Viruses

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Open AccessReview

Human Protoparvoviruses

by Elina Väisänen, Yu Fu, Klaus Hedman and Maria Söderlund-Venermo

Viruses 2017, 9(11), 354; https://doi.org/10.3390/v9110354 - 22 Nov 2017

Cited by 32 | Viewed by 5220

Next-generation sequencing and metagenomics have revolutionized the discovery of novel viruses. In recent years, three novel protoparvoviruses have been discovered in fecal samples of humans: bufavirus (BuV) in 2012, tusavirus (TuV) in 2014, and cutavirus (CuV) in 2016. BuV has since been studied [...] Read more.

Next-generation sequencing and metagenomics have revolutionized the discovery of novel viruses. In recent years, three novel protoparvoviruses have been discovered in fecal samples of humans: bufavirus (BuV) in 2012, tusavirus (TuV) in 2014, and cutavirus (CuV) in 2016. BuV has since been studied the most, disclosing three genotypes that also represent serotypes. Besides one nasal sample, BuV DNA has been found exclusively in diarrheal feces, but not in non-diarrheal feces, suggesting a causal relationship. According to both geno- and seroprevalences, BuV appears to be the most common of the three novel protoparvoviruses, whereas TuV DNA has been found in only a single fecal sample, with antibody detection being equally rare. Moreover, the TuV sequence is closer to those of non-human protoparvoviruses, and so the evidence of TuV being a human virus is thus far insufficient. Interestingly, besides in feces, CuV has also been detected in skin biopsies of patients with cutaneous T-cell lymphoma and a patient with melanoma, while all other skin samples have tested PCR negative. Even if preliminary disease associations exist, the full etiological roles of these viruses in human disease are yet to be resolved. Full article

(This article belongs to the Special Issue Protoparvoviruses: Friends or Foes?)

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Open AccessArticle

Pressure for Pattern-Specific Intertypic Recombination between Sabin Polioviruses: Evolutionary Implications

by Ekaterina Korotkova, Majid Laassri, Tatiana Zagorodnyaya, Svetlana Petrovskaya, Elvira Rodionova, Elena Cherkasova, Anatoly Gmyl, Olga E. Ivanova, Tatyana P. Eremeeva, Galina Y. Lipskaya, Vadim I. Agol and Konstantin Chumakov

Viruses 2017, 9(11), 353; https://doi.org/10.3390/v9110353 - 22 Nov 2017

Cited by 19 | Viewed by 4425

Abstract

Complete genomic sequences of a non-redundant set of 70 recombinants between three serotypes of attenuated Sabin polioviruses as well as location (based on partial sequencing) of crossover sites of 28 additional recombinants were determined and compared with the previously published data. It is [...] Read more.

Complete genomic sequences of a non-redundant set of 70 recombinants between three serotypes of attenuated Sabin polioviruses as well as location (based on partial sequencing) of crossover sites of 28 additional recombinants were determined and compared with the previously published data. It is demonstrated that the genomes of Sabin viruses contain distinct strain-specific segments that are eliminated by recombination. The presumed low fitness of these segments could be linked to mutations acquired upon derivation of the vaccine strains and/or may have been present in wild-type parents of Sabin viruses. These “weak” segments contribute to the propensity of these viruses to recombine with each other and with other enteroviruses as well as determine the choice of crossover sites. The knowledge of location of such segments opens additional possibilities for the design of more genetically stable and/or more attenuated variants, i.e., candidates for new oral polio vaccines. The results also suggest that the genome of wild polioviruses, and, by generalization, of other RNA viruses, may harbor hidden low-fitness segments that can be readily eliminated only by recombination. Full article

(This article belongs to the Special Issue Viral Recombination: Ecology, Evolution and Pathogenesis)

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Open AccessReview

Therapeutic Strategies against Epstein-Barr Virus-Associated Cancers Using Proteasome Inhibitors

by Kwai Fung Hui, Kam Pui Tam and Alan Kwok Shing Chiang

Viruses 2017, 9(11), 352; https://doi.org/10.3390/v9110352 - 21 Nov 2017

Cited by 16 | Viewed by 6705

Abstract

Epstein-Barr virus (EBV) is closely associated with several lymphomas (endemic Burkitt lymphoma, Hodgkin lymphoma and nasal NK/T-cell lymphoma) and epithelial cancers (nasopharyngeal carcinoma and gastric carcinoma). To maintain its persistence in the host cells, the virus manipulates the ubiquitin-proteasome system to regulate viral [...] Read more.

Epstein-Barr virus (EBV) is closely associated with several lymphomas (endemic Burkitt lymphoma, Hodgkin lymphoma and nasal NK/T-cell lymphoma) and epithelial cancers (nasopharyngeal carcinoma and gastric carcinoma). To maintain its persistence in the host cells, the virus manipulates the ubiquitin-proteasome system to regulate viral lytic reactivation, modify cell cycle checkpoints, prevent apoptosis and evade immune surveillance. In this review, we aim to provide an overview of the mechanisms by which the virus manipulates the ubiquitin-proteasome system in EBV-associated lymphoid and epithelial malignancies, to evaluate the efficacy of proteasome inhibitors on the treatment of these cancers and discuss potential novel viral-targeted treatment strategies against the EBV-associated cancers. Full article

(This article belongs to the Special Issue Viruses, ERAD, and the Proteasome)

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Open AccessArticle

Neurotropism In Vitro and Mouse Models of Severe and Mild Infection with Clinical Strains of Enterovirus 71

by Pin Yu, Linlin Bao, Lili Xu, Fengdi Li, Qi Lv, Wei Deng, Yanfeng Xu and Chuan Qin

Viruses 2017, 9(11), 351; https://doi.org/10.3390/v9110351 - 20 Nov 2017

Cited by 15 | Viewed by 4904

Abstract

Enterovirus 71 (EV71) is a common etiological agent of hand, foot, and mouth disease and fatal neurological diseases in children. The neuropathogenicity of severe EV71 infection has been documented, but studies comparing mouse models of severe and mild EV71 infection are lacking. The [...] Read more.

Enterovirus 71 (EV71) is a common etiological agent of hand, foot, and mouth disease and fatal neurological diseases in children. The neuropathogenicity of severe EV71 infection has been documented, but studies comparing mouse models of severe and mild EV71 infection are lacking. The aim of the study was to investigate the neurovirulence of EV71 strains and the differences in serum cytokine and chemokine levels in mouse models of severe and mild EV71 infection. Nine EV71 isolates belonging to the C4 subgenogroup (proposed as genotype D) displayed infectivity in human neuroblastoma SK-N-SH cells; moreover, ultrastructural observation confirmed viral particle replication. The survival rate of the severe model was 71.43% (5/7), and 60% (3/5) of the surviving severe model mice displayed sequelae of paralysis, whereas the only symptom in mild model mice was ruffled fur. Dynamic detection of serum cytokine and chemokine levels demonstrated that interleukin (IL)-5, IL-13, IL-6, monocyte chemotactic protein 1 (MCP-1), and chemokine (C-C motif) ligand 5 (also called Regulated upon Activation, Normal T-cell Expressed, and Secreted (CCL5/RANTES) were significantly up-regulated at the early period of infection, indicating that these factors might herald a severe outcome. Our findings suggest that elevated cytokines and chemokines may have potential value as prognostic markers in mouse models. Full article

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Open AccessArticle

The Role of Infected Cell Proliferation in the Clearance of Acute HBV Infection in Humans

by Ashish Goyal, Ruy M. Ribeiro and Alan S. Perelson

Viruses 2017, 9(11), 350; https://doi.org/10.3390/v9110350 - 18 Nov 2017

Cited by 25 | Viewed by 6754

Abstract

Around 90–95% of hepatitis B virus (HBV) infected adults do not progress to the chronic phase and, instead, recover naturally. The strengths of the cytolytic and non-cytolytic immune responses are key players that decide the fate of acute HBV infection. In addition, it [...] Read more.

