotype Asia-1 is often affected by this phenomenon. In this study, the Asia-1 strain Shamir was used to examine viral, cellular and environmental factors that contribute to resistance to cell culture infection. Cell media composition, pH and ammonium chloride concentration did not affect Asia-1 differently than other serotypes. Virus replication after transfection of viral genome was not impaired, but the adhesion to the cells was markedly reduced for Asia-1 in comparison to serotype A. The Asia-1 Shamir virus was successfully adapted to grow in the resistant cells by using a closely related but susceptible cell line. Sequence analysis of the adapted virus revealed two distinct mutations in the capsid protein VP1 that might mediate cell attachment and entry. Full article
(This article belongs to the Section Animal Viruses)

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Open AccessReview Somatic Host Cell Alterations in HPV Carcinogenesis
Viruses 2017, 9(8), 206; doi:10.3390/v9080206
Received: 11 July 2017 / Revised: 24 July 2017 / Accepted: 25 July 2017 / Published: 3 August 2017
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Abstract
High-risk human papilloma virus (HPV) infections cause cancers in different organ sites, most commonly cervical and head and neck cancers. While carcinogenesis is initiated by two viral oncoproteins, E6 and E7, increasing evidence shows the importance of specific somatic events in host cells
[...] Read more.
High-risk human papilloma virus (HPV) infections cause cancers in different organ sites, most commonly cervical and head and neck cancers. While carcinogenesis is initiated by two viral oncoproteins, E6 and E7, increasing evidence shows the importance of specific somatic events in host cells for malignant transformation. HPV-driven cancers share characteristic somatic changes, including apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC)-driven mutations and genomic instability leading to copy number variations and large chromosomal rearrangements. HPV-associated cancers have recurrent somatic mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and phosphatase and tensin homolog (PTEN), human leukocyte antigen A and B (HLA-A and HLA-B)-A/B, and the transforming growth factor beta (TGFβ) pathway, and rarely have mutations in the tumor protein p53 (TP53) and RB transcriptional corepressor 1 (RB1) tumor suppressor genes. There are some variations by tumor site, such as NOTCH1 mutations which are primarily found in head and neck cancers. Understanding the somatic events following HPV infection and persistence can aid the development of early detection biomarkers, particularly when mutations in precancers are characterized. Somatic mutations may also influence prognosis and treatment decisions. Full article
(This article belongs to the Special Issue Expert Views on HPV Infection)
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Open AccessReview Integration of Human Papillomavirus Genomes in Head and Neck Cancer: Is It Time to Consider a Paradigm Shift?
Viruses 2017, 9(8), 208; doi:10.3390/v9080208
Received: 30 June 2017 / Revised: 28 July 2017 / Accepted: 31 July 2017 / Published: 3 August 2017
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Abstract
Human papillomaviruses (HPV) are detected in 70–80% of oropharyngeal cancers in the developed world, the incidence of which has reached epidemic proportions. The current paradigm regarding the status of the viral genome in these cancers is that there are three situations: one where
[...] Read more.
Human papillomaviruses (HPV) are detected in 70–80% of oropharyngeal cancers in the developed world, the incidence of which has reached epidemic proportions. The current paradigm regarding the status of the viral genome in these cancers is that there are three situations: one where the viral genome remains episomal, one where the viral genome integrates into the host genome and a third where there is a mixture of both integrated and episomal HPV genomes. Our recent work suggests that this third category has been mischaracterized as having integrated HPV genomes; evidence indicates that this category consists of virus–human hybrid episomes. Most of these hybrid episomes are consistent with being maintained by replication from HPV origin. We discuss our evidence to support this new paradigm, how such genomes can arise, and more importantly the implications for the clinical management of HPV positive head and neck cancers following accurate determination of the viral genome status. Full article
(This article belongs to the Special Issue Expert Views on HPV Infection)
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Open AccessReview Exosomes and Other Extracellular Vesicles in HPV Transmission and Carcinogenesis
Viruses 2017, 9(8), 211; doi:10.3390/v9080211
Received: 7 July 2017 / Revised: 28 July 2017 / Accepted: 31 July 2017 / Published: 7 August 2017
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Abstract
Extracellular vesicles (EVs), including exosomes (Exos), microvesicles (MVs) and apoptotic bodies (ABs) are released in biofluids by virtually all living cells. Tumor-derived Exos and MVs are garnering increasing attention because of their ability to participate in cellular communication or transfer of bioactive molecules
[...] Read more.
