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Volume 8
Issue 11
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Viruses, Volume 8, Issue 11 (November 2016) – 28 articles

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2476 KiB  
Review
Interactions between the HIV-1 Unspliced mRNA and Host mRNA Decay Machineries
by Daniela Toro-Ascuy, Bárbara Rojas-Araya, Fernando Valiente-Echeverría and Ricardo Soto-Rifo
Viruses 2016, 8(11), 320; https://doi.org/10.3390/v8110320 - 23 Nov 2016
Cited by 20 | Viewed by 8009
Abstract
The human immunodeficiency virus type-1 (HIV-1) unspliced transcript is used both as mRNA for the synthesis of structural proteins and as the packaged genome. Given the presence of retained introns and instability AU-rich sequences, this viral transcript is normally retained and degraded in [...] Read more.
The human immunodeficiency virus type-1 (HIV-1) unspliced transcript is used both as mRNA for the synthesis of structural proteins and as the packaged genome. Given the presence of retained introns and instability AU-rich sequences, this viral transcript is normally retained and degraded in the nucleus of host cells unless the viral protein REV is present. As such, the stability of the HIV-1 unspliced mRNA must be particularly controlled in the nucleus and the cytoplasm in order to ensure proper levels of this viral mRNA for translation and viral particle formation. During its journey, the HIV-1 unspliced mRNA assembles into highly specific messenger ribonucleoproteins (mRNPs) containing many different host proteins, amongst which are well-known regulators of cytoplasmic mRNA decay pathways such as up-frameshift suppressor 1 homolog (UPF1), Staufen double-stranded RNA binding protein 1/2 (STAU1/2), or components of miRNA-induced silencing complex (miRISC) and processing bodies (PBs). More recently, the HIV-1 unspliced mRNA was shown to contain N6-methyladenosine (m6A), allowing the recruitment of YTH N6-methyladenosine RNA binding protein 2 (YTHDF2), an m6A reader host protein involved in mRNA decay. Interestingly, these host proteins involved in mRNA decay were shown to play positive roles in viral gene expression and viral particle assembly, suggesting that HIV-1 interacts with mRNA decay components to successfully accomplish viral replication. This review summarizes the state of the art in terms of the interactions between HIV-1 unspliced mRNA and components of different host mRNA decay machineries. Full article
(This article belongs to the Special Issue Viral Interactions with Host RNA Decay Pathways)
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1129 KiB  
Article
Pathogens Inactivated by Low-Energy-Electron Irradiation Maintain Antigenic Properties and Induce Protective Immune Responses
by Jasmin Fertey, Lea Bayer, Thomas Grunwald, Alexandra Pohl, Jana Beckmann, Gaby Gotzmann, Javier Portillo Casado, Jessy Schönfelder, Frank-Holm Rögner, Christiane Wetzel, Martin Thoma, Susanne M. Bailer, Ekkehard Hiller, Steffen Rupp and Sebastian Ulbert
Viruses 2016, 8(11), 319; https://doi.org/10.3390/v8110319 - 23 Nov 2016
Cited by 40 | Viewed by 8417
Abstract
Inactivated vaccines are commonly produced by incubating pathogens with chemicals such as formaldehyde or β-propiolactone. This is a time-consuming process, the inactivation efficiency displays high variability and extensive downstream procedures are often required. Moreover, application of chemicals alters the antigenic components of the [...] Read more.
Inactivated vaccines are commonly produced by incubating pathogens with chemicals such as formaldehyde or β-propiolactone. This is a time-consuming process, the inactivation efficiency displays high variability and extensive downstream procedures are often required. Moreover, application of chemicals alters the antigenic components of the viruses or bacteria, resulting in reduced antibody specificity and therefore stimulation of a less effective immune response. An alternative method for inactivation of pathogens is ionizing radiation. It acts very fast and predominantly damages nucleic acids, conserving most of the antigenic structures. However, currently used irradiation technologies (mostly gamma-rays and high energy electrons) require large and complex shielding constructions to protect the environment from radioactivity or X-rays generated during the process. This excludes them from direct integration into biological production facilities. Here, low-energy electron irradiation (LEEI) is presented as an alternative inactivation method for pathogens in liquid solutions. LEEI can be used in normal laboratories, including good manufacturing practice (GMP)- or high biosafety level (BSL)-environments, as only minor shielding is necessary. We show that LEEI efficiently inactivates different viruses (influenza A (H3N8), porcine reproductive and respiratory syndrome virus (PRRSV), equine herpesvirus 1 (EHV-1)) and bacteria (Escherichia coli) and maintains their antigenicity. Moreover, LEEI-inactivated influenza A viruses elicit protective immune responses in animals, as analyzed by virus neutralization assays and viral load determination upon challenge. These results have implications for novel ways of developing and manufacturing inactivated vaccines with improved efficacy. Full article
(This article belongs to the Section Viral Immunology, Vaccines, and Antivirals)
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2158 KiB  
Conference Report
Eleventh International Foamy Virus Conference—Meeting Report
by Florence Buseyne, Antoine Gessain, Marcelo A. Soares, André F. Santos, Magdalena Materniak-Kornas, Pascale Lesage, Alessia Zamborlini, Martin Löchelt, Wentao Qiao, Dirk Lindemann, Birgitta M. Wöhrl, Jonathan P. Stoye, Ian A. Taylor and Arifa S. Khan
Viruses 2016, 8(11), 318; https://doi.org/10.3390/v8110318 - 23 Nov 2016
Cited by 3 | Viewed by 4723
Abstract
The Eleventh International Foamy Virus Conference took place on 9–10 June 2016 at the Institut Pasteur, Paris, France. The meeting reviewed progress on foamy virus (FV) research, as well as related current topics in retrovirology. FVs are complex retroviruses that are widespread in [...] Read more.
The Eleventh International Foamy Virus Conference took place on 9–10 June 2016 at the Institut Pasteur, Paris, France. The meeting reviewed progress on foamy virus (FV) research, as well as related current topics in retrovirology. FVs are complex retroviruses that are widespread in several animal species. Several research topics on these viruses are relevant to human health: cross-species transmission and viral emergence, vectors for gene therapy, development of antiretroviral drugs, retroviral evolution and its influence on the human genome. In this article, we review the conference presentations on these viruses and highlight the major questions to be answered. Full article
1383 KiB  
Review
The Expanding Family of Virophages
by Meriem Bekliz, Philippe Colson and Bernard La Scola
Viruses 2016, 8(11), 317; https://doi.org/10.3390/v8110317 - 23 Nov 2016
Cited by 37 | Viewed by 9264
Abstract
Virophages replicate with giant viruses in the same eukaryotic cells. They are a major component of the specific mobilome of mimiviruses. Since their discovery in 2008, five other representatives have been isolated, 18 new genomes have been described, two of which being nearly [...] Read more.