Around 90–95% of hepatitis B virus (HBV) infected adults do not progress to the chronic phase and, instead, recover naturally. The strengths of the cytolytic and non-cytolytic immune responses are key players that decide the fate of acute HBV infection. In addition, it has been hypothesized that proliferation of infected cells resulting in uninfected progeny and/or cytokine-mediated degradation of covalently closed circular DNA (cccDNA) leading to the cure of infected cells are two major mechanisms assisting the adaptive immune response in the clearance of acute HBV infection in humans. We employed fitting of mathematical models to human acute infection data together with physiological constraints to investigate the role of these hypothesized mechanisms in the clearance of infection. Results suggest that cellular proliferation of infected cells resulting in two uninfected cells is required to minimize the destruction of the liver during the clearance of acute HBV infection. In contrast, we find that a cytokine-mediated cure of infected cells alone is insufficient to clear acute HBV infection. In conclusion, our modeling indicates that HBV clearance without lethal loss of liver mass is associated with the production of two uninfected cells upon proliferation of an infected cell. Full article

(This article belongs to the Special Issue Mathematical Modeling of Viral Infections)

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Open AccessReview

New Paradigms for the Study of Ocular Alphaherpesvirus Infections: Insights into the Use of Non-Traditional Host Model Systems

by Matthew R. Pennington, Eric C. Ledbetter and Gerlinde R. Van de Walle

Viruses 2017, 9(11), 349; https://doi.org/10.3390/v9110349 - 18 Nov 2017

Cited by 14 | Viewed by 8115

Abstract

Ocular herpesviruses, most notably human alphaherpesvirus 1 (HSV-1), canid alphaherpesvirus 1 (CHV-1) and felid alphaherpesvirus 1 (FHV-1), infect and cause severe disease that may lead to blindness. CHV-1 and FHV-1 have a pathogenesis and induce clinical disease in their hosts that is similar [...] Read more.

Ocular herpesviruses, most notably human alphaherpesvirus 1 (HSV-1), canid alphaherpesvirus 1 (CHV-1) and felid alphaherpesvirus 1 (FHV-1), infect and cause severe disease that may lead to blindness. CHV-1 and FHV-1 have a pathogenesis and induce clinical disease in their hosts that is similar to HSV-1 ocular infections in humans, suggesting that infection of dogs and cats with CHV-1 and FHV-1, respectively, can be used as a comparative natural host model of herpesvirus-induced ocular disease. In this review, we discuss both strengths and limitations of the various available model systems to study ocular herpesvirus infection, with a focus on the use of these non-traditional virus-natural host models. Recent work has demonstrated the robustness and reproducibility of experimental ocular herpesvirus infections in dogs and cats, and, therefore, these non-traditional models can provide additional insights into the pathogenesis of ocular herpesvirus infections. Full article

(This article belongs to the Section Animal Viruses)

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Open AccessArticle

Diversity of dsDNA Viruses in a South African Hot Spring Assessed by Metagenomics and Microscopy

by Olivier Zablocki, Leonardo Joaquim Van Zyl, Bronwyn Kirby and Marla Trindade

Viruses 2017, 9(11), 348; https://doi.org/10.3390/v9110348 - 18 Nov 2017

Cited by 19 | Viewed by 6670 | Correction

Abstract

The current view of virus diversity in terrestrial hot springs is limited to a few sampling sites. To expand our current understanding of hot spring viral community diversity, this study aimed to investigate the first African hot spring (Brandvlei hot spring; 60 °C, [...] Read more.

The current view of virus diversity in terrestrial hot springs is limited to a few sampling sites. To expand our current understanding of hot spring viral community diversity, this study aimed to investigate the first African hot spring (Brandvlei hot spring; 60 °C, pH 5.7) by means of electron microscopy and sequencing of the virus fraction. Microscopy analysis revealed a mixture of regular- and ‘jumbo’-sized tailed morphotypes (Caudovirales), lemon-shaped virions (Fuselloviridae-like; salterprovirus-like) and pleiomorphic virus-like particles. Metavirome analysis corroborated the presence of His1-like viruses and has expanded the current clade of salterproviruses using a polymerase B gene phylogeny. The most represented viral contig was to a cyanophage genome fragment, which may underline basic ecosystem functioning provided by these viruses. Furthermore, a putative Gemmata-related phage was assembled with high coverage, a previously undocumented phage-host association. This study demonstrated that a moderately thermophilic spring environment contained a highly novel pool of viruses and should encourage future characterization of a wider temperature range of hot springs throughout the world. Full article

(This article belongs to the Section Bacterial Viruses)

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Open AccessArticle

Epidemiological Investigations of Four Cowpox Virus Outbreaks in Alpaca Herds, Germany

by Almut Prkno, Donata Hoffmann, Daniela Goerigk, Matthias Kaiser, Anne Catherine Franscisca Van Maanen, Kathrin Jeske, Maria Jenckel, Florian Pfaff, Thomas W. Vahlenkamp, Martin Beer, Rainer G. Ulrich, Alexander Starke and Martin Pfeffer

Viruses 2017, 9(11), 344; https://doi.org/10.3390/v9110344 - 18 Nov 2017

Cited by 22 | Viewed by 6606

Abstract

Four cowpox virus (CPXV) outbreaks occurred in unrelated alpaca herds in Eastern Germany during 2012–2017. All incidents were initially noticed due to severe, generalized, and finally lethal CPXV infections, which were confirmed by testing of tissue and serum samples. As CPXV-infection has been [...] Read more.