Extracellular vesicles (EVs), including exosomes (Exos), microvesicles (MVs) and apoptotic bodies (ABs) are released in biofluids by virtually all living cells. Tumor-derived Exos and MVs are garnering increasing attention because of their ability to participate in cellular communication or transfer of bioactive molecules (mRNAs, microRNAs, DNA and proteins) between neighboring cancerous or normal cells, and to contribute to human cancer progression. Malignant traits can also be transferred from apoptotic cancer cells to phagocytizing cells, either professional or non-professional. In this review, we focus on Exos and ABs and their relationship with human papillomavirus (HPV)-associated tumor development. The potential implication of EVs as theranostic biomarkers is also addressed. Full article
(This article belongs to the Special Issue Expert Views on HPV Infection)
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Open AccessReview Can Antiretroviral Drugs Be Used to Treat Porcine Endogenous Retrovirus (PERV) Infection after Xenotransplantation?
Viruses 2017, 9(8), 213; doi:10.3390/v9080213
Received: 6 July 2017 / Revised: 2 August 2017 / Accepted: 2 August 2017 / Published: 8 August 2017
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Abstract
Porcine endogenous retroviruses (PERVs) are integrated in the genome of all pigs; they are released as infectious particles, and under certain conditions they can infect human cells. Therefore, they represent a risk when pigs are used as sources of cells, tissues, or organs
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Porcine endogenous retroviruses (PERVs) are integrated in the genome of all pigs; they are released as infectious particles, and under certain conditions they can infect human cells. Therefore, they represent a risk when pigs are used as sources of cells, tissues, or organs for xenotransplantation. Xenotransplantation is under development due to the increasing shortage of human transplants. Whereas most porcine microorganisms which may be able to induce a disease (zoonosis) in the transplant recipient can be eliminated, this is not possible in the case of PERVs. Antiretroviral drugs which had been developed for the treatment of human immunodeficiency virus-1 (HIV-1) infections have been tested in vitro for their efficacy in inhibiting PERV replication. Inhibitors of the viral reverse transcriptase and of the integrase have been found effective. The most effective inhibitor of the reverse transcriptase was azidothymidine (AZT); the integrase inhibitors were the most potent inhibitors of PERV. Although in the past PERV transmission has not been observed after experimental or clinical xenotransplantation of pig cells or organs, and although PERVs may one day be inactivated in pigs by genome editing using CRISPR/Cas, knowing which antiretroviral drugs can effectively restrict PERV infection will still be important. Full article
(This article belongs to the Section Antivirals & Vaccines)
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Open AccessReview Poxviruses Utilize Multiple Strategies to Inhibit Apoptosis
Viruses 2017, 9(8), 215; doi:10.3390/v9080215
Received: 30 June 2017 / Revised: 31 July 2017 / Accepted: 2 August 2017 / Published: 8 August 2017
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Abstract
Cells have multiple means to induce apoptosis in response to viral infection. Poxviruses must prevent activation of cellular apoptosis to ensure successful replication. These viruses devote a substantial portion of their genome to immune evasion. Many of these immune evasion products expressed during
[...] Read more.