Virophages replicate with giant viruses in the same eukaryotic cells. They are a major component of the specific mobilome of mimiviruses. Since their discovery in 2008, five other representatives have been isolated, 18 new genomes have been described, two of which being nearly completely sequenced, and they have been classified in a new viral family, Lavidaviridae. Virophages are small viruses with approximately 35–74 nm large icosahedral capsids and 17–29 kbp large double-stranded DNA genomes with 16–34 genes, among which a very small set is shared with giant viruses. Virophages have been isolated or detected in various locations and in a broad range of habitats worldwide, including the deep ocean and inland. Humans, therefore, could be commonly exposed to virophages, although currently limited evidence exists of their presence in humans based on serology and metagenomics. The distribution of virophages, the consequences of their infection and the interactions with their giant viral hosts within eukaryotic cells deserve further research. Full article
(This article belongs to the Special Issue Viruses of Protozoa)
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Erratum
Erratum: Tahara, M., et al. Measles Virus Hemagglutinin Protein Epitopes: The Basis of Antigenic Stability. Viruses 2016, 8, 216
by Maino Tahara, Jean-Philippe Bürckert, Kazuhiko Kanou, Katsumi Maenaka, Claude P. Muller and Makoto Takeda
Viruses 2016, 8(11), 313; https://doi.org/10.3390/v8110313 - 21 Nov 2016
Cited by 3 | Viewed by 3385
Abstract
The authors wish to make the following change to their paper [1].[...] Full article
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Article
Comparative Analysis of RNAi-Based Methods to Down-Regulate Expression of Two Genes Expressed at Different Levels in Myzus persicae
by Michaël Mulot, Sylvaine Boissinot, Baptiste Monsion, Maryam Rastegar, Gabriel Clavijo, David Halter, Nicole Bochet, Monique Erdinger and Véronique Brault
Viruses 2016, 8(11), 316; https://doi.org/10.3390/v8110316 - 19 Nov 2016
Cited by 20 | Viewed by 6390
Abstract
With the increasing availability of aphid genomic data, it is necessary to develop robust functional validation methods to evaluate the role of specific aphid genes. This work represents the first study in which five different techniques, all based on RNA interference and on [...] Read more.
With the increasing availability of aphid genomic data, it is necessary to develop robust functional validation methods to evaluate the role of specific aphid genes. This work represents the first study in which five different techniques, all based on RNA interference and on oral acquisition of double-stranded RNA (dsRNA), were developed to silence two genes, ALY and Eph, potentially involved in polerovirus transmission by aphids. Efficient silencing of only Eph transcripts, which are less abundant than those of ALY, could be achieved by feeding aphids on transgenic Arabidopsis thaliana expressing an RNA hairpin targeting Eph, on Nicotiana benthamiana infected with a Tobacco rattle virus (TRV)-Eph recombinant virus, or on in vitro-synthesized Eph-targeting dsRNA. These experiments showed that the silencing efficiency may differ greatly between genes and that aphid gut cells seem to be preferentially affected by the silencing mechanism after oral acquisition of dsRNA. In addition, the use of plants infected with recombinant TRV proved to be a promising technique to silence aphid genes as it does not require plant transformation. This work highlights the need to pursue development of innovative strategies to reproducibly achieve reduction of expression of aphid genes. Full article
(This article belongs to the Special Issue Molecular Plant Virus—Insect Vector Interactions)
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Article
Aphis Glycines Virus 2, a Novel Insect Virus with a Unique Genome Structure
by Sijun Liu, Diveena Vijayendran 1, Yuting Chen and Bryony C. Bonning
Viruses 2016, 8(11), 315; https://doi.org/10.3390/v8110315 - 19 Nov 2016
Cited by 18 | Viewed by 4983
Abstract
The invasive soybean aphid, Aphis glycines, is a major pest in soybeans, resulting in substantial economic loss. We analyzed the A. glycines transcriptome to identify sequences derived from viruses of A. glycines. We identified sequences derived from a novel virus named [...] Read more.
The invasive soybean aphid, Aphis glycines, is a major pest in soybeans, resulting in substantial economic loss. We analyzed the A. glycines transcriptome to identify sequences derived from viruses of A. glycines. We identified sequences derived from a novel virus named Aphis glycines virus 2 (ApGlV2). The assembled virus genome sequence was confirmed by reverse transcription polymerase chain reaction (RT-PCR) and Sanger sequencing, conserved domains were characterized, and distribution, and transmission examined. This virus has a positive sense, single-stranded RNA genome of ~4850 nt that encodes three proteins. The RNA-dependent RNA polymerase (RdRp) of ApGlV2 is a permuted RdRp similar to those of some tetraviruses, while the capsid protein is structurally similar to the capsid proteins of plant sobemoviruses. ApGlV2 also encodes a larger minor capsid protein, which is translated by a readthrough mechanism. ApGlV2 appears to be widespread in A. glycines populations and to persistently infect aphids with a 100% vertical transmission rate. ApGlV2 is susceptible to the antiviral RNA interference (RNAi) pathway. This virus, with its unique genome structure with both plant- and insect-virus characteristics, is of particular interest from an evolutionary standpoint. Full article
(This article belongs to the Section Insect Viruses)
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Review
Plant Virus Infection and the Ubiquitin Proteasome Machinery: Arms Race along the Endoplasmic Reticulum
by Jeanmarie Verchot
Viruses 2016, 8(11), 314; https://doi.org/10.3390/v8110314 - 19 Nov 2016
Cited by 43 | Viewed by 7038
Abstract
The endoplasmic reticulum (ER) is central to plant virus replication, translation, maturation, and egress. Ubiquitin modification of ER associated cellular and viral proteins, alongside the actions of the 26S proteasome, are vital for the regulation of infection. Viruses can arrogate ER associated ubiquitination [...] Read more.