Four cowpox virus (CPXV) outbreaks occurred in unrelated alpaca herds in Eastern Germany during 2012–2017. All incidents were initially noticed due to severe, generalized, and finally lethal CPXV infections, which were confirmed by testing of tissue and serum samples. As CPXV-infection has been described in South American camelids (SACs) only three times, all four herds were investigated to gain a deeper understanding of CPXV epidemiology in alpacas. The different herds were investigated twice, and various samples (serum, swab samples, and crusts of suspicious pox lesions, feces) were taken to identify additionally infected animals. Serum was used to detect CPXV-specific antibodies by performing an indirect immunofluorescence assay (iIFA); swab samples, crusts, and feces were used for detection of CPXV-specific DNA in a real-time PCR. In total, 28 out of 107 animals could be identified as affected by CPXV, by iIFA and/or PCR. Herd seroprevalence ranged from 16.1% to 81.2%. To investigate the potential source of infection, wild small mammals were trapped around all alpaca herds. In two herds, CPXV-specific antibodies were found in the local rodent population. In the third herd, CPXV could be isolated from a common vole (Microtus arvalis) found drowned in a water bucket used to water the alpacas. Full genome sequencing and comparison with the genome of a CPXV from an alpaca from the same herd reveal 99.997% identity, providing further evidence that the common vole is a reservoir host and infection source of CPXV. Only in the remaining fourth herd, none of the trapped rodents were found to be CPXV-infected. Rodents, as ubiquitous reservoir hosts, in combination with increasingly popular alpacas, as susceptible species, suggest an enhanced risk of future zoonotic infections. Full article

(This article belongs to the Special Issue Smallpox and Emerging Zoonotic Orthopoxviruses: What Is Coming Next?)

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Open AccessArticle

RNA Virus Evolution via a Quasispecies-Based Model Reveals a Drug Target with a High Barrier to Resistance

by Richard J. Bingham, Eric C. Dykeman and Reidun Twarock

Viruses 2017, 9(11), 347; https://doi.org/10.3390/v9110347 - 17 Nov 2017

Cited by 19 | Viewed by 6276

Abstract

The rapid occurrence of therapy-resistant mutant strains provides a challenge for anti-viral therapy. An ideal drug target would be a highly conserved molecular feature in the viral life cycle, such as the packaging signals in the genomes of RNA viruses that encode an [...] Read more.

The rapid occurrence of therapy-resistant mutant strains provides a challenge for anti-viral therapy. An ideal drug target would be a highly conserved molecular feature in the viral life cycle, such as the packaging signals in the genomes of RNA viruses that encode an instruction manual for their efficient assembly. The ubiquity of this assembly code in RNA viruses, including major human pathogens, suggests that it confers selective advantages. However, their impact on viral evolution cannot be assessed in current models of viral infection that lack molecular details of virus assembly. We introduce here a quasispecies-based model of a viral infection that incorporates structural and mechanistic knowledge of packaging signal function in assembly to construct a phenotype-fitness map, capturing the impact of this RNA code on assembly yield and efficiency. Details of viral replication and assembly inside an infected host cell are coupled with a population model of a viral infection, allowing the occurrence of therapy resistance to be assessed in response to drugs inhibiting packaging signal recognition. Stochastic simulations of viral quasispecies evolution in chronic HCV infection under drug action and/or immune clearance reveal that drugs targeting all RNA signals in the assembly code collectively have a high barrier to drug resistance, even though each packaging signal in isolation has a lower barrier than conventional drugs. This suggests that drugs targeting the RNA signals in the assembly code could be promising routes for exploitation in anti-viral drug design. Full article

(This article belongs to the Special Issue Mathematical Modeling of Viral Infections)

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Open AccessReview

Epigenetic Regulation of Viral Biological Processes

by Lata Balakrishnan and Barry Milavetz

Viruses 2017, 9(11), 346; https://doi.org/10.3390/v9110346 - 17 Nov 2017

Cited by 41 | Viewed by 9123

Abstract

It is increasingly clear that DNA viruses exploit cellular epigenetic processes to control their life cycles during infection. This review will address epigenetic regulation in members of the polyomaviruses, adenoviruses, human papillomaviruses, hepatitis B, and herpes viruses. For each type of virus, what [...] Read more.

It is increasingly clear that DNA viruses exploit cellular epigenetic processes to control their life cycles during infection. This review will address epigenetic regulation in members of the polyomaviruses, adenoviruses, human papillomaviruses, hepatitis B, and herpes viruses. For each type of virus, what is known about the roles of DNA methylation, histone modifications, nucleosome positioning, and regulatory RNA in epigenetic regulation of the virus infection will be discussed. The mechanisms used by certain viruses to dysregulate the host cell through manipulation of epigenetic processes and the role of cellular cofactors such as BRD4 that are known to be involved in epigenetic regulation of host cell pathways will also be covered. Specifically, this review will focus on the role of epigenetic regulation in maintaining viral episomes through the generation of chromatin, temporally controlling transcription from viral genes during the course of an infection, regulating latency and the switch to a lytic infection, and global dysregulation of cellular function. Full article

(This article belongs to the Special Issue Viral Subversion of Transcriptional Control)

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Open AccessArticle

Characterization of Ovine A3Z1 Restriction Properties against Small Ruminant Lentiviruses (SRLVs)

by Lorena De Pablo-Maiso, Idoia Glaria, Helena Crespo, Estanislao Nistal-Villán, Valgerdur Andrésdóttir, Damián De Andrés, Beatriz Amorena and Ramsés Reina

Viruses 2017, 9(11), 345; https://doi.org/10.3390/v9110345 - 17 Nov 2017

Cited by 5 | Viewed by 4062

Abstract

Intrinsic factors of the innate immune system include the apolipoprotein B editing enzyme catalytic polypeptide-like 3 (APOBEC3) protein family. APOBEC3 inhibits replication of different virus families by cytosine deamination of viral DNA and a not fully characterized cytosine deamination-independent mechanism. Sheep are susceptible [...] Read more.

Intrinsic factors of the innate immune system include the apolipoprotein B editing enzyme catalytic polypeptide-like 3 (APOBEC3) protein family. APOBEC3 inhibits replication of different virus families by cytosine deamination of viral DNA and a not fully characterized cytosine deamination-independent mechanism. Sheep are susceptible to small ruminant lentivirus (SRLVs) infection and contain three APOBEC3 genes encoding four proteins (A3Z1, Z2, Z3 and Z2-Z3) with yet not deeply described antiviral properties. Using sheep blood monocytes and in vitro-derived macrophages, we found that A3Z1 expression is associated with lower viral replication in this cellular type. A3Z1 transcripts may also contain spliced variants (A3Z1Tr) lacking the cytidine deaminase motif. A3Z1 exogenous expression in fully permissive fibroblast-like cells restricted SRLVs infection while A3Z1Tr allowed infection. A3Z1Tr was induced after SRLVs infection or stimulation of blood-derived macrophages with interferon gamma (IFN-γ). Interaction between truncated isoform and native A3Z1 protein was detected as well as incorporation of both proteins into virions. A3Z1 and A3Z1Tr interacted with SRLVs Vif, but this interaction was not associated with degradative properties. Similar A3Z1 truncated isoforms were also present in human and monkey cells suggesting a conserved alternative splicing regulation in primates. A3Z1-mediated retroviral restriction could be constrained by different means, including gene expression and specific alternative splicing regulation, leading to truncated protein isoforms lacking a cytidine-deaminase motif. Full article

(This article belongs to the Section Animal Viruses)

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Open AccessArticle

The Ms6 Mycolyl-Arabinogalactan Esterase LysB is Essential for an Efficient Mycobacteriophage-Induced Lysis

by Adriano M. Gigante, Cheri M. Hampton, Rebecca S. Dillard, Filipa Gil, Maria João Catalão, José Moniz-Pereira, Elizabeth R. Wright and Madalena Pimentel

Viruses 2017, 9(11), 343; https://doi.org/10.3390/v9110343 - 17 Nov 2017

Cited by 25 | Viewed by 4818

Abstract

All dsDNA phages encode two proteins involved in host lysis, an endolysin and a holin that target the peptidoglycan and cytoplasmic membrane, respectively. Bacteriophages that infect Gram-negative bacteria encode additional proteins, the spanins, involved in disruption of the outer membrane. Recently, a gene [...] Read more.