Cells have multiple means to induce apoptosis in response to viral infection. Poxviruses must prevent activation of cellular apoptosis to ensure successful replication. These viruses devote a substantial portion of their genome to immune evasion. Many of these immune evasion products expressed during infection antagonize cellular apoptotic pathways. Poxvirus products target multiple points in both the extrinsic and intrinsic apoptotic pathways, thereby mitigating apoptosis during infection. Interestingly, recent evidence indicates that poxviruses also hijack cellular means of eliminating apoptotic bodies as a means to spread cell to cell through a process called apoptotic mimicry. Poxviruses are the causative agent of many human and veterinary diseases. Further, there is substantial interest in developing these viruses as vectors for a variety of uses including vaccine delivery and as oncolytic viruses to treat certain human cancers. Therefore, an understanding of the molecular mechanisms through which poxviruses regulate the cellular apoptotic pathways remains a top research priority. In this review, we consider anti-apoptotic strategies of poxviruses focusing on three relevant poxvirus genera: Orthopoxvirus, Molluscipoxvirus, and Leporipoxvirus. All three genera express multiple products to inhibit both extrinsic and intrinsic apoptotic pathways with many of these products required for virulence. Full article
(This article belongs to the Special Issue Viral Infection and Apoptosis)
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Open AccessReview Regulation of Telomere Homeostasis during Epstein-Barr virus Infection and Immortalization
Viruses 2017, 9(8), 217; doi:10.3390/v9080217
Received: 3 July 2017 / Revised: 25 July 2017 / Accepted: 26 July 2017 / Published: 9 August 2017
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Abstract
The acquisition of unlimited proliferative potential is dependent on the activation of mechanisms for telomere maintenance, which counteracts telomere shortening and the consequent triggering of the DNA damage response, cell cycle arrest, and apoptosis. The capacity of Epstein Barr virus (EBV) to infect
[...] Read more.
The acquisition of unlimited proliferative potential is dependent on the activation of mechanisms for telomere maintenance, which counteracts telomere shortening and the consequent triggering of the DNA damage response, cell cycle arrest, and apoptosis. The capacity of Epstein Barr virus (EBV) to infect B-lymphocytes in vitro and transform the infected cells into autonomously proliferating immortal cell lines underlies the association of this human gamma-herpesvirus with a broad variety of lymphoid and epithelial cell malignancies. Current evidence suggests that both telomerase-dependent and -independent pathways of telomere elongation are activated in the infected cells during the early and late phases of virus-induced immortalization. Here we review the interaction of EBV with different components of the telomere maintenance machinery and the mechanisms by which the virus regulates telomere homeostasis in proliferating cells. We also discuss how these viral strategies may contribute to malignant transformation. Full article
(This article belongs to the Special Issue Viruses and Telomeres)
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Open AccessFeature PaperReview The Telomeric Response to Viral Infection
Viruses 2017, 9(8), 218; doi:10.3390/v9080218
Received: 9 July 2017 / Revised: 6 August 2017 / Accepted: 6 August 2017 / Published: 9 August 2017
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Abstract
The ends of linear genomes, whether viral or cellular, can elicit potent DNA damage and innate immune signals. DNA viruses entering the nucleus share many features with telomeres in their ability to either suppress or co-opt these pathways. Here, we review some of
[...] Read more.
The ends of linear genomes, whether viral or cellular, can elicit potent DNA damage and innate immune signals. DNA viruses entering the nucleus share many features with telomeres in their ability to either suppress or co-opt these pathways. Here, we review some of the common mechanisms that viruses and telomeres use to manage the DNA damage and innate immune response pathways. We highlight recent studies on the role of the telomere repeat-containing RNA (TERRA) in response to viral infection. We discuss how TERRA can be activated through a p53-response element embedded in a retrotransposon-like repeat found in human subtelomeres. We consider how TERRA can function as a danger signal when secreted in extracellular vesicles to induce inflammatory cytokines in neighboring cells. These findings suggest that TERRA may be part of the innate immune response to viral infection, and support the hypothesis that telomeres and viruses utilize common mechanisms to maintain genome integrity and regulate innate immunity. Full article
(This article belongs to the Special Issue Viruses and Telomeres)
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Open AccessReview Human Papillomavirus and the Stroma: Bidirectional Crosstalk during the Virus Life Cycle and Carcinogenesis
Viruses 2017, 9(8), 219; doi:10.3390/v9080219
Received: 30 June 2017 / Revised: 3 August 2017 / Accepted: 4 August 2017 / Published: 9 August 2017
PDF Full-text (1580 KB) | HTML Full-text | XML Full-text
Abstract
Human papillomaviruses (HPVs) are double-stranded DNA (dsDNA) tumor viruses that are causally associated with human cancers of the anogenital tract, skin, and oral cavity. Despite the availability of prophylactic vaccines, HPVs remain a major global health issue due to inadequate vaccine availability and
[...] Read more.
