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Viruses, Volume 9, Issue 12 (December 2017)

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Cover Story (view full-size image) Preclinical infection model systems are extremely valuable tools to aid our understanding of human [...] Read more.
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Open AccessReview Biology of Porcine Parvovirus (Ungulate parvovirus 1)
Viruses 2017, 9(12), 393; https://doi.org/10.3390/v9120393
Received: 1 December 2017 / Revised: 17 December 2017 / Accepted: 18 December 2017 / Published: 20 December 2017
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Abstract
Porcine parvovirus (PPV) is among the most important infectious agents causing infertility in pigs. Until recently, it was thought that the virus had low genetic variance, and that prevention of its harmful effect on pig fertility could be well-controlled by vaccination. However, at
[...] Read more.
Porcine parvovirus (PPV) is among the most important infectious agents causing infertility in pigs. Until recently, it was thought that the virus had low genetic variance, and that prevention of its harmful effect on pig fertility could be well-controlled by vaccination. However, at the beginning of the third millennium, field observations raised concerns about the effectiveness of the available vaccines against newly emerging strains. Subsequent investigations radically changed our view on the evolution and immunology of PPV, revealing that the virus is much more diverse than it was earlier anticipated, and that some of the “new” highly virulent isolates cannot be neutralized effectively by antisera raised against “old” PPV vaccine strains. These findings revitalized PPV research that led to significant advancements in the understanding of early and late viral processes during PPV infection. Our review summarizes the recent results of PPV research and aims to give a comprehensive update on the present understanding of PPV biology. Full article
(This article belongs to the Special Issue Protoparvoviruses: Friends or Foes?)
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Open AccessArticle Characterization of HIV-1 Near Full-Length Proviral Genome Quasispecies from Patients with Undetectable Viral Load Undergoing First-Line HAART Therapy
Viruses 2017, 9(12), 392; https://doi.org/10.3390/v9120392
Received: 1 December 2017 / Revised: 16 December 2017 / Accepted: 18 December 2017 / Published: 19 December 2017
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Abstract
Increased access to highly active antiretroviral therapy (HAART) by human immunodeficiency virus postive (HIV+) individuals has become a reality worldwide. In Brazil, HAART currently reaches over half of HIV-infected subjects. In the context of a remarkable HIV-1 genetic variability, highly related
[...] Read more.
Increased access to highly active antiretroviral therapy (HAART) by human immunodeficiency virus postive (HIV+) individuals has become a reality worldwide. In Brazil, HAART currently reaches over half of HIV-infected subjects. In the context of a remarkable HIV-1 genetic variability, highly related variants, called quasispecies, are generated. HIV quasispecies generated during infection can influence virus persistence and pathogenicity, representing a challenge to treatment. However, the clinical relevance of minority quasispecies is still uncertain. In this study, we have determined the archived proviral sequences, viral subtype and drug resistance mutations from a cohort of HIV+ patients with undetectable viral load undergoing HAART as first-line therapy using next-generation sequencing for near full-length virus genome (NFLG) assembly. HIV-1 consensus sequences representing NFLG were obtained for eleven patients, while for another twelve varying genome coverage rates were obtained. Phylogenetic analysis showed the predominance of subtype B (83%; 19/23). Considering the minority variants, 18 patients carried archived virus harboring at least one mutation conferring antiretroviral resistance; for six patients, the mutations correlated with the current ARVs used. These data highlight the importance of monitoring HIV minority drug resistant variants and their clinical impact, to guide future regimen switches and improve HIV treatment success. Full article
(This article belongs to the Special Issue Homage to Mark Wainberg)
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Open AccessArticle Experimental Cowpox Virus (CPXV) Infections of Bank Voles: Exceptional Clinical Resistance and Variable Reservoir Competence
Viruses 2017, 9(12), 391; https://doi.org/10.3390/v9120391
Received: 27 September 2017 / Revised: 13 December 2017 / Accepted: 14 December 2017 / Published: 19 December 2017
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Abstract
Cowpox virus (CPXV) is a zoonotic virus and endemic in wild rodent populations in Eurasia. Serological surveys in Europe have reported high prevalence in different vole and mouse species. Here, we report on experimental CPXV infections of bank voles (Myodes glareolus)
[...] Read more.
Cowpox virus (CPXV) is a zoonotic virus and endemic in wild rodent populations in Eurasia. Serological surveys in Europe have reported high prevalence in different vole and mouse species. Here, we report on experimental CPXV infections of bank voles (Myodes glareolus) from different evolutionary lineages with a spectrum of CPXV strains. All bank voles, independently of lineage, sex and age, were resistant to clinical signs following CPXV inoculation, and no virus shedding was detected in nasal or buccal swabs. In-contact control animals became only rarely infected. However, depending on the CPXV strain used, inoculated animals seroconverted and viral DNA could be detected preferentially in the upper respiratory tract. The highest antibody titers and virus DNA loads in the lungs were detected after inoculation with two strains from Britain and Finland. We conclude from our experiments that the role of bank voles as an efficient and exclusive CPXV reservoir seems questionable, and that CPXV may be maintained in most regions by other hosts, including other vole species. Further investigations are needed to identify factors that allow and modulate CPXV maintenance in bank voles and other potential reservoirs, which may also influence spill-over infections to accidental hosts. Full article
(This article belongs to the Special Issue Smallpox and Emerging Zoonotic Orthopoxviruses: What Is Coming Next?)
Open AccessReview How Human Papillomavirus Replication and Immune Evasion Strategies Take Advantage of the Host DNA Damage Repair Machinery
Viruses 2017, 9(12), 390; https://doi.org/10.3390/v9120390
Received: 13 November 2017 / Revised: 14 December 2017 / Accepted: 16 December 2017 / Published: 19 December 2017
Cited by 1 | PDF Full-text (808 KB) | HTML Full-text | XML Full-text
Abstract
The DNA damage response (DDR) is a complex signalling network activated when DNA is altered by intrinsic or extrinsic agents. DDR plays important roles in genome stability and cell cycle regulation, as well as in tumour transformation. Viruses have evolved successful life cycle
[...] Read more.