All dsDNA phages encode two proteins involved in host lysis, an endolysin and a holin that target the peptidoglycan and cytoplasmic membrane, respectively. Bacteriophages that infect Gram-negative bacteria encode additional proteins, the spanins, involved in disruption of the outer membrane. Recently, a gene located in the lytic cassette was identified in the genomes of mycobacteriophages, which encodes a protein (LysB) with mycolyl-arabinogalactan esterase activity. Taking in consideration the complex mycobacterial cell envelope that mycobacteriophages encounter during their life cycle, it is valuable to evaluate the role of these proteins in lysis. In the present work, we constructed an Ms6 mutant defective on lysB and showed that Ms6 LysB has an important role in lysis. In the absence of LysB, lysis still occurs but the newly synthesized phage particles are deficiently released to the environment. Using cryo-electron microscopy and tomography to register the changes in the lysis phenotype, we show that at 150 min post-adsorption, mycobacteria cells are incompletely lysed and phage particles are retained inside the cell, while cells infected with Ms6wt are completely lysed. Our results confirm that Ms6 LysB is necessary for an efficient lysis of Mycobacterium smegmatis, acting, similarly to spanins, in the third step of the lysis process. Full article

(This article belongs to the Section Bacterial Viruses)

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Open AccessArticle

The Non-Homologous End Joining Protein PAXX Acts to Restrict HSV-1 Infection

by Ben J. Trigg, Katharina B. Lauer, Paula Fernandes dos Santos, Heather Coleman, Gabriel Balmus, Daniel S. Mansur and Brian J. Ferguson

Viruses 2017, 9(11), 342; https://doi.org/10.3390/v9110342 - 16 Nov 2017

Cited by 8 | Viewed by 6768

Abstract

Herpes simplex virus 1 (HSV-1) has extensive interactions with the host DNA damage response (DDR) machinery that can be either detrimental or beneficial to the virus. Proteins in the homologous recombination pathway are known to be required for efficient replication of the viral [...] Read more.

Herpes simplex virus 1 (HSV-1) has extensive interactions with the host DNA damage response (DDR) machinery that can be either detrimental or beneficial to the virus. Proteins in the homologous recombination pathway are known to be required for efficient replication of the viral genome, while different members of the classical non-homologous end-joining (c-NHEJ) pathway have opposing effects on HSV-1 infection. Here, we have investigated the role of the recently-discovered c-NHEJ component, PAXX (Paralogue of XRCC4 and XLF), which we found to be excluded from the nucleus during HSV-1 infection. We have established that cells lacking PAXX have an intact innate immune response to HSV-1 but show a defect in viral genome replication efficiency. Counterintuitively, PAXX^−/− cells were able to produce greater numbers of infectious virions, indicating that PAXX acts to restrict HSV-1 infection in a manner that is different from other c-NHEJ factors. Full article

(This article belongs to the Special Issue Viruses and the DNA Damage Response)

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Open AccessReview

Epstein–Barr Virus Hijacks DNA Damage Response Transducers to Orchestrate Its Life Cycle

by Pok Man Hau and Sai Wah Tsao

Viruses 2017, 9(11), 341; https://doi.org/10.3390/v9110341 - 16 Nov 2017

Cited by 36 | Viewed by 8212

Abstract

The Epstein–Barr virus (EBV) is a ubiquitous virus that infects most of the human population. EBV infection is associated with multiple human cancers, including Burkitt’s lymphoma, Hodgkin’s lymphoma, a subset of gastric carcinomas, and almost all undifferentiated non-keratinizing nasopharyngeal carcinoma. Intensive research has [...] Read more.

The Epstein–Barr virus (EBV) is a ubiquitous virus that infects most of the human population. EBV infection is associated with multiple human cancers, including Burkitt’s lymphoma, Hodgkin’s lymphoma, a subset of gastric carcinomas, and almost all undifferentiated non-keratinizing nasopharyngeal carcinoma. Intensive research has shown that EBV triggers a DNA damage response (DDR) during primary infection and lytic reactivation. The EBV-encoded viral proteins have been implicated in deregulating the DDR signaling pathways. The consequences of DDR inactivation lead to genomic instability and promote cellular transformation. This review summarizes the current understanding of the relationship between EBV infection and the DDR transducers, including ATM (ataxia telangiectasia mutated), ATR (ATM and Rad3-related), and DNA-PK (DNA-dependent protein kinase), and discusses how EBV manipulates the DDR signaling pathways to complete the replication process of viral DNA during lytic reactivation. Full article

(This article belongs to the Special Issue Viruses and the DNA Damage Response)

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Open AccessReview

Vaccinia Virus Natural Infections in Brazil: The Good, the Bad, and the Ugly

by Jaqueline Silva de Oliveira, Poliana De Oliveira Figueiredo, Galileu Barbosa Costa, Felipe Lopes de Assis, Betânia Paiva Drumond, Flávio Guimarães Da Fonseca, Maurício Lacerda Nogueira, Erna Geessien Kroon and Giliane De Souza Trindade

Viruses 2017, 9(11), 340; https://doi.org/10.3390/v9110340 - 15 Nov 2017

Cited by 33 | Viewed by 8239

Abstract

The orthopoxviruses (OPV) comprise several emerging viruses with great importance to human and veterinary medicine, including vaccinia virus (VACV), which causes outbreaks of bovine vaccinia (BV) in South America. Historically, VACV is the most comprehensively studied virus, however, its origin and natural hosts [...] Read more.

The orthopoxviruses (OPV) comprise several emerging viruses with great importance to human and veterinary medicine, including vaccinia virus (VACV), which causes outbreaks of bovine vaccinia (BV) in South America. Historically, VACV is the most comprehensively studied virus, however, its origin and natural hosts remain unknown. VACV was the primary component of the smallpox vaccine, largely used during the smallpox eradication campaign. After smallpox was declared eradicated, the vaccination that conferred immunity to OPV was discontinued, favoring a new contingent of susceptible individuals to OPV. VACV infections occur naturally after direct contact with infected dairy cattle, in recently vaccinated individuals, or through alternative routes of exposure. In Brazil, VACV outbreaks are frequently reported in rural areas, affecting mainly farm animals and humans. Recent studies have shown the role of wildlife in the VACV transmission chain, exploring the role of wild rodents as reservoirs that facilitate VACV spread throughout rural areas. Furthermore, VACV circulation in urban environments and the significance of this with respect to public health, have also been explored. In this review, we discuss the history, epidemiological, ecological and clinical aspects of natural VACV infections in Brazil, also highlighting alternative routes of VACV transmission, the factors involved in susceptibility to infection, and the natural history of the disease in humans and animals, and the potential for dissemination to urban environments. Full article

(This article belongs to the Special Issue Smallpox and Emerging Zoonotic Orthopoxviruses: What Is Coming Next?)