Human papillomaviruses (HPVs) are double-stranded DNA (dsDNA) tumor viruses that are causally associated with human cancers of the anogenital tract, skin, and oral cavity. Despite the availability of prophylactic vaccines, HPVs remain a major global health issue due to inadequate vaccine availability and vaccination coverage. The HPV life cycle is established and completed in the terminally differentiating stratified epithelia, and decades of research using in vitro organotypic raft cultures and in vivo genetically engineered mouse models have contributed to our understanding of the interactions between HPVs and the epithelium. More recently, important and emerging roles for the underlying stroma, or microenvironment, during the HPV life cycle and HPV-induced disease have become clear. This review discusses the current understanding of the bidirectional communication and relationship between HPV-infected epithelia and the surrounding microenvironment. As is the case with other human cancers, evidence suggests that the stroma functions as a significant partner in tumorigenesis and helps facilitate the oncogenic potential of HPVs in the stratified epithelium. Full article
(This article belongs to the Special Issue Expert Views on HPV Infection)
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Open AccessReview Changing Stem Cell Dynamics during Papillomavirus Infection: Potential Roles for Cellular Plasticity in the Viral Lifecycle and Disease
Viruses 2017, 9(8), 221; doi:10.3390/v9080221
Received: 7 July 2017 / Revised: 7 August 2017 / Accepted: 8 August 2017 / Published: 12 August 2017
PDF Full-text (1120 KB) | HTML Full-text | XML Full-text
Abstract
Stem cells and cellular plasticity are likely important components of tissue response to infection. There is emerging evidence that stem cells harbor receptors for common pathogen motifs and that they are receptive to local inflammatory signals in ways suggesting that they are critical
[...] Read more.
Stem cells and cellular plasticity are likely important components of tissue response to infection. There is emerging evidence that stem cells harbor receptors for common pathogen motifs and that they are receptive to local inflammatory signals in ways suggesting that they are critical responders that determine the balance between health and disease. In the field of papillomaviruses stem cells have been speculated to play roles during the viral life cycle, particularly during maintenance, and virus-promoted carcinogenesis but little has been conclusively determined. I summarize here evidence that gives clues to the potential role of stem cells and cellular plasticity in the lifecycle papillomavirus and linked carcinogenesis. I also discuss outstanding questions which need to be resolved. Full article
(This article belongs to the Special Issue Expert Views on HPV Infection)
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Open AccessReview Influenza Virus Infection, Interferon Response, Viral Counter-Response, and Apoptosis
Viruses 2017, 9(8), 223; doi:10.3390/v9080223
Received: 30 June 2017 / Revised: 27 July 2017 / Accepted: 8 August 2017 / Published: 12 August 2017
PDF Full-text (819 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Human influenza A viruses (IAVs) cause global pandemics and epidemics, which remain serious threats to public health because of the shortage of effective means of control. To combat the surge of viral outbreaks, new treatments are urgently needed. Developing new virus control modalities
[...] Read more.
Human influenza A viruses (IAVs) cause global pandemics and epidemics, which remain serious threats to public health because of the shortage of effective means of control. To combat the surge of viral outbreaks, new treatments are urgently needed. Developing new virus control modalities requires better understanding of virus-host interactions. Here, we describe how IAV infection triggers cellular apoptosis and how this process can be exploited towards the development of new therapeutics, which might be more effective than the currently available anti-influenza drugs. Full article
(This article belongs to the Special Issue Viral Infection and Apoptosis)
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Open AccessReview Hepatitis C Virus-Induced Autophagy and Host Innate Immune Response
Viruses 2017, 9(8), 224; doi:10.3390/v9080224
Received: 5 July 2017 / Revised: 4 August 2017 / Accepted: 11 August 2017 / Published: 12 August 2017
PDF Full-text (787 KB) | HTML Full-text | XML Full-text
Abstract
Autophagy is a catabolic process that is important for maintaining cellular homeostasis. This pathway in hepatocytes is stimulated and controlled by the hepatitis C virus (HCV)—upon infection—to promote its own replication. HCV induces autophagy indirectly and directly through different mechanisms and temporally controls
[...] Read more.