The DNA damage response (DDR) is a complex signalling network activated when DNA is altered by intrinsic or extrinsic agents. DDR plays important roles in genome stability and cell cycle regulation, as well as in tumour transformation. Viruses have evolved successful life cycle strategies in order to ensure a chronic persistence in the host, virtually avoiding systemic sequelae and death. This process promotes the periodic shedding of large amounts of infectious particles to maintain a virus reservoir in individual hosts, while allowing virus spreading within the community. To achieve such a successful lifestyle, the human papilloma virus (HPV) needs to escape the host defence systems. The key to understanding how this is achieved is in the virus replication process that provides by itself an evasion mechanism by inhibiting and delaying the host immune response against the viral infection. Numerous studies have demonstrated that HPV exploits both the ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia and rad3-related (ATR) DDR pathways to replicate its genome and maintain a persistent infection by downregulating the innate and cell-mediated immunity. This review outlines how HPV interacts with the ATM- and ATR-dependent DDR machinery during the viral life cycle to create an environment favourable to viral replication, and how the interaction with the signal transducers and activators of transcription (STAT) protein family and the deregulation of the Janus kinase (JAK)–STAT pathways may impact the expression of interferon-inducible genes and the innate immune responses. Full article
(This article belongs to the Special Issue Viruses and the DNA Damage Response)
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Open AccessArticle The Influence of E1A C-Terminus on Adenovirus Replicative Cycle
Viruses 2017, 9(12), 387; https://doi.org/10.3390/v9120387
Received: 27 November 2017 / Revised: 15 December 2017 / Accepted: 16 December 2017 / Published: 19 December 2017
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Abstract
Adenovirus Early 1A proteins (E1A) are crucial for initiation of the viral life cycle after infection. The E1A gene is encoded at the left end of the viral genome and consists of two exons, the first encoding 185 amino acids in the 289
[...] Read more.
Adenovirus Early 1A proteins (E1A) are crucial for initiation of the viral life cycle after infection. The E1A gene is encoded at the left end of the viral genome and consists of two exons, the first encoding 185 amino acids in the 289 residues adenovirus 5 E1A, while the second exon encodes 104 residues. The second exon-encoded region of E1A is conserved across all E1A isoforms except for the 55 residues protein, which has a unique C-terminus due to a frame shift following splicing into the second exon. This region of E1A contributes to a variety of processes including the regulation of viral and cellular gene expression, immortalization and transformation. Here we evaluated the contributions that different regions of the second exon of E1A make to the viral life cycle using deletion mutants. The region of E1A encoded by the second exon was found to be important for overall virus growth, induction of viral and cellular gene expression, viral genome replication and deregulation of the cell cycle. Efficient viral replication was found to require exon 2 and the nuclear localization signal, as loss of either resulted in severe growth deficiency. Induction of cellular DNA synthesis was also deficient with any deletion of E1A within the C-terminus even if these deletions were outside of conserved region 4. Overall, our study provides the first comprehensive insight into the contributions of the C-terminus of E1A to the replicative fitness of human adenovirus 5 in arrested lung fibroblasts. Full article
(This article belongs to the Special Issue Viral Subversion of Transcriptional Control)
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Open AccessArticle Mutations in HPV18 E1^E4 Impact Virus Capsid Assembly, Infectivity Competence, and Maturation
Viruses 2017, 9(12), 385; https://doi.org/10.3390/v9120385
Received: 15 November 2017 / Revised: 14 December 2017 / Accepted: 15 December 2017 / Published: 19 December 2017
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Abstract
The most highly expressed protein during the productive phase of the human papillomavirus (HPV) life cycle is E1^E4. Its full role during infection remains to be established. HPV E1^E4 is expressed during both the early and late stages of the virus life cycle
[...] Read more.
The most highly expressed protein during the productive phase of the human papillomavirus (HPV) life cycle is E1^E4. Its full role during infection remains to be established. HPV E1^E4 is expressed during both the early and late stages of the virus life cycle and contributes to viral genome amplification. In an attempt to further outline the functions of E1^E4, and determine whether it plays a role in viral capsid assembly and viral infectivity, we examined wild-type E1^E4 as well as four E1^E4 truncation mutants. Our study revealed that HPV18 genomes containing the shortest truncated form of E1^E4, the 17/18 mutant, produced viral titers that were similar to wild-type virus and significantly higher compared to virions containing the three longer E1^E4 mutants. Additionally, the infectivity of virus containing the shortest E1^E4 mutation was equivalent to wild-type and significantly higher than the other three mutants. In contrast, infectivity was completely abrogated for virus containing the longer E1^E4 mutants, regardless of virion maturity. Taken together, our results indicate for the first time that HPV18 E1^E4 impacts capsid assembly and viral infectivity as well as virus maturation. Full article
(This article belongs to the Section Animal Viruses)
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Open AccessReview Implication of Different HIV-1 Genes in the Modulation of Autophagy
Viruses 2017, 9(12), 389; https://doi.org/10.3390/v9120389
Received: 22 November 2017 / Revised: 12 December 2017 / Accepted: 13 December 2017 / Published: 18 December 2017
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Abstract
Autophagy is a complex cellular degradation pathway, which plays important roles in the regulation of several developmental processes, cellular stress responses, and immune responses induced by pathogens. A number of studies have previously demonstrated that HIV-1 was capable of altering the regulation of
[...] Read more.
Autophagy is a complex cellular degradation pathway, which plays important roles in the regulation of several developmental processes, cellular stress responses, and immune responses induced by pathogens. A number of studies have previously demonstrated that HIV-1 was capable of altering the regulation of autophagy and that this biological process could be induced in uninfected and infected cells. Furthermore, previous reports have indicated that the involvement of HIV-1 in autophagy regulation is a complex phenomenon and that different viral proteins are contributing in its modulation upon viral infection. Herein, we review the recent literature over the complex crosstalk of the autophagy pathway and HIV-1, with a particular focus on HIV-1 viral proteins, which have been shown to modulate autophagy. Full article
(This article belongs to the Special Issue Viruses and Autophagy)
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Open AccessArticle Stress Granule-Inducing Eukaryotic Translation Initiation Factor 4A Inhibitors Block Influenza A Virus Replication
Viruses 2017, 9(12), 388; https://doi.org/10.3390/v9120388
Received: 2 November 2017 / Revised: 3 December 2017 / Accepted: 15 December 2017 / Published: 18 December 2017
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Abstract
Eukaryotic translation initiation factor 4A (eIF4A) is a helicase that facilitates assembly of the translation preinitiation complex by unwinding structured mRNA 5′ untranslated regions. Pateamine A (PatA) and silvestrol are natural products that disrupt eIF4A function and arrest translation, thereby triggering the formation
[...] Read more.