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Open AccessReview

EBV and Apoptosis: The Viral Master Regulator of Cell Fate?

by Leah Fitzsimmons and Gemma L. Kelly

Viruses 2017, 9(11), 339; https://doi.org/10.3390/v9110339 - 13 Nov 2017

Cited by 57 | Viewed by 10861

Abstract

Epstein–Barr virus (EBV) was first discovered in cells from a patient with Burkitt lymphoma (BL), and is now known to be a contributory factor in 1–2% of all cancers, for which there are as yet, no EBV-targeted therapies available. Like other herpesviruses, EBV [...] Read more.

Epstein–Barr virus (EBV) was first discovered in cells from a patient with Burkitt lymphoma (BL), and is now known to be a contributory factor in 1–2% of all cancers, for which there are as yet, no EBV-targeted therapies available. Like other herpesviruses, EBV adopts a persistent latent infection in vivo and only rarely reactivates into replicative lytic cycle. Although latency is associated with restricted patterns of gene expression, genes are never expressed in isolation; always in groups. Here, we discuss (1) the ways in which the latent genes of EBV are known to modulate cell death, (2) how these mechanisms relate to growth transformation and lymphomagenesis, and (3) how EBV genes cooperate to coordinately regulate key cell death pathways in BL and lymphoblastoid cell lines (LCLs). Since manipulation of the cell death machinery is critical in EBV pathogenesis, understanding the mechanisms that underpin EBV regulation of apoptosis therefore provides opportunities for novel therapeutic interventions. Full article

(This article belongs to the Special Issue Viral Infection and Apoptosis)

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Open AccessReview

Structures and Functions of the Envelope Glycoprotein in Flavivirus Infections

by Xingcui Zhang, Renyong Jia, Haoyue Shen, Mingshu Wang, Zhongqiong Yin and Anchun Cheng

Viruses 2017, 9(11), 338; https://doi.org/10.3390/v9110338 - 13 Nov 2017

Cited by 119 | Viewed by 12073

Abstract

Flaviviruses are enveloped, single-stranded RNA viruses that widely infect many animal species. The envelope protein, a structural protein of flavivirus, plays an important role in host cell viral infections. It is composed of three separate structural envelope domains I, II, and III (EDI, [...] Read more.

Flaviviruses are enveloped, single-stranded RNA viruses that widely infect many animal species. The envelope protein, a structural protein of flavivirus, plays an important role in host cell viral infections. It is composed of three separate structural envelope domains I, II, and III (EDI, EDII, and EDIII). EDI is a structurally central domain of the envelope protein which stabilizes the overall orientation of the protein, and the glycosylation sites in EDI are related to virus production, pH sensitivity, and neuroinvasiveness. EDII plays an important role in membrane fusion because of the immunodominance of the fusion loop epitope and the envelope dimer epitope. Additionally, EDIII is the major target of neutralization antibodies. The envelope protein is an important target for research to develop vaccine candidates and antiviral therapeutics. This review summarizes the structures and functions of ED I/II/III, and provides practical applications for the three domains, with the ultimate goal of implementing strategies to utilize the envelope protein against flavivirus infections, thus achieving better diagnostics and developing potential flavivirus therapeutics and vaccines. Full article

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

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Open AccessArticle

Combined Proteomics/Genomics Approach Reveals Proteomic Changes of Mature Virions as a Novel Poxvirus Adaptation Mechanism

by Marica Grossegesse, Joerg Doellinger, Alona Tyshaieva, Lars Schaade and Andreas Nitsche

Viruses 2017, 9(11), 337; https://doi.org/10.3390/v9110337 - 10 Nov 2017

Cited by 6 | Viewed by 4834

Abstract

DNA viruses, like poxviruses, possess a highly stable genome, suggesting that adaptation of virus particles to specific cell types is not restricted to genomic changes. Cowpox viruses are zoonotic poxviruses with an extraordinarily broad host range, demonstrating their adaptive potential in vivo. To [...] Read more.

DNA viruses, like poxviruses, possess a highly stable genome, suggesting that adaptation of virus particles to specific cell types is not restricted to genomic changes. Cowpox viruses are zoonotic poxviruses with an extraordinarily broad host range, demonstrating their adaptive potential in vivo. To elucidate adaptation mechanisms of poxviruses, we isolated cowpox virus particles from a rat and passaged them five times in a human and a rat cell line. Subsequently, we analyzed the proteome and genome of the non-passaged virions and each passage. While the overall viral genome sequence was stable during passaging, proteomics revealed multiple changes in the virion composition. Interestingly, an increased viral fitness in human cells was observed in the presence of increased immunomodulatory protein amounts. As the only minor variant with increasing frequency during passaging was located in a viral RNA polymerase subunit and, moreover, most minor variants were found in transcription-associated genes, protein amounts were presumably regulated at transcription level. This study is the first comparative proteome analysis of virus particles before and after cell culture propagation, revealing proteomic changes as a novel poxvirus adaptation mechanism. Full article

(This article belongs to the Special Issue Smallpox and Emerging Zoonotic Orthopoxviruses: What Is Coming Next?)

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Open AccessArticle

Antibody Competition Reveals Surface Location of HPV L2 Minor Capsid Protein Residues 17–36

by Stephanie M. Bywaters, Sarah A. Brendle, Kerstin P. Tossi, Jennifer Biryukov, Craig Meyers and Neil D. Christensen

Viruses 2017, 9(11), 336; https://doi.org/10.3390/v9110336 - 10 Nov 2017

Cited by 10 | Viewed by 5409

Abstract

The currently available nonavalent human papillomavirus (HPV) vaccine exploits the highly antigenic L1 major capsid protein to promote high-titer neutralizing antibodies, but is limited to the HPV types included in the vaccine since the responses are highly type-specific. The limited cross-protection offered by [...] Read more.

The currently available nonavalent human papillomavirus (HPV) vaccine exploits the highly antigenic L1 major capsid protein to promote high-titer neutralizing antibodies, but is limited to the HPV types included in the vaccine since the responses are highly type-specific. The limited cross-protection offered by the L1 virus-like particle (VLP) vaccine warrants further investigation into cross-protective L2 epitopes. The L2 proteins are yet to be fully characterized as to their precise placement in the virion. Adding to the difficulties in localizing L2, studies have suggested that L2 epitopes are not well exposed on the surface of the mature capsid prior to cellular engagement. Using a series of competition assays between previously mapped anti-L1 monoclonal antibodies (mAbs) (H16.V5, H16.U4 and H16.7E) and novel anti-L2 mAbs, we probed the capsid surface for the location of an L2 epitope (aa17–36). The previously characterized L1 epitopes together with our competition data is consistent with a proposed L2 epitope within the canyons of pentavalent capsomers. Full article

(This article belongs to the Section Animal Viruses)

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Open AccessArticle

Crystal Structure of the Full-Length Feline Immunodeficiency Virus Capsid Protein Shows an N-Terminal β-Hairpin in the Absence of N-Terminal Proline

by Christelle Folio, Natalia Sierra, Marie Dujardin, Guzman Alvarez and Christophe Guillon

Viruses 2017, 9(11), 335; https://doi.org/10.3390/v9110335 - 09 Nov 2017

Cited by 9 | Viewed by 5620

Abstract

Feline immunodeficiency virus (FIV) is a member of the Retroviridae family. It is the causative agent of an acquired immunodeficiency syndrome (AIDS) in cats and wild felines. Its capsid protein (CA) drives the assembly of the viral particle, which is a critical step [...] Read more.