Autophagy is a catabolic process that is important for maintaining cellular homeostasis. This pathway in hepatocytes is stimulated and controlled by the hepatitis C virus (HCV)—upon infection—to promote its own replication. HCV induces autophagy indirectly and directly through different mechanisms and temporally controls the autophagic flux. This enables the virus to maximize its replication and attenuate the innate immune responses that it activates. In this review, we discuss the relationship between HCV and autophagy, and the crosstalk between HCV-induced autophagy and host innate immune responses. Full article
(This article belongs to the Special Issue Viruses and Autophagy)
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Open AccessReview Disentangling the Frames, the State of Research on the Alphavirus 6K and TF Proteins
Viruses 2017, 9(8), 228; doi:10.3390/v9080228 (registering DOI)
Received: 17 June 2017 / Revised: 3 August 2017 / Accepted: 16 August 2017 / Published: 18 August 2017
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Abstract
For 30 years it was thought the alphavirus 6K gene encoded a single 6 kDa protein. However, through a bioinformatics search 10 years ago, it was discovered that there is a frameshifting event and two proteins, 6K and transframe (TF), are translated from
[...] Read more.
For 30 years it was thought the alphavirus 6K gene encoded a single 6 kDa protein. However, through a bioinformatics search 10 years ago, it was discovered that there is a frameshifting event and two proteins, 6K and transframe (TF), are translated from the 6K gene. Thus, many functions attributed to the 6K protein needed reevaluation to determine if they properly belong to 6K, TF, or both proteins. In this mini-review, we reevaluate the past research on 6K and put those results in context where there are two proteins, 6K and TF, instead of one. Additionally, we discuss the most cogent outstanding questions for 6K and TF research, including their collective importance in alphavirus budding and their potential importance in disease based on the latest virulence data. Full article
(This article belongs to the Special Issue Advances in Alphavirus Research)
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Open AccessReview Targeting Persistent Human Papillomavirus Infection
Viruses 2017, 9(8), 229; doi:10.3390/v9080229 (registering DOI)
Received: 30 July 2017 / Revised: 30 July 2017 / Accepted: 15 August 2017 / Published: 18 August 2017
PDF Full-text (1478 KB) | HTML Full-text | XML Full-text
Abstract
While the majority of Human papillomavirus (HPV) infections are transient and cleared within a couple of years following exposure, 10–20% of infections persist latently, leading to disease progression and, ultimately, various forms of invasive cancer. Despite the clinical efficiency of recently developed multivalent
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While the majority of Human papillomavirus (HPV) infections are transient and cleared within a couple of years following exposure, 10–20% of infections persist latently, leading to disease progression and, ultimately, various forms of invasive cancer. Despite the clinical efficiency of recently developed multivalent prophylactic HPV vaccines, these preventive measures are not effective against pre-existing infection. Additionally, considering that the burden associated with HPV is greatest in regions with limited access to preventative vaccination, the development of effective therapies targeting persistent infection remains imperative. This review discusses not only the mechanisms underlying persistent HPV infection, but also the promise of immunomodulatory therapeutic vaccines and small-molecular inhibitors, which aim to augment the host immune response against the viral infection as well as obstruct critical viral–host interactions. Full article
(This article belongs to the Special Issue Expert Views on HPV Infection)
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Open AccessReview Interference of Apoptosis by Hepatitis B Virus
Viruses 2017, 9(8), 230; doi:10.3390/v9080230 (registering DOI)
Received: 30 June 2017 / Revised: 7 August 2017 / Accepted: 10 August 2017 / Published: 18 August 2017
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Abstract
Hepatitis B virus (HBV) causes liver diseases that have been a consistent problem for human health, leading to more than one million deaths every year worldwide. A large proportion of hepatocellular carcinoma (HCC) cases across the world are closely associated with chronic HBV