Eukaryotic translation initiation factor 4A (eIF4A) is a helicase that facilitates assembly of the translation preinitiation complex by unwinding structured mRNA 5′ untranslated regions. Pateamine A (PatA) and silvestrol are natural products that disrupt eIF4A function and arrest translation, thereby triggering the formation of cytoplasmic aggregates of stalled preinitiation complexes known as stress granules (SGs). Here we examined the effects of eIF4A inhibition by PatA and silvestrol on influenza A virus (IAV) protein synthesis and replication in cell culture. Treatment of infected cells with either PatA or silvestrol at early times post-infection resulted in SG formation, arrest of viral protein synthesis and failure to replicate the viral genome. PatA, which irreversibly binds to eIF4A, sustained long-term blockade of IAV replication following drug withdrawal, and inhibited IAV replication at concentrations that had minimal cytotoxicity. By contrast, the antiviral effects of silvestrol were fully reversible; drug withdrawal caused rapid SG dissolution and resumption of viral protein synthesis. IAV inhibition by silvestrol was invariably associated with cytotoxicity. PatA blocked replication of genetically divergent IAV strains, suggesting common dependence on host eIF4A activity. This study demonstrates that the core host protein synthesis machinery can be targeted to block viral replication. Full article
(This article belongs to the Section Antivirals & Vaccines)
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Open AccessReview Recognizing the SINEs of Infection: Regulation of Retrotransposon Expression and Modulation of Host Cell Processes
Viruses 2017, 9(12), 386; https://doi.org/10.3390/v9120386
Received: 28 November 2017 / Revised: 12 December 2017 / Accepted: 17 December 2017 / Published: 18 December 2017
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Abstract
Short interspersed elements (SINEs) are a family of retrotransposons evolutionarily derived from cellular RNA polymerase III transcripts. Over evolutionary time, SINEs have expanded throughout the human genome and today comprise ~11% of total chromosomal DNA. While generally transcriptionally silent in healthy somatic cells,
[...] Read more.
Short interspersed elements (SINEs) are a family of retrotransposons evolutionarily derived from cellular RNA polymerase III transcripts. Over evolutionary time, SINEs have expanded throughout the human genome and today comprise ~11% of total chromosomal DNA. While generally transcriptionally silent in healthy somatic cells, SINE expression increases during a variety of types of stresses, including DNA virus infection. The relevance of SINE expression to viral infection was largely unexplored, however, recent years have seen great progress towards defining the impact of SINE expression on viral replication and host gene expression. Here we review the origin and diversity of SINE elements and their transcriptional control, with an emphasis on how their expression impacts host cell biology during viral infection. Full article
(This article belongs to the Special Issue Long Non-Coding RNAs and Antiviral Immunity)
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Open AccessArticle Cleavage and Structural Transitions during Maturation of Staphylococcus aureus Bacteriophage 80α and SaPI1 Capsids
Viruses 2017, 9(12), 384; https://doi.org/10.3390/v9120384
Received: 17 November 2017 / Revised: 8 December 2017 / Accepted: 15 December 2017 / Published: 16 December 2017
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Abstract
In the tailed bacteriophages, DNA is packaged into spherical procapsids, leading to expansion into angular, thin-walled mature capsids. In many cases, this maturation is accompanied by cleavage of the major capsid protein (CP) and other capsid-associated proteins, including the scaffolding protein (SP) that
[...] Read more.
In the tailed bacteriophages, DNA is packaged into spherical procapsids, leading to expansion into angular, thin-walled mature capsids. In many cases, this maturation is accompanied by cleavage of the major capsid protein (CP) and other capsid-associated proteins, including the scaffolding protein (SP) that serves as a chaperone for the assembly process. Staphylococcus aureus bacteriophage 80α is capable of high frequency mobilization of mobile genetic elements called S. aureus pathogenicity islands (SaPIs), such as SaPI1. SaPI1 redirects the assembly pathway of 80α to form capsids that are smaller than those normally made by the phage alone. Both CP and SP of 80α are N-terminally processed by a host-encoded protease, Prp. We have analyzed phage mutants that express pre-cleaved or uncleavable versions of CP or SP, and show that the N-terminal sequence in SP is absolutely required for assembly, but does not need to be cleaved in order to produce viable capsids. Mutants with pre-cleaved or uncleavable CP display normal viability. We have used cryo-EM to solve the structures of mature capsids from an 80α mutant expressing uncleavable CP, and from wildtype SaPI1. Comparisons with structures of 80α and SaPI1 procapsids show that capsid maturation involves major conformational changes in CP, consistent with a release of the CP N-arm by SP. The hexamers reorganize during maturation to accommodate the different environments in the 80α and SaPI1 capsids. Full article
(This article belongs to the Special Issue Advances in Structural Virology via Cryo-EM)
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Open AccessArticle Zika Virus Exhibits Lineage-Specific Phenotypes in Cell Culture, in Aedes aegypti Mosquitoes, and in an Embryo Model
Viruses 2017, 9(12), 383; https://doi.org/10.3390/v9120383
Received: 25 October 2017 / Revised: 7 December 2017 / Accepted: 13 December 2017 / Published: 16 December 2017
Cited by 4 | PDF Full-text (2862 KB) | HTML Full-text | XML Full-text
Abstract
Zika virus (ZIKV) has quietly circulated in Africa and Southeast Asia for the past 65 years. However, the recent ZIKV epidemic in the Americas propelled this mosquito-borne virus to the forefront of flavivirus research. Based on historical evidence, ZIKV infections in Africa were
[...] Read more.
Zika virus (ZIKV) has quietly circulated in Africa and Southeast Asia for the past 65 years. However, the recent ZIKV epidemic in the Americas propelled this mosquito-borne virus to the forefront of flavivirus research. Based on historical evidence, ZIKV infections in Africa were sporadic and caused mild symptoms such as fever, skin rash, and general malaise. In contrast, recent Asian-lineage ZIKV infections in the Pacific Islands and the Americas are linked to birth defects and neurological disorders. The aim of this study is to compare replication, pathogenicity, and transmission efficiency of two historic and two contemporary ZIKV isolates in cell culture, the mosquito host, and an embryo model to determine if genetic variation between the African and Asian lineages results in phenotypic differences. While all tested isolates replicated at similar rates in Vero cells, the African isolates displayed more rapid viral replication in the mosquito C6/36 cell line, yet they exhibited poor infection rates in Aedes aegypti mosquitoes compared to the contemporary Asian-lineage isolates. All isolates could infect chicken embryos; however, infection with African isolates resulted in higher embryo mortality than infection with Asian-lineage isolates. These results suggest that genetic variation between ZIKV isolates can significantly alter experimental outcomes. Full article
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Open AccessCommunication Immunotherapeutic Potential of Oncolytic H-1 Parvovirus: Hints of Glioblastoma Microenvironment Conversion towards Immunogenicity
Viruses 2017, 9(12), 382; https://doi.org/10.3390/v9120382
Received: 17 November 2017 / Revised: 8 December 2017 / Accepted: 11 December 2017 / Published: 15 December 2017
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Abstract
Glioblastoma, one of the most aggressive primary brain tumors, is characterized by highly immunosuppressive microenvironment. This contributes to glioblastoma resistance to standard treatment modalities and allows tumor growth and recurrence. Several immune-targeted approaches have been recently developed and are currently under preclinical and
[...] Read more.