Feline immunodeficiency virus (FIV) is a member of the Retroviridae family. It is the causative agent of an acquired immunodeficiency syndrome (AIDS) in cats and wild felines. Its capsid protein (CA) drives the assembly of the viral particle, which is a critical step in the viral replication cycle. Here, the first atomic structure of full-length FIV CA to 1.67 Å resolution is determined. The crystallized protein exhibits an original tetrameric assembly, composed of dimers which are stabilized by an intermolecular disulfide bridge induced by the crystallogenesis conditions. The FIV CA displays a standard α-helical CA topology with two domains, separated by a linker shorter than other retroviral CAs. The β-hairpin motif at its amino terminal end, which interacts with nucleotides in HIV-1, is unusually long in FIV CA. Interestingly, this functional β-motif is formed in this construct in the absence of the conserved N-terminal proline. The FIV CA exhibits a cis Arg–Pro bond in the CypA-binding loop, which is absent in known structures of lentiviral CAs. This structure represents the first tri-dimensional structure of a functional, full-length FIV CA. Full article

(This article belongs to the Section Animal Viruses)

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Open AccessArticle

Begomoviral Movement Protein Effects in Human and Plant Cells: Towards New Potential Interaction Partners

by Susanna Krapp, Christian Schuy, Eva Greiner, Irina Stephan, Barbara Alberter, Christina Funk, Manfred Marschall, Christina Wege, Susanne M. Bailer, Tatjana Kleinow and Björn Krenz

Viruses 2017, 9(11), 334; https://doi.org/10.3390/v9110334 - 09 Nov 2017

Cited by 13 | Viewed by 7839

Abstract

Geminiviral single-stranded circular DNA genomes replicate in nuclei so that the progeny DNA has to cross both the nuclear envelope and the plasmodesmata for systemic spread within plant tissues. For intra- and intercellular transport, two proteins are required: a nuclear shuttle protein (NSP) [...] Read more.

Geminiviral single-stranded circular DNA genomes replicate in nuclei so that the progeny DNA has to cross both the nuclear envelope and the plasmodesmata for systemic spread within plant tissues. For intra- and intercellular transport, two proteins are required: a nuclear shuttle protein (NSP) and a movement protein (MP). New characteristics of ectopically produced Abutilon mosaic virus (AbMV) MP (MP^AbMV), either authentically expressed or fused to a yellow fluorescent protein or epitope tags, respectively, were determined by localization studies in mammalian cell lines in comparison to plant cells. Wild-type MP^AbMV and the distinct MP^AbMV: reporter protein fusions appeared as curled threads throughout mammalian cells. Co-staining with cytoskeleton markers for actin, intermediate filaments, or microtubules identified these threads as re-organized microtubules. These were, however, not stabilized by the viral MP, as demonstrated by nocodazole treatment. The MP of a related bipartite New World begomovirus, Cleome leaf crumple virus (ClLCrV), resulted in the same intensified microtubule bundling, whereas that of a nanovirus did not. The C-terminal section of MP^AbMV, i.e., the protein’s oligomerization domain, was dispensable for the effect. However, MP expression in plant cells did not affect the microtubules network. Since plant epidermal cells are quiescent whilst mammalian cells are proliferating, the replication-associated protein Rep^AbMV protein was then co-expressed with MP^AbMV to induce cell progression into S-phase, thereby inducing distinct microtubule bundling without MP recruitment to the newly formed threads. Co-immunoprecipitation of MP^AbMV in the presence of Rep^AbMV, followed by mass spectrometry identified potential novel MP^AbMV-host interaction partners: the peptidyl-prolyl cis-trans isomerase NIMA-interacting 4 (Pin4) and stomatal cytokinesis defective 2 (SCD2) proteins. Possible roles of these putative interaction partners in the begomoviral life cycle and cytoskeletal association modes are discussed. Full article

(This article belongs to the Special Issue Geminiviruses)

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Open AccessConference Report

The 17th Rocky Mountain Virology Association Meeting

by Joel Rovnak, Rushika Perera, Matthew W. Hopken, Jenna Read, Derrick M. Waller and Randall J. Cohrs

Viruses 2017, 9(11), 333; https://doi.org/10.3390/v9110333 - 08 Nov 2017

Viewed by 5090

Abstract

Since 2000, scientists and students from the greater Rocky Mountain region, along with invited speakers, both national and international, have gathered at the Mountain Campus of Colorado State University to discuss their area of study, present recent findings, establish or strengthen collaborations, and [...] Read more.

Since 2000, scientists and students from the greater Rocky Mountain region, along with invited speakers, both national and international, have gathered at the Mountain Campus of Colorado State University to discuss their area of study, present recent findings, establish or strengthen collaborations, and mentor the next generation of virologists and prionologists through formal presentations and informal discussions concerning science, grantsmanship and network development. This year, approximately 100 people attended the 17th annual Rocky Mountain Virology Association meeting, that began with a keynote presentation, and featured 29 oral and 35 poster presentations covering RNA and DNA viruses, prions, virus-host interactions and guides to successful mentorship. Since the keynote address focused on the structure and function of Zika and related flaviviruses, a special session was held to discuss RNA control. The secluded meeting at the foot of the Colorado Rocky Mountains gave ample time for in-depth discussions amid the peak of fall colors in the aspen groves while the random bear provided excitement. On behalf of the Rocky Mountain Virology Association, this report summarizes the >50 reports. Full article

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Open AccessArticle

Characterization of Nucleoside Reverse Transcriptase Inhibitor-Associated Mutations in the RNase H Region of HIV-1 Subtype C Infected Individuals

by Sinaye Ngcapu, Kristof Theys, Pieter Libin, Vincent C. Marconi, Henry Sunpath, Thumbi Ndung’u and Michelle L. Gordon

Viruses 2017, 9(11), 330; https://doi.org/10.3390/v9110330 - 08 Nov 2017

Cited by 4 | Viewed by 4014

Abstract

The South African national treatment programme includes nucleoside reverse transcriptase inhibitors (NRTIs) in both first and second line highly active antiretroviral therapy regimens. Mutations in the RNase H domain have been associated with resistance to NRTIs but primarily in HIV-1 subtype B studies. [...] Read more.