The endoplasmic reticulum (ER) is central to plant virus replication, translation, maturation, and egress. Ubiquitin modification of ER associated cellular and viral proteins, alongside the actions of the 26S proteasome, are vital for the regulation of infection. Viruses can arrogate ER associated ubiquitination as well as cytosolic ubiquitin ligases with the purpose of directing the ubiquitin proteasome system (UPS) to new targets. Such targets include necessary modification of viral proteins which may stabilize certain complexes, or modification of Argonaute to suppress gene silencing. The UPS machinery also contributes to the regulation of effector triggered immunity pattern recognition receptor immunity. Combining the results of unrelated studies, many positive strand RNA plant viruses appear to interact with cytosolic Ub-ligases to provide novel avenues for controlling the deleterious consequences of disease. Viral interactions with the UPS serve to regulate virus infection in a manner that promotes replication and movement, but also modulates the levels of RNA accumulation to ensure successful biotrophic interactions. In other instances, the UPS plays a central role in cellular immunity. These opposing roles are made evident by contrasting studies where knockout mutations in the UPS can either hamper viruses or lead to more aggressive diseases. Understanding how viruses manipulate ER associated post-translational machineries to better manage virus–host interactions will provide new targets for crop improvement. Full article
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Article
Role of Pea Enation Mosaic Virus Coat Protein in the Host Plant and Aphid Vector
by Juliette Doumayrou, Melissa Sheber, Bryony C. Bonning and W. Allen Miller
Viruses 2016, 8(11), 312; https://doi.org/10.3390/v8110312 - 18 Nov 2016
Cited by 8 | Viewed by 8694
Abstract
Understanding the molecular mechanisms involved in plant virus–vector interactions is essential for the development of effective control measures for aphid-vectored epidemic plant diseases. The coat proteins (CP) are the main component of the viral capsids, and they are implicated in practically every stage [...] Read more.
Understanding the molecular mechanisms involved in plant virus–vector interactions is essential for the development of effective control measures for aphid-vectored epidemic plant diseases. The coat proteins (CP) are the main component of the viral capsids, and they are implicated in practically every stage of the viral infection cycle. Pea enation mosaic virus 1 (PEMV1, Enamovirus, Luteoviridae) and Pea enation mosaic virus 2 (PEMV2, Umbravirus, Tombusviridae) are two RNA viruses in an obligate symbiosis causing the pea enation mosaic disease. Sixteen mutant viruses were generated with mutations in different domains of the CP to evaluate the role of specific amino acids in viral replication, virion assembly, long-distance movement in Pisum sativum, and aphid transmission. Twelve mutant viruses were unable to assemble but were able to replicate in inoculated leaves, move long-distance, and express the CP in newly infected leaves. Four mutant viruses produced virions, but three were not transmissible by the pea aphid, Acyrthosiphon pisum. Three-dimensional modeling of the PEMV CP, combined with biological assays for virion assembly and aphid transmission, allowed for a model of the assembly of PEMV coat protein subunits. Full article
(This article belongs to the Special Issue Molecular Plant Virus—Insect Vector Interactions)
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4045 KiB  
Article
Studies in a Murine Model Confirm the Safety of Griffithsin and Advocate Its Further Development as a Microbicide Targeting HIV-1 and Other Enveloped Viruses
by Joseph Calvin Kouokam, Amanda B. Lasnik and Kenneth E. Palmer
Viruses 2016, 8(11), 311; https://doi.org/10.3390/v8110311 - 17 Nov 2016
Cited by 34 | Viewed by 4327
Abstract
Griffithsin (GRFT), a lectin from Griffithsia species, inhibits human immunodeficiency virus-1 (HIV-1) replication at sub-nanomolar concentrations, with limited cellular toxicity. However, in vivo safety of GRFT is not fully understood, especially following parenteral administration. We first assessed GRFT’s effects in vitro, on mouse [...] Read more.
Griffithsin (GRFT), a lectin from Griffithsia species, inhibits human immunodeficiency virus-1 (HIV-1) replication at sub-nanomolar concentrations, with limited cellular toxicity. However, in vivo safety of GRFT is not fully understood, especially following parenteral administration. We first assessed GRFT’s effects in vitro, on mouse peripheral blood mononuclear cell (mPBMC) viability, mitogenicity, and activation using flow-cytometry, as well as cytokine secretion through enzyme-linked immunosorbent assay (ELISA). Toxicological properties of GRFT were determined after a single subcutaneous administration of 50 mg/kg or 14 daily doses of 10 mg/kg in BALB/c mice. In the context of microbicide development, toxicity of GRFT at 2 mg/kg was determined after subcutaneous, intravaginal, and intraperitoneal administrations, respectively. Interestingly, GRFT caused no significant cell death, mitogenicity, activation, or cytokine release in mPBMCs, validating the usefulness of a mouse model. An excellent safety profile for GRFT was obtained in vivo: no overt changes were observed in animal fitness, blood chemistry or CBC parameters. Following GRFT treatment, reversible splenomegaly was observed with activation of certain spleen B and T cells. However, spleen tissues were not pathologically altered by GRFT (either with a single high dose or chronic doses). Finally, no detectable toxicity was found after mucosal or systemic treatment with 2 mg/kg GRFT, which should be further developed as a microbicide for HIV prevention. Full article
(This article belongs to the Special Issue Lectins as Antiviral)
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6501 KiB  
Article
Two Novel Myoviruses from the North of Iraq Reveal Insights into Clostridium difficile Phage Diversity and Biology
by Srwa J. Rashid, Jakub Barylski, Katherine R. Hargreaves, Andrew A. Millard, Gurinder K. Vinner and Martha R. J. Clokie
Viruses 2016, 8(11), 310; https://doi.org/10.3390/v8110310 - 16 Nov 2016
Cited by 26 | Viewed by 7362
Abstract
Bacteriophages (phages) are increasingly being explored as therapeutic agents to combat bacterial diseases, including Clostridium difficile infections. Therapeutic phages need to be able to efficiently target and kill a wide range of clinically relevant strains. While many phage groups have yet to be [...] Read more.
Bacteriophages (phages) are increasingly being explored as therapeutic agents to combat bacterial diseases, including Clostridium difficile infections. Therapeutic phages need to be able to efficiently target and kill a wide range of clinically relevant strains. While many phage groups have yet to be investigated in detail, those with new and useful properties can potentially be identified when phages from newly studied geographies are characterised. Here, we report the isolation of C. difficile phages from soil samples from the north of Iraq. Two myoviruses, CDKM15 and CDKM9, were selected for detailed sequence analysis on the basis of their broad and potentially useful host range. CDKM9 infects 25/80 strains from 12/20 C. difficile ribotypes, and CDKM15 infects 20/80 strains from 9/20 ribotypes. Both phages can infect the clinically relevant ribotypes R027 and R001. Phylogenetic analysis based on whole genome sequencing revealed that the phages are genetically distinct from each other but closely related to other long-tailed myoviruses. A comparative genomic analysis revealed key differences in the genes predicted to encode for proteins involved in bacterial infection. Notably, CDKM15 carries a clustered regularly interspaced short palindromic repeat (CRISPR) array with spacers that are homologous to sequences in the CDKM9 genome and of phages from diverse localities. The findings presented suggest a possible shared evolutionary past for these phages and provides evidence of their widespread dispersal. Full article
(This article belongs to the Special Issue Viruses of Microbes)
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Review
Host–Pathogen Interactions in Measles Virus Replication and Anti-Viral Immunity
by Yanliang Jiang, Yali Qin and Mingzhou Chen
Viruses 2016, 8(11), 308; https://doi.org/10.3390/v8110308 - 16 Nov 2016
Cited by 15 | Viewed by 12855
Abstract
The measles virus (MeV) is a contagious pathogenic RNA virus of the family Paramyxoviridae, genus Morbillivirus, that can cause serious symptoms and even fetal complications. Here, we summarize current molecular advances in MeV research, and emphasize the connection between host cells [...] Read more.