Glioblastoma, one of the most aggressive primary brain tumors, is characterized by highly immunosuppressive microenvironment. This contributes to glioblastoma resistance to standard treatment modalities and allows tumor growth and recurrence. Several immune-targeted approaches have been recently developed and are currently under preclinical and clinical investigation. Oncolytic viruses, including the autonomous protoparvovirus H-1 (H-1PV), show great promise as novel immunotherapeutic tools. In a first phase I/IIa clinical trial (ParvOryx01), H-1PV was safe and well tolerated when locally or systemically administered to recurrent glioblastoma patients. The virus was able to cross the blood–brain (tumor) barrier after intravenous infusion. Importantly, H-1PV treatment of glioblastoma patients was associated with immunogenic changes in the tumor microenvironment. Tumor infiltration with activated cytotoxic T cells, induction of cathepsin B and inducible nitric oxide (NO) synthase (iNOS) expression in tumor-associated microglia/macrophages (TAM), and accumulation of activated TAM in cluster of differentiation (CD) 40 ligand (CD40L)-positive glioblastoma regions was detected. These are the first-in-human observations of H-1PV capacity to switch the immunosuppressed tumor microenvironment towards immunogenicity. Based on this pilot study, we present a tentative model of H-1PV-mediated modulation of glioblastoma microenvironment and propose a combinatorial therapeutic approach taking advantage of H-1PV-induced microglia/macrophage activation for further (pre)clinical testing. Full article
(This article belongs to the Special Issue Protoparvoviruses: Friends or Foes?)
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Open AccessCommentary The Platonic Receptacle (Hypodoché), Whitehead’s Philosophy, and Genome Evolution
Viruses 2017, 9(12), 381; https://doi.org/10.3390/v9120381
Received: 1 November 2017 / Revised: 5 December 2017 / Accepted: 11 December 2017 / Published: 14 December 2017
Cited by 1 | PDF Full-text (172 KB) | HTML Full-text | XML Full-text
Abstract
The discovery of a universal genetic code utilized by all existing organisms became the backbone of biology. The coding capacity underwent changes during evolution, but its main fluctuation results from its different reading and regulation. The genetic code thus represents a sort of
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The discovery of a universal genetic code utilized by all existing organisms became the backbone of biology. The coding capacity underwent changes during evolution, but its main fluctuation results from its different reading and regulation. The genetic code thus represents a sort of receptacle of living organism evolution. In this article, we propose an analogy between the genetic code and a broader Platonic hypodoché, a concept that Alfred North Whitehead used to explain various aspects of science. Full article
Open AccessReview Improving the Care and Treatment of Monkeypox Patients in Low-Resource Settings: Applying Evidence from Contemporary Biomedical and Smallpox Biodefense Research
Viruses 2017, 9(12), 380; https://doi.org/10.3390/v9120380
Received: 6 October 2017 / Revised: 16 November 2017 / Accepted: 7 December 2017 / Published: 12 December 2017
Cited by 1 | PDF Full-text (1269 KB) | HTML Full-text | XML Full-text
Abstract
Monkeypox is a smallpox-like illness that can be accompanied by a range of significant medical complications. To date there are no standard or optimized guidelines for the clinical management of monkeypox (MPX) patients, particularly in low-resource settings. Consequently, patients can experience protracted illness
[...] Read more.
Monkeypox is a smallpox-like illness that can be accompanied by a range of significant medical complications. To date there are no standard or optimized guidelines for the clinical management of monkeypox (MPX) patients, particularly in low-resource settings. Consequently, patients can experience protracted illness and poor outcomes. Improving care necessitates developing a better understanding of the range of clinical manifestations—including complications and sequelae—as well as of features of illness that may be predictive of illness severity and poor outcomes. Experimental and natural infection of non-human primates with monkeypox virus can inform the approach to improving patient care, and may suggest options for pharmaceutical intervention. These studies have traditionally been performed to address the threat of smallpox bioterrorism and were designed with the intent of using MPX as a disease surrogate for smallpox. In many cases this necessitated employing high-dose, inhalational or intravenous challenge to recapitulate the severe manifestations of illness seen with smallpox. Overall, these data—and data from biomedical research involving burns, superficial wounds, herpes, eczema vaccinatum, and so forth—suggest that MPX patients could benefit from clinical support to mitigate the consequences of compromised skin and mucosa. This should include prevention and treatment of secondary bacterial infections (and other complications), ensuring adequate hydration and nutrition, and protecting vulnerable anatomical locations such as the eyes and genitals. A standard of care that considers these factors should be developed and assessed in different settings, using clinical metrics specific for MPX alongside consideration of antiviral therapies. Full article
(This article belongs to the Special Issue Smallpox and Emerging Zoonotic Orthopoxviruses: What Is Coming Next?)
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Open AccessBrief Report A Two-Dimensional Human Minilung System (Model) for Respiratory Syncytial Virus Infections
Viruses 2017, 9(12), 379; https://doi.org/10.3390/v9120379
Received: 9 November 2017 / Revised: 4 December 2017 / Accepted: 8 December 2017 / Published: 10 December 2017
Cited by 1 | PDF Full-text (1188 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Human respiratory syncytial virus (HRSV) is a major cause of serious pediatric respiratory diseases that lacks effective vaccine or specific therapeutics. Although our understanding about HRSV biology has dramatically increased during the last decades, the need for adequate models of HRSV infection is
[...] Read more.