The South African national treatment programme includes nucleoside reverse transcriptase inhibitors (NRTIs) in both first and second line highly active antiretroviral therapy regimens. Mutations in the RNase H domain have been associated with resistance to NRTIs but primarily in HIV-1 subtype B studies. Here, we investigated the prevalence and association of RNase H mutations with NRTI resistance in sequences from HIV-1 subtype C infected individuals. RNase H sequences from 112 NRTI treated but virologically failing individuals and 28 antiretroviral therapy (ART)-naive individuals were generated and analysed. In addition, sequences from 359 subtype C ART-naive sequences were downloaded from Los Alamos database to give a total of 387 sequences from ART-naive individuals for the analysis. Fisher’s exact test was used to identify mutations and Bayesian network learning was applied to identify novel NRTI resistance mutation pathways in RNase H domain. The mutations A435L, S468A, T470S, L484I, A508S, Q509L, L517I, Q524E and E529D were more prevalent in sequences from treatment-experienced compared to antiretroviral treatment naive individuals, however, only the E529D mutation remained significant after correction for multiple comparison. Our findings suggest a potential interaction between E529D and NRTI-treatment; however, site-directed mutagenesis is needed to understand the impact of this RNase H mutation. Full article

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

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Open AccessArticle

Rapid Construction of Complex Plant RNA Virus Infectious cDNA Clones for Agroinfection Using a Yeast-E. coli-Agrobacterium Shuttle Vector

by Kai Sun, Danyang Zhao, Yong Liu, Changjun Huang, Wei Zhang and Zhenghe Li

Viruses 2017, 9(11), 332; https://doi.org/10.3390/v9110332 - 07 Nov 2017

Cited by 37 | Viewed by 11551

Abstract

The availability of infectious full-length clone is indispensable for reverse genetics studies of virus biology, pathology and construction of viral vectors. However, for RNA viruses with large genome sizes or those exhibiting inherent cloning difficulties, procedure to generate biologically active complementary DNA (cDNA) [...] Read more.

The availability of infectious full-length clone is indispensable for reverse genetics studies of virus biology, pathology and construction of viral vectors. However, for RNA viruses with large genome sizes or those exhibiting inherent cloning difficulties, procedure to generate biologically active complementary DNA (cDNA) clones can be time-consuming or technically challenging. Here we have constructed a yeast-Escherichia coli-Agrobacterium shuttle vector that enables highly efficient homologous recombination in yeast for assembly of Agrobacterium compatible plant virus clones. Using this vector, we show that infectious cDNA clones of a plant negative-stranded RNA virus, sonchus yellow net rhabdovirus, can be rapidly assembled. In addition, one-step assembly of infectious clones of potato virus Y in yeast, either with or without intron, was readily achieved from as many as eight overlapping DNA fragments. More importantly, the recovered yeast plasmids can be transformed directly into Agrobacterium for inoculation, thereby obviating the E. coli cloning steps and associated toxicity issues. This method is rapid, highly efficient and cost-effective and should be readily applicable to a broad range of plant viruses. Full article

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

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Open AccessReview

Poxvirus Host Range Genes and Virus–Host Spectrum: A Critical Review

by Graziele Pereira Oliveira, Rodrigo Araújo Lima Rodrigues, Maurício Teixeira Lima, Betânia Paiva Drumond and Jônatas Santos Abrahão

Viruses 2017, 9(11), 331; https://doi.org/10.3390/v9110331 - 07 Nov 2017

Cited by 70 | Viewed by 9585

Abstract

The Poxviridae family is comprised of double-stranded DNA viruses belonging to nucleocytoplasmic large DNA viruses (NCLDV). Among the NCLDV, poxviruses exhibit the widest known host range, which is likely observed because this viral family has been more heavily investigated. However, relative to each [...] Read more.

The Poxviridae family is comprised of double-stranded DNA viruses belonging to nucleocytoplasmic large DNA viruses (NCLDV). Among the NCLDV, poxviruses exhibit the widest known host range, which is likely observed because this viral family has been more heavily investigated. However, relative to each member of the Poxviridae family, the spectrum of the host is variable, where certain viruses can infect a large range of hosts, while others are restricted to only one host species. It has been suggested that the variability in host spectrum among poxviruses is linked with the presence or absence of some host range genes. Would it be possible to extrapolate the restriction of viral replication in a specific cell lineage to an animal, a far more complex organism? In this study, we compare and discuss the relationship between the host range of poxvirus species and the abundance/diversity of host range genes. We analyzed the sequences of 38 previously identified and putative homologs of poxvirus host range genes, and updated these data with deposited sequences of new poxvirus genomes. Overall, the term host range genes might not be the most appropriate for these genes, since no correlation between them and the viruses’ host spectrum was observed, and a change in nomenclature should be considered. Finally, we analyzed the evolutionary history of these genes, and reaffirmed the occurrence of horizontal gene transfer (HGT) for certain elements, as previously suggested. Considering the data presented in this study, it is not possible to associate the diversity of host range factors with the amount of hosts of known poxviruses, and this traditional nomenclature creates misunderstandings. Full article

(This article belongs to the Special Issue Smallpox and Emerging Zoonotic Orthopoxviruses: What Is Coming Next?)

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Open AccessReview

Structure and Function of Caliciviral RNA Polymerases

by Ji-Hye Lee, Mi Sook Chung and Kyung Hyun Kim

Viruses 2017, 9(11), 329; https://doi.org/10.3390/v9110329 - 06 Nov 2017

Cited by 14 | Viewed by 6505

Abstract

Caliciviruses are a leading agent of human and animal gastroenteritis and respiratory tract infections, which are growing concerns in immunocompromised individuals. However, no vaccines or therapeutics are yet available. Since the rapid rate of genetic evolution of caliciviruses is mainly due to the [...] Read more.

Caliciviruses are a leading agent of human and animal gastroenteritis and respiratory tract infections, which are growing concerns in immunocompromised individuals. However, no vaccines or therapeutics are yet available. Since the rapid rate of genetic evolution of caliciviruses is mainly due to the error-prone nature of RNA-dependent RNA polymerase (RdRp), this article focuses on recent studies of the structures and functions of RdRp from caliciviruses. It also provides recent advances in the interactions of RdRp with virion protein genome-linked (VPg) and RNA and the structural and functional features of its precursor. Full article

(This article belongs to the Special Issue Structure-Function Relationships in Viral Polymerases)

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Open AccessArticle

Metagenomic Analysis of Therapeutic PYO Phage Cocktails from 1997 to 2014

by Julia Villarroel, Mette Voldby Larsen, Mogens Kilstrup and Morten Nielsen

Viruses 2017, 9(11), 328; https://doi.org/10.3390/v9110328 - 03 Nov 2017

Cited by 49 | Viewed by 10083

Abstract

Phage therapy has regained interest in recent years due to the alarming spread of antibiotic resistance. Whilst phage cocktails are commonly sold in pharmacies in countries such as Georgia and Russia, this is not the case in western countries due to western regulatory [...] Read more.