The measles virus (MeV) is a contagious pathogenic RNA virus of the family Paramyxoviridae, genus Morbillivirus, that can cause serious symptoms and even fetal complications. Here, we summarize current molecular advances in MeV research, and emphasize the connection between host cells and MeV replication. Although measles has reemerged recently, the potential for its eradication is promising with significant progress in our understanding of the molecular mechanisms of its replication and host-pathogen interactions. Full article
(This article belongs to the Special Issue Recent Progress in Measles Virus Research)
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3641 KiB  
Article
The E3 Ubiquitin Ligase TMEM129 Is a Tri-Spanning Transmembrane Protein
by Michael L. Van de Weijer, Guus H. Van Muijlwijk, Linda J. Visser, Ana I. Costa, Emmanuel J. H. J. Wiertz and Robert Jan Lebbink
Viruses 2016, 8(11), 309; https://doi.org/10.3390/v8110309 - 15 Nov 2016
Cited by 4 | Viewed by 5981
Abstract
Misfolded proteins from the endoplasmic reticulum (ER) are transported back into the cytosol for degradation via the ubiquitin-proteasome system. The human cytomegalovirus protein US11 hijacks this ER-associated protein degradation (ERAD) pathway to downregulate human leukocyte antigen (HLA) class I molecules in virus-infected cells, [...] Read more.
Misfolded proteins from the endoplasmic reticulum (ER) are transported back into the cytosol for degradation via the ubiquitin-proteasome system. The human cytomegalovirus protein US11 hijacks this ER-associated protein degradation (ERAD) pathway to downregulate human leukocyte antigen (HLA) class I molecules in virus-infected cells, thereby evading elimination by cytotoxic T-lymphocytes. Recently, we identified the E3 ubiquitin ligase transmembrane protein 129 (TMEM129) as a key player in this process, where interference with TMEM129 activity in human cells completely abrogates US11-mediated class I degradation. Here, we set out to further characterize TMEM129. We show that TMEM129 is a non-glycosylated protein containing a non-cleaved signal anchor sequence. By glycosylation scanning mutagenesis, we show that TMEM129 is a tri-spanning ER-membrane protein that adopts an Nexo–Ccyto orientation. This insertion in the ER membrane positions the C-terminal really interesting new gene (RING) domain of TMEM129 in the cytosol, making it available to catalyze ubiquitination reactions that are required for cytosolic degradation of secretory proteins. Full article
(This article belongs to the Special Issue Viruses, ERAD, and the Proteasome)
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3139 KiB  
Review
KSHV Entry and Trafficking in Target Cells—Hijacking of Cell Signal Pathways, Actin and Membrane Dynamics
by Binod Kumar and Bala Chandran
Viruses 2016, 8(11), 305; https://doi.org/10.3390/v8110305 - 14 Nov 2016
Cited by 44 | Viewed by 9449
Abstract
Kaposi’s sarcoma associated herpesvirus (KSHV) is etiologically associated with human endothelial cell hyperplastic Kaposi’s sarcoma and B-cell primary effusion lymphoma. KSHV infection of adherent endothelial and fibroblast cells are used as in vitro models for infection and KSHV enters these cells by host [...] Read more.
Kaposi’s sarcoma associated herpesvirus (KSHV) is etiologically associated with human endothelial cell hyperplastic Kaposi’s sarcoma and B-cell primary effusion lymphoma. KSHV infection of adherent endothelial and fibroblast cells are used as in vitro models for infection and KSHV enters these cells by host membrane bleb and actin mediated macropinocytosis or clathrin endocytosis pathways, respectively. Infection in endothelial and fibroblast cells is initiated by the interactions between multiple viral envelope glycoproteins and cell surface associated heparan sulfate (HS), integrins (α3β1, αVβ3 and αVβ5), and EphA2 receptor tyrosine kinase (EphA2R). This review summarizes the accumulated studies demonstrating that KSHV manipulates the host signal pathways to enter and traffic in the cytoplasm of the target cells, to deliver the viral genome into the nucleus, and initiate viral gene expression. KSHV interactions with the cell surface receptors is the key platform for the manipulations of host signal pathways which results in the simultaneous induction of FAK, Src, PI3-K, Rho-GTPase, ROS, Dia-2, PKC ζ, c-Cbl, CIB1, Crk, p130Cas and GEF-C3G signal and adaptor molecules that play critical roles in the modulation of membrane and actin dynamics, and in the various steps of the early stages of infection such as entry and trafficking towards the nucleus. The Endosomal Sorting Complexes Required for Transport (ESCRT) proteins are also recruited to assist in viral entry and trafficking. In addition, KSHV interactions with the cell surface receptors also induces the host transcription factors NF-κB, ERK1/2, and Nrf2 early during infection to initiate and modulate viral and host gene expression. Nuclear delivery of the viral dsDNA genome is immediately followed by the host innate responses such as the DNA damage response (DDR), inflammasome and interferon responses. Overall, these studies form the initial framework for further studies of simultaneous targeting of KSHV glycoproteins, host receptor, signal molecules and trafficking machinery that would lead into novel therapeutic methods to prevent KSHV infection of target cells and consequently the associated malignancies. Full article
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Article
A Novel Strain of Tomato Leaf Curl New Delhi Virus Has Spread to the Mediterranean Basin
by Isabel M. Fortes, Sonia Sánchez-Campos, Elvira Fiallo-Olivé, Juan A. Díaz-Pendón, Jesús Navas-Castillo and Enrique Moriones
Viruses 2016, 8(11), 307; https://doi.org/10.3390/v8110307 - 10 Nov 2016
Cited by 77 | Viewed by 7687
Abstract
Tomato leaf curl New Delhi virus (ToLCNDV) is a whitefly-transmitted bipartite begomovirus (genus Begomovirus, family Geminiviridae) that causes damage to multiple cultivated plant species mainly belonging to the Solanaceae and Cucurbitaceae families. ToLCNDV was limited to Asian countries until 2012, when [...] Read more.