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Hepatitis B virus (HBV) causes liver diseases that have been a consistent problem for human health, leading to more than one million deaths every year worldwide. A large proportion of hepatocellular carcinoma (HCC) cases across the world are closely associated with chronic HBV infection. Apoptosis is a programmed cell death and is frequently altered in cancer development. HBV infection interferes with the apoptosis signaling to promote HCC progression and viral proliferation. The HBV-mediated alteration of apoptosis is achieved via interference with cellular signaling pathways and regulation of epigenetics. HBV X protein (HBX) plays a major role in the interference of apoptosis. There are conflicting reports on the HBV interference of apoptosis with the majority showing inhibition of and the rest reporting induction of apoptosis. In this review, we described recent studies on the mechanisms of the HBV interference with the apoptosis signaling during the virus infection and provided perspective. Full article
(This article belongs to the Special Issue Viral Infection and Apoptosis)
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Open AccessReview Human Papillomavirus and the DNA Damage Response: Exploiting Host Repair Pathways for Viral Replication
Viruses 2017, 9(8), 232; doi:10.3390/v9080232 (registering DOI)
Received: 22 June 2017 / Revised: 11 August 2017 / Accepted: 14 August 2017 / Published: 18 August 2017
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Abstract
High-risk human papillomaviruses (HPVs) are the causative agents of cervical and other genital cancers. In addition, HPV infections are associated with the development of many oropharyngeal cancers. HPVs activate and repress a number of host cellular pathways to promote their viral life cycles,
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High-risk human papillomaviruses (HPVs) are the causative agents of cervical and other genital cancers. In addition, HPV infections are associated with the development of many oropharyngeal cancers. HPVs activate and repress a number of host cellular pathways to promote their viral life cycles, including those of the DNA damage response. High-risk HPVs activate the ataxia telangiectasia-mutated (ATM) and ATM and Rad3-related (ATR) DNA damage repair pathways, which are essential for viral replication (particularly differentiation-dependent genome amplification). These DNA repair pathways are critical in maintaining host genomic integrity and stability and are often dysregulated or mutated in human cancers. Understanding how these pathways contribute to HPV replication and transformation may lead to the identification of new therapeutic targets for the treatment of existing HPV infections. Full article
(This article belongs to the Special Issue Viruses and the DNA Damage Response)

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Open AccessShort Communication Characterization of a Novel RNA Virus Discovered in the Autumnal Moth Epirrita autumnata in Sweden
Viruses 2017, 9(8), 214; doi:10.3390/v9080214
Received: 4 July 2017 / Revised: 28 July 2017 / Accepted: 2 August 2017 / Published: 8 August 2017
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Abstract
A novel, 10 kb RNA virus—tentatively named ‘Abisko virus’—was discovered in the transcriptome data of a diseased autumnal moth (Epirrita autumnata) larva, as part of a search for the possible causes of the cyclical nature and mortality associated with geometrid moth
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A novel, 10 kb RNA virus—tentatively named ‘Abisko virus’—was discovered in the transcriptome data of a diseased autumnal moth (Epirrita autumnata) larva, as part of a search for the possible causes of the cyclical nature and mortality associated with geometrid moth dynamics and outbreaks in northern Fennoscandia. Abisko virus has a genome organization similar to that of the insect-infecting negeviruses, but phylogenetic and compositional bias analyses also reveal strong affiliations with plant-infecting viruses, such that both the primary host origin and taxonomic identity of the virus remain in doubt. In an extensive set of larval, pupal, and adult autumnal moth and winter moth (Operophtera brumata) outbreak samples, the virus was only detected in a few adult E. autumnata moths as well as the single larval transcriptome. The Abisko virus is therefore unlikely to be a factor in the Fennoscandia geometrid population dynamics. Full article
(This article belongs to the Section Insect Viruses)
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