Phage therapy has regained interest in recent years due to the alarming spread of antibiotic resistance. Whilst phage cocktails are commonly sold in pharmacies in countries such as Georgia and Russia, this is not the case in western countries due to western regulatory agencies requiring a thorough characterization of the drug. Here, DNA sequencing of constituent biological entities constitutes a first step. The pyophage (PYO) cocktail is one of the main commercial products of the Georgian Eliava Institute of Bacteriophage, Microbiology and Virology and is used to cure skin infections. Since its first production in the 1930s, the composition of the cocktail has been periodically modified to add phages effective against emerging pathogenic strains. In this paper, we compared the composition of three PYO cocktails from 1997 (PYO97), 2000 (PYO2000) and 2014 (PYO2014). Based on next generation sequencing, de novo assembly and binning of contigs into draft genomes based on tetranucleotide distance, thirty and twenty-nine phage draft genomes were predicted in PYO97 and PYO2014, respectively. Of these, thirteen and fifteen shared high similarity to known phages. Eleven draft genomes were found to be common in the two cocktails. One of these showed no similarity to publicly available phage genomes. Representatives of phages targeting E. faecalis, E. faecium, E. coli, Proteus, P. aeruginosa and S. aureus were found in both cocktails. Finally, we estimated larger overlap of the PYO2000 cocktail to PYO97 compared to PYO2014. Using next generation sequencing and metagenomics analysis, we were able to characterize and compare the content of PYO cocktails separated by 17 years in time. Even though the cocktail composition is upgraded every six months, we found it to remain relatively stable over the years. Full article

(This article belongs to the Special Issue Bacteriophage Genomes and Genomics: News from the Wild)

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Open AccessReview

Biology of the BKPyV: An Update

by Francois Helle, Etienne Brochot, Lynda Handala, Elodie Martin, Sandrine Castelain, Catherine Francois and Gilles Duverlie

Viruses 2017, 9(11), 327; https://doi.org/10.3390/v9110327 - 03 Nov 2017

Cited by 57 | Viewed by 11866

Abstract

The BK virus (BKPyV) is a member of the Polyomaviridae family first isolated in 1971. BKPyV causes frequent infections during childhood and establishes persistent infections with minimal clinical implications within renal tubular cells and the urothelium. However, reactivation of BKPyV in immunocompromised individuals [...] Read more.

The BK virus (BKPyV) is a member of the Polyomaviridae family first isolated in 1971. BKPyV causes frequent infections during childhood and establishes persistent infections with minimal clinical implications within renal tubular cells and the urothelium. However, reactivation of BKPyV in immunocompromised individuals may cause serious complications. In particular, with the implementation of more potent immunosuppressive drugs in the last decade, BKPyV has become an emerging pathogen in kidney and bone marrow transplant recipients where it often causes associated nephropathy and haemorrhagic cystitis, respectively. Unfortunately, no specific antiviral against BKPyV has been approved yet and the only therapeutic option is a modulation of the immunosuppressive drug regimen to improve immune control though it may increase the risk of rejection. A better understanding of the BKPyV life cycle is thus needed to develop efficient treatment against this virus. In this review, we provide an update on recent advances in understanding the biology of BKPyV. Full article

(This article belongs to the Section Animal Viruses)

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Open AccessArticle

Helicase Domain of West Nile Virus NS3 Protein Plays a Role in Inhibition of Type I Interferon Signalling

by Yin Xiang Setoh, Parthiban Periasamy, Nias Yong Gao Peng, Alberto A. Amarilla, Andrii Slonchak and Alexander A. Khromykh

Viruses 2017, 9(11), 326; https://doi.org/10.3390/v9110326 - 02 Nov 2017

Cited by 13 | Viewed by 5268

Abstract

West Nile virus (WNV) is a neurotropic flavivirus that can cause encephalitis in mammalian and avian hosts. In America, the virulent WNV strain (NY99) is causing yearly outbreaks of encephalitis in humans and horses, while in Australia the less virulent Kunjin strain of [...] Read more.

West Nile virus (WNV) is a neurotropic flavivirus that can cause encephalitis in mammalian and avian hosts. In America, the virulent WNV strain (NY99) is causing yearly outbreaks of encephalitis in humans and horses, while in Australia the less virulent Kunjin strain of WNV strain has not been associated with significant disease outbreaks until a recent 2011 large outbreak in horses (but not in humans) caused by NSW2011 strain. Using chimeric viruses between NY99 and NSW2011 strains we previously identified a role for the non-structural proteins of NY99 strain and especially the NS3 protein, in enhanced virus replication in type I interferon response-competent cells and increased virulence in mice. To further define the role of NY99 NS3 protein in inhibition of type I interferon response, we have generated and characterised additional chimeric viruses containing the protease or the helicase domains of NY99 NS3 on the background of the NSW2011 strain. The results identified the role for the helicase but not the protease domain of NS3 protein in the inhibition of type I interferon signalling and showed that helicase domain of the more virulent NY99 strain performs this function more efficiently than helicase domain of the less virulent NSW2011 strain. Further analysis with individual amino acid mutants identified two amino acid residues in the helicase domain primarily responsible for this difference. Using chimeric replicons, we also showed that the inhibition of type I interferon (IFN) signalling was independent of other known functions of NS3 in RNA replication and assembly of virus particles. Full article

(This article belongs to the Section Animal Viruses)

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Open AccessArticle

Gene Editing in Human Lymphoid Cells: Role for Donor DNA, Type of Genomic Nuclease and Cell Selection Method

by Anastasia Zotova, Elena Lopatukhina, Alexander Filatov, Musa Khaitov and Dmitriy Mazurov

Viruses 2017, 9(11), 325; https://doi.org/10.3390/v9110325 - 02 Nov 2017

Cited by 4 | Viewed by 5812

Abstract

Programmable endonucleases introduce DNA breaks at specific sites, which are repaired by non-homologous end joining (NHEJ) or homology recombination (HDR). Genome editing in human lymphoid cells is challenging as these difficult-to-transfect cells may also inefficiently repair DNA by HDR. Here, we estimated efficiencies [...] Read more.

Programmable endonucleases introduce DNA breaks at specific sites, which are repaired by non-homologous end joining (NHEJ) or homology recombination (HDR). Genome editing in human lymphoid cells is challenging as these difficult-to-transfect cells may also inefficiently repair DNA by HDR. Here, we estimated efficiencies and dynamics of knockout (KO) and knockin (KI) generation in human T and B cell lines depending on repair template, target loci and types of genomic endonucleases. Using zinc finger nuclease (ZFN), we have engineered Jurkat and CEM cells with the 8.2 kb human immunodeficiency virus type 1 (HIV-1) ∆Env genome integrated at the adeno-associated virus integration site 1 (AAVS1) locus that stably produce virus particles and mediate infection upon transfection with helper vectors. Knockouts generated by ZFN or clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) double nicking techniques were comparably efficient in lymphoid cells. However, unlike polyclonal sorted cells, gene-edited cells selected by cloning exerted tremendous deviations in functionality as estimated by replication of HIV-1 and human T cell leukemia virus type 1 (HTLV-1) in these cells. Notably, the recently reported high-fidelity eCas9 1.1 when combined to the nickase mutation displayed gene-dependent decrease in on-target activity. Thus, the balance between off-target effects and on-target efficiency of nucleases, as well as choice of the optimal method of edited cell selection should be taken into account for proper gene function validation in lymphoid cells. Full article

(This article belongs to the Section Animal Viruses)

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