Tomato leaf curl New Delhi virus (ToLCNDV) is a whitefly-transmitted bipartite begomovirus (genus Begomovirus, family Geminiviridae) that causes damage to multiple cultivated plant species mainly belonging to the Solanaceae and Cucurbitaceae families. ToLCNDV was limited to Asian countries until 2012, when it was first reported in Spain, causing severe epidemics in cucurbit crops. Here, we show that a genetically-uniform ToLCNDV population is present in Spain, compatible with a recent introduction. Analyses of ToLCNDV isolates reported from other parts of the world indicated that this virus has a highly heterogeneous population genetically with no evident geographical, plant host or year-based phylogenetic groups observed. Isolates emerging in Spain belong to a strain that seems to have evolved by recombination. Isolates of this strain seem adapted to infecting cucurbits, but poorly infect tomatoes. Full article
(This article belongs to the Section Viruses of Plants, Fungi and Protozoa)
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Article
Epitope Identification and Application for Diagnosis of Duck Tembusu Virus Infections in Ducks
by Chenxi Li, Junyan Liu, Wulin Shaozhou, Xiaofei Bai, Qingshan Zhang, Ronghong Hua, Jyung-Hurng Liu, Ming Liu and Yun Zhang
Viruses 2016, 8(11), 306; https://doi.org/10.3390/v8110306 - 10 Nov 2016
Cited by 12 | Viewed by 5583
Abstract
Duck Tembusu virus (DTMUV) causes substantial egg drop disease. DTMUV was first identified in China and rapidly spread to Malaysia and Thailand. The antigenicity of the DTMUV E protein has not yet been characterized. Here, we investigated antigenic sites on the E protein [...] Read more.
Duck Tembusu virus (DTMUV) causes substantial egg drop disease. DTMUV was first identified in China and rapidly spread to Malaysia and Thailand. The antigenicity of the DTMUV E protein has not yet been characterized. Here, we investigated antigenic sites on the E protein using the non-neutralizing monoclonal antibodies (mAbs) 1F3 and 1A5. Two minimal epitopes were mapped to 221LD/NLPW225 and 87YAEYI91 by using phage display and mutagenesis. DTMUV-positive duck sera reacted with the epitopes, thus indicating the importance of the minimal amino acids of the epitopes for antibody-epitope binding. The performance of the dot blotting assay with the corresponding positive sera indicated that YAEYI was DTMUV type-specific, whereas 221LD/NLPW225 was a cross-reactive epitope for West Nile virus (WNV), dengue virus (DENV), and Japanese encephalitis virus (JEV) and corresponded to conserved and variable amino acid sequences among these strains. The structure model of the E protein revealed that YAEYI and LD/NLPW were located on domain (D) II, which confirmed that DII might contain a type-specific non-neutralizing epitope. The YAEYI epitope-based antigen demonstrated its diagnostic potential by reacting with high specificity to serum samples obtained from DTMUV-infected ducks. Based on these observations, a YAEYI-based serological test could be used for DTMUV surveillance and could differentiate DTMUV infections from JEV or WNV infections. These findings provide new insights into the organization of epitopes on flavivirus E proteins that might be valuable for the development of epitope-based serological diagnostic tests for DTMUV. Full article
(This article belongs to the Special Issue Advances in Flavivirus Research)
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Review
Three-Dimensional Rotating Wall Vessel-Derived Cell Culture Models for Studying Virus-Host Interactions
by Jameson K. Gardner and Melissa M. Herbst-Kralovetz
Viruses 2016, 8(11), 304; https://doi.org/10.3390/v8110304 - 09 Nov 2016
Cited by 37 | Viewed by 9688
Abstract
The key to better understanding complex virus-host interactions is the utilization of robust three-dimensional (3D) human cell cultures that effectively recapitulate native tissue architecture and model the microenvironment. A lack of physiologically-relevant animal models for many viruses has limited the elucidation of factors [...] Read more.
The key to better understanding complex virus-host interactions is the utilization of robust three-dimensional (3D) human cell cultures that effectively recapitulate native tissue architecture and model the microenvironment. A lack of physiologically-relevant animal models for many viruses has limited the elucidation of factors that influence viral pathogenesis and of complex host immune mechanisms. Conventional monolayer cell cultures may support viral infection, but are unable to form the tissue structures and complex microenvironments that mimic host physiology and, therefore, limiting their translational utility. The rotating wall vessel (RWV) bioreactor was designed by the National Aeronautics and Space Administration (NASA) to model microgravity and was later found to more accurately reproduce features of human tissue in vivo. Cells grown in RWV bioreactors develop in a low fluid-shear environment, which enables cells to form complex 3D tissue-like aggregates. A wide variety of human tissues (from neuronal to vaginal tissue) have been grown in RWV bioreactors and have been shown to support productive viral infection and physiological meaningful host responses. The in vivo-like characteristics and cellular features of the human 3D RWV-derived aggregates make them ideal model systems to effectively recapitulate pathophysiology and host responses necessary to conduct rigorous basic science, preclinical and translational studies. Full article
(This article belongs to the Special Issue Novel Use of Cell Culture Systems to Understand Viral-Host Interactions)
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955 KiB  
Review
Plant Virus–Insect Vector Interactions: Current and Potential Future Research Directions
by Ralf G. Dietzgen, Krin S. Mann and Karyn N. Johnson
Viruses 2016, 8(11), 303; https://doi.org/10.3390/v8110303 - 09 Nov 2016
Cited by 149 | Viewed by 18139
Abstract
Acquisition and transmission by an insect vector is central to the infection cycle of the majority of plant pathogenic viruses. Plant viruses can interact with their insect host in a variety of ways including both non-persistent and circulative transmission; in some cases, the [...] Read more.