Human respiratory syncytial virus (HRSV) is a major cause of serious pediatric respiratory diseases that lacks effective vaccine or specific therapeutics. Although our understanding about HRSV biology has dramatically increased during the last decades, the need for adequate models of HRSV infection is compelling. We have generated a two-dimensional minilung from human embryonic stem cells (hESCs). The differentiation protocol yielded at least six types of lung and airway cells, although it is biased toward the generation of distal cells. We show evidence of HRSV replication in lung cells, and the induction of innate and proinflammatory responses, thus supporting its use as a model for the study of HRSV–host interactions. Full article
(This article belongs to the Section Animal Viruses)
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Open AccessArticle Protection of Mice from Lethal Vaccinia Virus Infection by Vaccinia Virus Protein Subunits with a CpG Adjuvant
Viruses 2017, 9(12), 378; https://doi.org/10.3390/v9120378
Received: 17 November 2017 / Revised: 3 December 2017 / Accepted: 4 December 2017 / Published: 9 December 2017
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Abstract
Smallpox vaccination carries a high risk of adverse events in recipients with a variety of contra-indications for live vaccines. Although alternative non-replicating vaccines have been described in the form of replication-deficient vaccine viruses, DNA vaccines, and subunit vaccines, these are less efficacious than
[...] Read more.
Smallpox vaccination carries a high risk of adverse events in recipients with a variety of contra-indications for live vaccines. Although alternative non-replicating vaccines have been described in the form of replication-deficient vaccine viruses, DNA vaccines, and subunit vaccines, these are less efficacious than replicating vaccines in animal models. DNA and subunit vaccines in particular have not been shown to give equivalent protection to the traditional replicating smallpox vaccine. We show here that combinations of the orthopoxvirus A27, A33, B5 and L1 proteins give differing levels of protection when administered in different combinations with different adjuvants. In particular, the combination of B5 and A27 proteins adjuvanted with CpG oligodeoxynucleotides (ODN) gives a level of protection in mice that is equivalent to the Lister traditional vaccine in a lethal vaccinia virus challenge model. Full article
(This article belongs to the Special Issue Smallpox and Emerging Zoonotic Orthopoxviruses: What Is Coming Next?)
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Open AccessReview Host Cell Restriction Factors that Limit Influenza A Infection
Viruses 2017, 9(12), 376; https://doi.org/10.3390/v9120376
Received: 21 November 2017 / Revised: 4 December 2017 / Accepted: 5 December 2017 / Published: 7 December 2017
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Abstract
Viral infection of different cell types induces a unique spectrum of host defence genes, including interferon-stimulated genes (ISGs) and genes encoding other proteins with antiviral potential. Although hundreds of ISGs have been described, the vast majority have not been functionally characterised. Cellular proteins
[...] Read more.
Viral infection of different cell types induces a unique spectrum of host defence genes, including interferon-stimulated genes (ISGs) and genes encoding other proteins with antiviral potential. Although hundreds of ISGs have been described, the vast majority have not been functionally characterised. Cellular proteins with putative antiviral activity (hereafter referred to as “restriction factors”) can target various steps in the virus life-cycle. In the context of influenza virus infection, restriction factors have been described that target virus entry, genomic replication, translation and virus release. Genome wide analyses, in combination with ectopic overexpression and/or gene silencing studies, have accelerated the identification of restriction factors that are active against influenza and other viruses, as well as providing important insights regarding mechanisms of antiviral activity. Herein, we review current knowledge regarding restriction factors that mediate anti-influenza virus activity and consider the viral countermeasures that are known to limit their impact. Moreover, we consider the strengths and limitations of experimental approaches to study restriction factors, discrepancies between in vitro and in vivo studies, and the potential to exploit restriction factors to limit disease caused by influenza and other respiratory viruses. Full article
(This article belongs to the Section Animal Viruses)
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Open AccessCase Report Two Distinct Clinical Courses of Human Cowpox, Germany, 2015
Viruses 2017, 9(12), 375; https://doi.org/10.3390/v9120375
Received: 23 November 2017 / Revised: 4 December 2017 / Accepted: 6 December 2017 / Published: 7 December 2017
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Abstract
Here we present two cases of human infection with cowpox virus with distinct clinical courses. A series of clinical photographs documents lesion progression over time. In the first case—an unvaccinated young veterinary assistant—a pustule was treated locally with cortisone. The lesion turned into
[...] Read more.
Here we present two cases of human infection with cowpox virus with distinct clinical courses. A series of clinical photographs documents lesion progression over time. In the first case—an unvaccinated young veterinary assistant—a pustule was treated locally with cortisone. The lesion turned into a large ulcer accompanied by severe lymphadenitis. Based on her close contact to a sick stray cat, infection with cowpox virus was assumed and confirmed by virus isolation, PCR, and serology. The clinical course took up to eleven months until healing of the wound was complete. Transmission of cowpox virus from the cat was likely because a skin swab was PCR-positive and the cat had a high titer of anti-orthopoxvirus antibodies. In contrast, a rather mild clinical course of cowpox was confirmed in a 49-year-old male farmer vaccinated against smallpox. Only a small eschar developed, and wound closure was complete after 6 weeks. Full article
(This article belongs to the Special Issue Smallpox and Emerging Zoonotic Orthopoxviruses: What Is Coming Next?)