Acquisition and transmission by an insect vector is central to the infection cycle of the majority of plant pathogenic viruses. Plant viruses can interact with their insect host in a variety of ways including both non-persistent and circulative transmission; in some cases, the latter involves virus replication in cells of the insect host. Replicating viruses can also elicit both innate and specific defense responses in the insect host. A consistent feature is that the interaction of the virus with its insect host/vector requires specific molecular interactions between virus and host, commonly via proteins. Understanding the interactions between plant viruses and their insect host can underpin approaches to protect plants from infection by interfering with virus uptake and transmission. Here, we provide a perspective focused on identifying novel approaches and research directions to facilitate control of plant viruses by better understanding and targeting virus–insect molecular interactions. We also draw parallels with molecular interactions in insect vectors of animal viruses, and consider technical advances for their control that may be more broadly applicable to plant virus vectors. Full article
(This article belongs to the Special Issue Molecular Plant Virus—Insect Vector Interactions)
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1412 KiB  
Article
The European Classical Swine Fever Virus Database: Blueprint for a Pathogen-Specific Sequence Database with Integrated Sequence Analysis Tools
by Alexander Postel, Stefanie Schmeiser, Bernd Zimmermann and Paul Becher
Viruses 2016, 8(11), 302; https://doi.org/10.3390/v8110302 - 07 Nov 2016
Cited by 15 | Viewed by 5026
Abstract
Molecular epidemiology has become an indispensable tool in the diagnosis of diseases and in tracing the infection routes of pathogens. Due to advances in conventional sequencing and the development of high throughput technologies, the field of sequence determination is in the process of [...] Read more.
Molecular epidemiology has become an indispensable tool in the diagnosis of diseases and in tracing the infection routes of pathogens. Due to advances in conventional sequencing and the development of high throughput technologies, the field of sequence determination is in the process of being revolutionized. Platforms for sharing sequence information and providing standardized tools for phylogenetic analyses are becoming increasingly important. The database (DB) of the European Union (EU) and World Organisation for Animal Health (OIE) Reference Laboratory for classical swine fever offers one of the world’s largest semi-public virus-specific sequence collections combined with a module for phylogenetic analysis. The classical swine fever (CSF) DB (CSF-DB) became a valuable tool for supporting diagnosis and epidemiological investigations of this highly contagious disease in pigs with high socio-economic impacts worldwide. The DB has been re-designed and now allows for the storage and analysis of traditionally used, well established genomic regions and of larger genomic regions including complete viral genomes. We present an application example for the analysis of highly similar viral sequences obtained in an endemic disease situation and introduce the new geographic “CSF Maps” tool. The concept of this standardized and easy-to-use DB with an integrated genetic typing module is suited to serve as a blueprint for similar platforms for other human or animal viruses. Full article
(This article belongs to the Section Animal Viruses)
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2123 KiB  
Article
Recombinant Marek’s Disease Virus as a Vector-Based Vaccine against Avian Leukosis Virus Subgroup J in Chicken
by Yongzhen Liu, Kai Li, Yulong Gao, Li Gao, Li Zhong, Yao Zhang, Changjun Liu, Yanping Zhang and Xiaomei Wang
Viruses 2016, 8(11), 301; https://doi.org/10.3390/v8110301 - 04 Nov 2016
Cited by 15 | Viewed by 6684
Abstract
Avian leukosis virus subgroup J (ALV-J) is an immunosuppressive virus that causes considerable economic losses to the chicken industry in China. However, there is currently no effective vaccine to prevent ALV-J infection. In order to reduce the losses caused by ALV-J, we constructed [...] Read more.
Avian leukosis virus subgroup J (ALV-J) is an immunosuppressive virus that causes considerable economic losses to the chicken industry in China. However, there is currently no effective vaccine to prevent ALV-J infection. In order to reduce the losses caused by ALV-J, we constructed two effective ALV-J vaccines by inserting the ALV-J (strain JL093-1) env or gag+env genes into the US2 gene of the Marek’s disease herpesviruses (MDV) by transfection of overlapping fosmid DNAs, creating two recombinant MDVs, rMDV/ALV-gag+env and rMDV/ALV-env. Analysis of cultured chicken embryo fibroblasts infected with the rMDVs revealed that Env and Gag were successfully expressed and that there was no difference in growth kinetics in cells infected with rMDVs compared with that of cells infected with the parent MDV. Chickens vaccinated with either rMDV revealed that positive serum antibodies were induced. Both rMDVs also effectively reduced the rate of positive viremia in chicken flocks challenged with ALV-J. The protective effect provided by rMDV/ALV-env inoculation was slightly stronger than that provided by rMDV/ALV-gag+env. This represents the first study where a potential rMDV vaccine, expressing ALV-J antigenic genes, has been shown to be effective in the prevention of ALV-J. Our study also opens new avenues for the control of MDV and ALV-J co-infection. Full article
(This article belongs to the Section Viral Immunology, Vaccines, and Antivirals)
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4572 KiB  
Article
Cedratvirus, a Double-Cork Structured Giant Virus, is a Distant Relative of Pithoviruses
by Julien Andreani, Sarah Aherfi, Jacques Yaacoub Bou Khalil, Fabrizio Di Pinto, Idir Bitam, Didier Raoult, Philippe Colson and Bernard La Scola
Viruses 2016, 8(11), 300; https://doi.org/10.3390/v8110300 - 03 Nov 2016
Cited by 74 | Viewed by 9184
Abstract
Most viruses are known for the ability to cause symptomatic diseases in humans and other animals. The discovery of Acanthamoeba polyphaga mimivirus and other giant amoebal viruses revealed a considerable and previously unknown area of uncharacterized viral particles. Giant viruses have been isolated [...] Read more.
Most viruses are known for the ability to cause symptomatic diseases in humans and other animals. The discovery of Acanthamoeba polyphaga mimivirus and other giant amoebal viruses revealed a considerable and previously unknown area of uncharacterized viral particles. Giant viruses have been isolated from various environmental samples collected from very distant geographic places, revealing a ubiquitous distribution. Their morphological and genomic features are fundamental elements for classifying them. Herein, we report the isolation and draft genome of Cedratvirus, a new amoebal giant virus isolated in Acanthamoeba castellanii, from an Algerian environmental sample. The viral particles are ovoid-shaped, resembling Pithovirus sibericum, but differing notably in the presence of two corks at each extremity of the virion. The draft genome of Cedratvirus—589,068 base pairs in length—is a close relative of the two previously described pithoviruses, sharing 104 and 113 genes with P. sibericum and Pithovirus massiliensis genomes, respectively. Interestingly, analysis of these viruses’ core genome reveals that only 21% of Cedratvirus genes are involved in best reciprocal hits with the two pithoviruses. Phylogeny reconstructions and comparative genomics indicate that Cedratvirus is most closely related to pithoviruses, and questions their membership in an enlarged putative Pithoviridae family. Full article
(This article belongs to the Special Issue Viruses of Protozoa)
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886 KiB  
Review
Acute Hepatitis E: Two Sides of the Same Coin
by Johannes Hartl, Malte H. Wehmeyer and Sven Pischke
Viruses 2016, 8(11), 299; https://doi.org/10.3390/v8110299 - 03 Nov 2016
Cited by 47 | Viewed by 10796
Abstract
The relevance of acute hepatitis E virus (HEV) infections has been underestimated for a long time. In the past, HEV infection had been interpreted falsely as a disease limited to the tropics until the relevance of autochthonous HEV infections in the Western world [...] Read more.
The relevance of acute hepatitis E virus (HEV) infections has been underestimated for a long time. In the past, HEV infection had been interpreted falsely as a disease limited to the tropics until the relevance of autochthonous HEV infections in the Western world became overt. Due to increased awareness, the incidence of diagnosed autochthonous HEV infections (predominantly genotype 3) in industrialized countries has risen within the last decade. The main source of infections in industrialized countries seems to be infected swine meat, while infections with the tropical HEV genotypes 1 and 2 usually are mainly transmitted fecal-orally by contaminated drinking water. In the vast majority of healthy individuals, acute HEV infection is either clinically silent or takes a benign self-limited course. In patients who develop a symptomatic HEV infection, a short prodromal phase with unspecific symptoms is followed by liver specific symptoms like jaundice, itching, uncoloured stool and darkened urine. Importantly, tropical HEV infections may lead to acute liver failure, especially in pregnant women, while autochthonous HEV infections may lead to acute-on-chronic liver failure in patients with underlying liver diseases. Immunosuppressed individuals, such as transplant recipients or human immunodeficiency virus (HIV)-infected patients, are at risk for developing chronic hepatitis E, which may lead to liver fibrosis and cirrhosis in the long term. Importantly, specific treatment options for hepatitis E are not approved by the regulation authorities, but off-label ribavirin treatment seems to be effective in the treatment of chronic HEV-infection and may reduce the disease severity in patients suffering from acute liver failure. Full article
(This article belongs to the Special Issue Recent Progress in Hepatitis E Virus Research)
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1507 KiB  
Review
The Peculiar Characteristics of Fish Type I Interferons
by Pierre Boudinot, Christelle Langevin, Christopher J. Secombes and Jean-Pierre Levraud
Viruses 2016, 8(11), 298; https://doi.org/10.3390/v8110298 - 02 Nov 2016
Cited by 51 | Viewed by 7876
Abstract
Antiviral type I interferons (IFNs) have been discovered in fish. Genomic studies revealed their considerable number in many species; some genes encode secreted and non-secreted isoforms. Based on cysteine motifs, fish type I IFNs fall in two subgroups, which use two different receptors. [...] Read more.
Antiviral type I interferons (IFNs) have been discovered in fish. Genomic studies revealed their considerable number in many species; some genes encode secreted and non-secreted isoforms. Based on cysteine motifs, fish type I IFNs fall in two subgroups, which use two different receptors. Mammalian type I IFN genes are intronless while type III have introns; in fish, all have introns, but structurally, both subgroups belong to type I. Type I IFNs likely appeared early in vertebrates as intron containing genes, and evolved in parallel in tetrapods and fishes. The diversity of their repertoires in fish and mammals is likely a convergent feature, selected as a response to the variety of viral strategies. Several alternative nomenclatures have been established for different taxonomic fish groups, calling for a unified system. The specific functions of each type I gene remains poorly understood, as well as their interactions in antiviral responses. However, distinct induction pathways, kinetics of response, and tissue specificity indicate that fish type I likely are highly specialized, especially in groups where they are numerous such as salmonids or cyprinids. Unravelling their functional integration constitutes the next challenge to understand how these cytokines evolved to orchestrate antiviral innate immunity in vertebrates. Full article
(This article belongs to the Special Issue Viruses 2016 - At the Forefront of Virus-Host Interactions)
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Review
The Importance of Physiologically Relevant Cell Lines for Studying Virus–Host Interactions
by David Hare, Susan Collins, Breanne Cuddington and Karen Mossman
Viruses 2016, 8(11), 297; https://doi.org/10.3390/v8110297 - 01 Nov 2016
Cited by 23 | Viewed by 5960
Abstract
Viruses interact intimately with the host cell at nearly every stage of replication, and the cell model that is chosen to study virus infection is critically important. Although primary cells reflect the phenotype of healthy cells in vivo better than cell lines, their [...] Read more.
Viruses interact intimately with the host cell at nearly every stage of replication, and the cell model that is chosen to study virus infection is critically important. Although primary cells reflect the phenotype of healthy cells in vivo better than cell lines, their limited lifespan makes experimental manipulation challenging. However, many tumor-derived and artificially immortalized cell lines have defects in induction of interferon-stimulated genes and other antiviral defenses. These defects can affect virus replication, especially when cells are infected at lower, more physiologically relevant, multiplicities of infection. Understanding the selective pressures and mechanisms underlying the loss of innate signaling pathways is helpful to choose immortalized cell lines without impaired antiviral defense. We describe the trials and tribulations we encountered while searching for an immortalized cell line with intact innate signaling, and how directed immortalization of primary cells avoids many of the pitfalls of spontaneous immortalization. Full article
(This article belongs to the Special Issue Novel Use of Cell Culture Systems to Understand Viral-Host Interactions)
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Article
Comparative Analysis of HaSNPV-AC53 and Derived Strains
by Christopher Noune and Caroline Hauxwell
Viruses 2016, 8(11), 280; https://doi.org/10.3390/v8110280 - 31 Oct 2016
Cited by 4 | Viewed by 4545
Abstract
Complete genome sequences of two Australian isolates of H. armigera single nucleopolyhedrovirus (HaSNPV) and nine strains isolated by plaque selection in tissue culture identified multiple polymorphisms in tissue culture-derived strains compared to the consensus sequence of the parent isolate. Nine open reading frames [...] Read more.