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Open AccessArticle High-Resolution Structure Analysis of Antibody V5 and U4 Conformational Epitopes on Human Papillomavirus 16
Viruses 2017, 9(12), 374; https://doi.org/10.3390/v9120374
Received: 16 October 2017 / Revised: 13 November 2017 / Accepted: 18 November 2017 / Published: 6 December 2017
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Abstract
Cancers attributable to human papillomavirus (HPV) place a huge burden on the health of both men and women. The current commercial vaccines are genotype specific and provide little therapeutic benefit to patients with existing HPV infections. Identifying the conformational epitopes on the virus
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Cancers attributable to human papillomavirus (HPV) place a huge burden on the health of both men and women. The current commercial vaccines are genotype specific and provide little therapeutic benefit to patients with existing HPV infections. Identifying the conformational epitopes on the virus capsid supports the development of improved recombinant vaccines to maximize long-term protection against multiple types of HPV. Fragments of antibody (Fab) digested from the neutralizing monoclonal antibodies H16.V5 (V5) and H16.U4 (U4) were bound to HPV16 capsids and the structures of the two virus-Fab complexes were solved to near atomic resolution using cryo-electron microscopy. The structures reveal virus conformational changes, the Fab-binding mode to the capsid, the residues comprising the epitope and indicate a potential interaction of U4 with the minor structural protein, L2. Competition enzyme-linked immunosorbent assay (ELISA) showed V5 outcompetes U4 when added sequentially, demonstrating a steric interference even though the footprints do not overlap. Combined with our previously reported immunological and structural results, we propose that the virus may initiate host entry through an interaction between the icosahedral five-fold vertex of the capsid and receptors on the host cell. The highly detailed epitopes identified for the two antibodies provide a framework for continuing biochemical, genetic and biophysical studies. Full article
(This article belongs to the Special Issue Advances in Structural Virology via Cryo-EM)
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Open AccessArticle Genomic Characterisation of Vinegar Hill Virus, An Australian Nairovirus Isolated in 1983 from Argas Robertsi Ticks Collected from Cattle Egrets
Viruses 2017, 9(12), 373; https://doi.org/10.3390/v9120373
Received: 8 November 2017 / Revised: 27 November 2017 / Accepted: 28 November 2017 / Published: 5 December 2017
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Abstract
This report describes the near complete genomic sequence and subsequent analysis of Vinegar Hill virus (VINHV; tentative member of the genus Orthonairovirus, family Nairoviridae, order Bunyavirales). VINHV is the second nairovirus reported to be isolated on mainland Australia and the
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This report describes the near complete genomic sequence and subsequent analysis of Vinegar Hill virus (VINHV; tentative member of the genus Orthonairovirus, family Nairoviridae, order Bunyavirales). VINHV is the second nairovirus reported to be isolated on mainland Australia and the first to be sequenced and analysed. Our genetic analysis shows that VINHV belongs to the Dera Ghazi Khan genogroup, a group of viruses previously isolated in other parts of the world including Asia, South Africa, and the USA. We discuss possible routes of entry for nairoviruses into Australia and the need to understand the virome of Australian ticks in the context of new and emerging disease. Full article
(This article belongs to the Section Animal Viruses)
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Open AccessReview Herpesvirus and Autophagy: “All Right, Everybody Be Cool, This Is a Robbery!”
Viruses 2017, 9(12), 372; https://doi.org/10.3390/v9120372
Received: 18 October 2017 / Revised: 26 November 2017 / Accepted: 27 November 2017 / Published: 4 December 2017
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Abstract
Autophagy is an essential vacuolar process of the cell, leading to lysosomal degradation and recycling of proteins and organelles, which is extremely important in maintaining homeostasis. Multiple roles have been now associated with autophagy, in particular a pro-survival role in nutrient starvation or
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Autophagy is an essential vacuolar process of the cell, leading to lysosomal degradation and recycling of proteins and organelles, which is extremely important in maintaining homeostasis. Multiple roles have been now associated with autophagy, in particular a pro-survival role in nutrient starvation or in stressful environments, a role in life span extension, in development, or in innate and adaptive immunity. This cellular process can also take over microorganisms or viral proteins inside autophagosomes and degrade them directly in autolysosomes and is then called xenophagy and virophagy, respectively. Several Herpesviruses have developed strategies to escape this degradation, by expression of specific anti-autophagic proteins. However, we are increasingly discovering that Herpesviruses hijack autophagy, rather than just fight it. This beneficial effect is obvious since inhibition of autophagy will lead to decreased viral titers for human cytomegalovirus (HCMV), Epstein-Barr virus (EBV) or Varicella-Zoster virus (VZV), for example. Conversely, autophagy stimulation will improve viral multiplication. The autophagic machinery can be used in whole or in part, and can optimize viral propagation or persistence. Some viruses block maturation of autophagosomes to avoid the degradation step, then autophagosomal membranes are used to contribute to the envelopment and/or the egress of viral particles. On the other hand, VZV stimulates the whole process of autophagy to subvert it in order to use vesicles containing ATG (autophagy-related) proteins and resembling amphisomes for their transport in the cytoplasm. During latency, autophagy can also be activated by latent proteins encoded by different oncogenic Herpesviruses to promote cell survival and achieve long term viral persistence in vivo. Finally, reactivation of gammaherpesvirus Murid Herpesvirus 68 (MHV68) in mice appears to be positively modulated by autophagy, in order to control the level of inflammation. Therefore, Herpesviruses appear to behave more like thieves than fugitives. Full article
(This article belongs to the Special Issue Viruses and Autophagy)
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Open AccessArticle Characterization of a Novel Bat Adenovirus Isolated from Straw-Colored Fruit Bat (Eidolon helvum)
Viruses 2017, 9(12), 371; https://doi.org/10.3390/v9120371
Received: 10 November 2017 / Revised: 27 November 2017 / Accepted: 30 November 2017 / Published: 4 December 2017
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Abstract
Bats are important reservoirs for emerging zoonotic viruses. For extensive surveys of potential pathogens in straw-colored fruit bats (Eidolon helvum) in Zambia, a total of 107 spleen samples of E. helvum in 2006 were inoculated onto Vero E6 cells. The cell
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Bats are important reservoirs for emerging zoonotic viruses. For extensive surveys of potential pathogens in straw-colored fruit bats (Eidolon helvum) in Zambia, a total of 107 spleen samples of E. helvum in 2006 were inoculated onto Vero E6 cells. The cell culture inoculated with one of the samples (ZFB06-106) exhibited remarkable cytopathic changes. Based on the ultrastructural property in negative staining and cross-reactivity in immunofluorescence assays, the virus was suspected to be an adenovirus, and tentatively named E. helvum adenovirus 06-106 (EhAdV 06-106). Analysis of the full-length genome of 30,134 bp, determined by next-generation sequencing, showed the presence of 28 open reading frames. Phylogenetic analyses confirmed that EhAdV 06-106 represented a novel bat adenovirus species in the genus Mastadenovirus. The virus shared similar characteristics of low G + C contents with recently isolated members of species Bat mastadenoviruses E, F and G, from which EhAdV 06-106 diverged by more than 15% based on the distance matrix analysis of DNA polymerase amino acid sequences. According to the taxonomic criteria, we propose the tentative new species name “Bat mastadenovirus H”. Because EhAdV 06-106 exhibited a wide in vitro cell tropism, the virus might have a potential risk as an emerging virus through cross-species transmission. Full article
(This article belongs to the Section Animal Viruses)
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Open AccessReview Subcellular Trafficking of the Papillomavirus Genome during Initial Infection: The Remarkable Abilities of Minor Capsid Protein L2
Viruses 2017, 9(12), 370; https://doi.org/10.3390/v9120370
Received: 31 October 2017 / Revised: 1 December 2017 / Accepted: 2 December 2017 / Published: 3 December 2017
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Abstract
Since 2012, our understanding of human papillomavirus (HPV) subcellular trafficking has undergone a drastic paradigm shift. Work from multiple laboratories has revealed that HPV has evolved a unique means to deliver its viral genome (vDNA) to the cell nucleus, relying on myriad host
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Since 2012, our understanding of human papillomavirus (HPV) subcellular trafficking has undergone a drastic paradigm shift. Work from multiple laboratories has revealed that HPV has evolved a unique means to deliver its viral genome (vDNA) to the cell nucleus, relying on myriad host cell proteins and processes. The major breakthrough finding from these recent endeavors has been the realization of L2-dependent utilization of cellular sorting factors for the retrograde transport of vDNA away from degradative endo/lysosomal compartments to the Golgi, prior to mitosis-dependent nuclear accumulation of L2/vDNA. An overview of current models of HPV entry, subcellular trafficking, and the role of L2 during initial infection is provided below, highlighting unresolved questions and gaps in knowledge. Full article
(This article belongs to the Special Issue Expert Views on HPV Infection) Printed Edition available
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Open AccessReview An Opportunistic Pathogen Afforded Ample Opportunities: Middle East Respiratory Syndrome Coronavirus
Viruses 2017, 9(12), 369; https://doi.org/10.3390/v9120369
Received: 14 November 2017 / Revised: 28 November 2017 / Accepted: 1 December 2017 / Published: 2 December 2017
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Abstract
The human coronaviruses (CoV) include HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1, some of which have been known for decades. The severe acute respiratory syndrome (SARS) CoV briefly emerged into the human population but was controlled. In 2012, another novel severely human pathogenic CoV—the Middle
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The human coronaviruses (CoV) include HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1, some of which have been known for decades. The severe acute respiratory syndrome (SARS) CoV briefly emerged into the human population but was controlled. In 2012, another novel severely human pathogenic CoV—the Middle East Respiratory Syndrome (MERS)-CoV—was identified in the Kingdom of Saudi Arabia; 80% of over 2000 human cases have been recorded over five years. Targeted research remains key to developing control strategies for MERS-CoV, a cause of mild illness in its camel reservoir. A new therapeutic toolbox being developed in response to MERS is also teaching us more about how CoVs cause disease. Travel-related cases continue to challenge the world’s surveillance and response capabilities, and more data are needed to understand unexplained primary transmission. Signs of genetic change have been recorded, but it remains unclear whether there is any impact on clinical disease. How camels came to carry the virus remains academic to the control of MERS. To date, human-to-human transmission has been inefficient, but virus surveillance, characterisation, and reporting are key to responding to any future change. MERS-CoV is not currently a pandemic threat; it is spread mainly with the aid of human habit and error. Full article
(This article belongs to the Section Animal Viruses)
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Open AccessReview Chikungunya Virus: Pathophysiology, Mechanism, and Modeling
Viruses 2017, 9(12), 368; https://doi.org/10.3390/v9120368
Received: 16 September 2017 / Revised: 21 November 2017 / Accepted: 23 November 2017 / Published: 1 December 2017
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Abstract
Chikungunya virus (CHIKV), a mosquito-transmitted alphavirus, is recurring in epidemic waves. In the past decade and a half, the disease has resurged in several countries around the globe, with outbreaks becoming increasingly severe. Though CHIKV was first isolated in 1952, there remain significant
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Chikungunya virus (CHIKV), a mosquito-transmitted alphavirus, is recurring in epidemic waves. In the past decade and a half, the disease has resurged in several countries around the globe, with outbreaks becoming increasingly severe. Though CHIKV was first isolated in 1952, there remain significant gaps in knowledge of CHIKV biology, pathogenesis, transmission, and mechanism. Diagnosis is largely simplified and based on symptoms, while treatment is supportive rather than curative. Here we present an overview of the disease, the challenges that lie ahead for future research, and what directions current studies are headed towards, with emphasis on improvement of current animal models and potential use of 3D models. Full article
(This article belongs to the collection Advances in Ebolavirus, Marburgvirus, and Cuevavirus Research)
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Open AccessReview The Interplay between Natural Killer Cells and Human Herpesvirus-6
Viruses 2017, 9(12), 367; https://doi.org/10.3390/v9120367
Received: 24 October 2017 / Revised: 27 November 2017 / Accepted: 29 November 2017 / Published: 1 December 2017
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Abstract
Human Herpesvirus 6 (HHV-6) is a set of two closely related herpes viruses known as HHV-6A and HHV-6B. Both are lymphotropic viruses that establish latency in the host. The ability to evade the immune responses of effector cells is likely a major factor
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Human Herpesvirus 6 (HHV-6) is a set of two closely related herpes viruses known as HHV-6A and HHV-6B. Both are lymphotropic viruses that establish latency in the host. The ability to evade the immune responses of effector cells is likely a major factor contributing to the development of a persistent HHV-6A/B (collectively termed HHV-6) infection. Natural killer (NK) cells are lymphocytes that, along with neutrophils and monocytes/macrophages, participate in the critical innate immune response during viral infections, but can also mediate the antigen-specific memory responses generally associated with adaptive immunity. NK cells compose the first barrier that viruses must break through to continue replication and dissemination, and a weak NK cell response may predispose an individual to chronic viral infections. Both HHV-6A and HHV-6B can interfere with NK cell-mediated anti-viral responses but the mechanisms by which each of these viruses affect NK cell activity differs. In this review, we will explore the nuanced relationships between the two viruses and NK cells, discussing, in addition, relevant disease associations. Full article
(This article belongs to the Section Animal Viruses)
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Open AccessArticle Characterization of the EBV-Induced Persistent DNA Damage Response
Viruses 2017, 9(12), 366; https://doi.org/10.3390/v9120366