Complete genome sequences of two Australian isolates of H. armigera single nucleopolyhedrovirus (HaSNPV) and nine strains isolated by plaque selection in tissue culture identified multiple polymorphisms in tissue culture-derived strains compared to the consensus sequence of the parent isolate. Nine open reading frames (ORFs) in all tissue culture-derived strains contained changes in nucleotide sequences that resulted in changes in predicted amino acid sequence compared to the parent isolate. Of these, changes in predicted amino acid sequence of six ORFs were identical in all nine derived strains. Comparison of sequences and maximum likelihood estimation (MLE) of specific ORFs and whole genome sequences were used to compare the isolates and derived strains to published sequence data from other HaSNPV isolates. The Australian isolates and derived strains had greater sequence similarity to New World SNPV isolates from H. zea than to Old World isolates from H. armigera, but with characteristics associated with both. Three distinct geographic clusters within HaSNPV genome sequences were identified: Australia/Americas, Europe/Africa/India, and China. Comparison of sequences and fragmentation of ORFs suggest that geographic movement and passage in vitro result in distinct patterns of baculovirus strain selection and evolution. Full article
(This article belongs to the Section Insect Viruses)
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283 KiB  
Review
Rabies Control and Treatment: From Prophylaxis to Strategies with Curative Potential
by Shimao Zhu and Caiping Guo
Viruses 2016, 8(11), 279; https://doi.org/10.3390/v8110279 - 28 Oct 2016
Cited by 48 | Viewed by 8474
Abstract
Rabies is an acute, fatal, neurological disease that affects almost all kinds of mammals. Vaccination (using an inactivated rabies vaccine), combined with administration of rabies immune globulin, is the only approved, effective method for post-exposure prophylaxis against rabies in humans. In the search [...] Read more.
Rabies is an acute, fatal, neurological disease that affects almost all kinds of mammals. Vaccination (using an inactivated rabies vaccine), combined with administration of rabies immune globulin, is the only approved, effective method for post-exposure prophylaxis against rabies in humans. In the search for novel rabies control and treatment strategies, live-attenuated viruses have recently emerged as a practical and promising approach for immunizing and controlling rabies. Unlike the conventional, inactivated rabies vaccine, live-attenuated viruses are genetically modified viruses that are able to replicate in an inoculated recipient without causing adverse effects, while still eliciting robust and effective immune responses against rabies virus infection. A number of viruses with an intrinsic capacity that could be used as putative candidates for live-attenuated rabies vaccine have been intensively evaluated for therapeutic purposes. Additional novel strategies, such as a monoclonal antibody-based approach, nucleic acid-based vaccines, or small interfering RNAs (siRNAs) interfering with virus replication, could further add to the arena of strategies to combat rabies. In this review, we highlight current advances in rabies therapy and discuss the role that they might have in the future of rabies treatment. Given the pronounced and complex impact of rabies on a patient, a combination of these novel modalities has the potential to achieve maximal anti-rabies efficacy, or may even have promising curative effects in the future. However, several hurdles regarding clinical safety considerations and public awareness should be overcome before these approaches can ultimately become clinically relevant therapies. Full article
(This article belongs to the Section Viral Immunology, Vaccines, and Antivirals)
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Article
Kaumoebavirus, a New Virus That Clusters with Faustoviruses and Asfarviridae
by Leena H. Bajrai, Samia Benamar, Esam I. Azhar, Catherine Robert, Anthony Levasseur, Didier Raoult and Bernard La Scola
Viruses 2016, 8(11), 278; https://doi.org/10.3390/v8110278 - 28 Oct 2016
Cited by 63 | Viewed by 7794
Abstract
In this study, we report the isolation of a new giant virus found in sewage water from the southern area of Jeddah (Saudi Arabia), with morphological and genomic resemblance to Faustoviruses. This new giant virus, named Kaumoebavirus, was obtained from co-culture with Vermamoeba [...] Read more.
In this study, we report the isolation of a new giant virus found in sewage water from the southern area of Jeddah (Saudi Arabia), with morphological and genomic resemblance to Faustoviruses. This new giant virus, named Kaumoebavirus, was obtained from co-culture with Vermamoeba vermiformis, an amoeboid protozoa considered to be of special interest to human health and the environment. This new virus has ~250 nm icosahedral capsids and a 350,731 bp DNA genome length. The genome of Kaumoebavirus has a coding density of 86%, corresponding to 465 genes. Most of these genes (59%) are closely related to genes from members of the proposed order Megavirales, and the best matches to its proteins with other members of the Megavirales are Faustoviruses (43%) and Asfarviruses (23%). Unsurprisingly, phylogenetic reconstruction places Kaumoebavirus as a distant relative of Faustoviruses and Asfarviruses. Full article
(This article belongs to the Special Issue Viruses of Protozoa)
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602 KiB  
Article
Antiviral Screening of Multiple Compounds against Ebola Virus
by Stuart D. Dowall, Kevin Bewley, Robert J. Watson, Seshadri S. Vasan, Chandradhish Ghosh, Mohini M. Konai, Gro Gausdal, James B. Lorens, Jason Long, Wendy Barclay, Isabel Garcia-Dorival, Julian Hiscox, Andrew Bosworth, Irene Taylor, Linda Easterbrook, James Pitman, Sian Summers, Jenny Chan-Pensley, Simon Funnell, Julia Vipond, Sue Charlton, Jayanta Haldar, Roger Hewson and Miles W. Carrolladd Show full author list remove Hide full author list
Viruses 2016, 8(11), 277; https://doi.org/10.3390/v8110277 - 27 Oct 2016
Cited by 37 | Viewed by 8843
Abstract
In light of the recent outbreak of Ebola virus (EBOV) disease in West Africa, there have been renewed efforts to search for effective antiviral countermeasures. A range of compounds currently available with broad antimicrobial activity have been tested for activity against EBOV. Using [...] Read more.
In light of the recent outbreak of Ebola virus (EBOV) disease in West Africa, there have been renewed efforts to search for effective antiviral countermeasures. A range of compounds currently available with broad antimicrobial activity have been tested for activity against EBOV. Using live EBOV, eighteen candidate compounds were screened for antiviral activity in vitro. The compounds were selected on a rational basis because their mechanisms of action suggested that they had the potential to disrupt EBOV entry, replication or exit from cells or because they had displayed some antiviral activity against EBOV in previous tests. Nine compounds caused no reduction in viral replication despite cells remaining healthy, so they were excluded from further analysis (zidovudine; didanosine; stavudine; abacavir sulphate; entecavir; JB1a; Aimspro; celgosivir; and castanospermine). A second screen of the remaining compounds and the feasibility of appropriateness for in vivo testing removed six further compounds (ouabain; omeprazole; esomeprazole; Gleevec; D-LANA-14; and Tasigna). The three most promising compounds (17-DMAG; BGB324; and NCK-8) were further screened for in vivo activity in the guinea pig model of EBOV disease. Two of the compounds, BGB324 and NCK-8, showed some effect against lethal infection in vivo at the concentrations tested, which warrants further investigation. Further, these data add to the body of knowledge on the antiviral activities of multiple compounds against EBOV and indicate that the scientific community should invest more effort into the development of novel and specific antiviral compounds to treat Ebola virus disease. Full article
(This article belongs to the Collection Advances in Ebolavirus, Marburgvirus, and Cuevavirus Research)
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