Received: 19 October 2017 / Revised: 21 November 2017 / Accepted: 23 November 2017 / Published: 1 December 2017
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Abstract
Epstein-Barr virus (EBV) is an oncogenic herpesvirus that is ubiquitous in the human population. Early after EBV infection in vitro, primary human B cells undergo a transient period of hyper-proliferation, which results in replicative stress and DNA damage, activation of the DNA damage
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Epstein-Barr virus (EBV) is an oncogenic herpesvirus that is ubiquitous in the human population. Early after EBV infection in vitro, primary human B cells undergo a transient period of hyper-proliferation, which results in replicative stress and DNA damage, activation of the DNA damage response (DDR) pathway and, ultimately, senescence. In this study, we investigated DDR-mediated senescence in early arrested EBV-infected B cells and characterized the establishment of persistent DNA damage foci. We found that arrested EBV-infected B cells exhibited an increase in promyelocytic leukemia nuclear bodies (PML NBs), which predominantly localized to markers of DNA damage, as well as telomeric DNA. Furthermore, arrested EBV-infected B cells exhibited an increase in the presence of telomere dysfunction-induced foci. Importantly, we found that increasing human telomerase reverse transcriptase (hTERT) expression with danazol, a drug used to treat telomere diseases, permitted early EBV-infected B cells to overcome cellular senescence and enhanced transformation. Finally, we report that EBV-infected B cells undergoing hyper-proliferation are more sensitive than lymphoblastoid cell lines (LCLs) to inhibition of Bloom syndrome-associated helicase, which facilitates telomere replication. Together, our results describe the composition of persistent DNA damage foci in the early stages of EBV infection and define key regulators of this barrier to long-term outgrowth. Full article
(This article belongs to the Special Issue Viruses and the DNA Damage Response)
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Open AccessArticle Human Cytomegalovirus Encoded miR-US25-1-5p Attenuates CD147/EMMPRIN-Mediated Early Antiviral Response
Viruses 2017, 9(12), 365; https://doi.org/10.3390/v9120365
Received: 26 October 2017 / Revised: 23 November 2017 / Accepted: 28 November 2017 / Published: 1 December 2017
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Abstract
Cellular receptor-mediated signaling pathways play critical roles during the initial immune response to Human Cytomegalovirus (HCMV) infection. However, the involvement of type-I transmembrane glycoprotein CD147/EMMPRIN (extracellular matrix metalloproteinase inducer) in the antiviral response to HCMV infection is still unknown. Here, we demonstrated the
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Cellular receptor-mediated signaling pathways play critical roles during the initial immune response to Human Cytomegalovirus (HCMV) infection. However, the involvement of type-I transmembrane glycoprotein CD147/EMMPRIN (extracellular matrix metalloproteinase inducer) in the antiviral response to HCMV infection is still unknown. Here, we demonstrated the specific knockdown of CD147 significantly decreased HCMV-induced activation of NF-κB and Interferon-beta (IFN-β), which contribute to the cellular antiviral responses. Next, we confirmed that HCMV-encoded miR-US25-1-5p could target the 3′ UTR (Untranslated Region) of CD147 mRNA, and thus facilitate HCMV lytic propagation at a low multiplicity of infection (MOI). The expression and secretion of Cyclophilin A (sCyPA), as a ligand for CD147 and a proinflammatory cytokine, were up-regulated in response to HCMV stimuli. Finally, we confirmed that CD147 mediated HCMV-triggered antiviral signaling via the sCyPA-CD147-ERK (extracellular regulated protein kinases)/NF-κB axis signaling pathway. These findings reveal an important HCMV mechanism for evading antiviral innate immunity through its encoded microRNA by targeting transmembrane glycoprotein CD147, and a potential cause of HCMV inflammatory disorders due to the secretion of proinflammatory cytokine CyPA. Full article
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Open AccessArticle Identification of Alpha and Beta Coronavirus in Wildlife Species in France: Bats, Rodents, Rabbits, and Hedgehogs
Viruses 2017, 9(12), 364; https://doi.org/10.3390/v9120364
Received: 2 November 2017 / Revised: 20 November 2017 / Accepted: 21 November 2017 / Published: 29 November 2017
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Abstract
Coronaviruses are closely monitored in the context of emerging diseases and, as illustrated with Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) and Middle East Respiratory Syndrome-coronavirus (MERS-CoV), are known to cross the species barrier and eventually to move from wildlife to humans. Knowledge of
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Coronaviruses are closely monitored in the context of emerging diseases and, as illustrated with Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) and Middle East Respiratory Syndrome-coronavirus (MERS-CoV), are known to cross the species barrier and eventually to move from wildlife to humans. Knowledge of the diversity of coronaviruses in wildlife is therefore essential to better understand and prevent emergence events. This study explored the presence of coronaviruses in four wild mammal orders in France: Bats, rodents, lagomorphs, and hedgehogs. Betacoronavirus and Alphacoronavirus genera were identified. The results obtained suggest the circulation of potentially evolving virus strains, with the potential to cross the species barrier. Full article
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Open AccessArticle Dynamics of Pathological and Virological Findings During Experimental Calpox Virus Infection of Common Marmosets (Callithrix jacchus)
Viruses 2017, 9(12), 363; https://doi.org/10.3390/v9120363
Received: 30 October 2017 / Revised: 17 November 2017 / Accepted: 20 November 2017 / Published: 28 November 2017
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Abstract
Experimental intranasal infection of marmosets (Callithrix jacchus) with calpox virus results in fatal disease. Route and dose used for viral inoculation of the test animals mimics the natural transmission of smallpox, thus representing a suitable model to study pathogenesis and to
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Experimental intranasal infection of marmosets (Callithrix jacchus) with calpox virus results in fatal disease. Route and dose used for viral inoculation of the test animals mimics the natural transmission of smallpox, thus representing a suitable model to study pathogenesis and to evaluate new vaccines against orthopoxvirus infection. However, the pathogenic mechanisms leading to death are still unclear. Therefore, our study aimed at investigating the kinetics of pathological alterations to clarify the pathogenesis in calpox virus infection. Following intranasal inoculation with two different viral doses, common marmosets were sacrificed on days 3, 5, 7, 10 and 12 post inoculation. Collected tissue was screened using histopathology, immunohistochemistry, transmission electron microscopy, and virological assays. Our data suggest that primary replication took place in nasal and bronchial epithelia followed by secondary replication in submandibular lymph nodes and spleen. Parallel to viremia at day 7, virus was detectable in many organs, mainly located in epithelial cells and macrophages, as well as in endothelial cells. Based on the onset of clinical signs, the histological and ultrastructural lesions and the immunohistochemical distribution pattern of the virus, the incubation period was defined to last 11 days, which resembles human smallpox. In conclusion, the data indicate that the calpox model is highly suitable for studying orthopoxvirus-induced disease. Full article
(This article belongs to the Special Issue Smallpox and Emerging Zoonotic Orthopoxviruses: What Is Coming Next?)
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