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Volume 99,
Issue 10,
2018
Volume 99, Issue 10, 2018
- Review
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Mechanisms and consequences of positive-strand RNA virus recombination
More LessGenetic recombination in positive-strand RNA viruses is a significant evolutionary mechanism that drives the creation of viral diversity by the formation of novel chimaeric genomes. The process and its consequences, for example the generation of viruses with novel phenotypes, has historically been studied by analysis of the end products. More recently, with an appreciation that there are both replicative and non-replicative mechanisms at work, and with new approaches and techniques to analyse intermediate products, the viral and cellular factors that influence the process are becoming understood. The major influence on replicative recombination is the fidelity of viral polymerase, although RNA structures and sequences may also have an impact. In replicative recombination the viral polymerase is necessary and sufficient, although roles for other viral or cellular proteins may exist. In contrast, non-replicative recombination appears to be mediated solely by cellular components. Despite these insights, the relative importance of replicative and non-replicative mechanisms is not clear. Using single-stranded positive-sense RNA viruses as exemplars, we review the current state of understanding of the processes and consequences of recombination.
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- ICTV Virus Taxonomy Profile
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ICTV Virus Taxonomy Profile: Globuloviridae
More LessThe family Globuloviridae comprises enveloped viruses with linear, double-stranded DNA genomes of about 21–28 kbp. The virions are spherical with a diameter of 70–100 nm. No information is available about genome replication. Globuloviruses infect hyperthermophilic archaea belonging to the genera Pyrobaculum and Thermoproteus, which thrive in extreme geothermal environments. Infection does not cause lysis of host cells and is noncytocidal. The viral genome does not integrate into the host chromosome. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the taxonomy of the Globuloviridae, which is available at www.ictv.global/report/globuloviridae.
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- Animal
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- Negative-strand RNA Viruses
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Innate immune responses elicited by Sin Nombre virus or type I IFN agonists protect hamsters from lethal Andes virus infections
Sin Nombre virus (SNV) and Andes virus (ANDV) cause hantavirus pulmonary syndrome (HPS) in humans. Both SNV and ANDV infect Syrian hamsters, but only ANDV causes lethal disease. A co-infection study was performed to determine which virus, SNV or ANDV, would dominate the survival outcome in hamsters. Infection of hamsters with SNV 1 day before ANDV challenge did not result in disease characteristic of the latter virus, and all animals survived challenge. Control animals infected solely with ANDV all succumbed by day 14. In contrast, when viruses were injected at the same site concurrently, all hamsters succumbed to HPS disease. Hantaviruses are segmented viruses; therefore we investigated which segment might be responsible for the protective phenotype of SNV by using two SNV/ANDV reassortant viruses, both with reciprocal M-segments from the other virus (denoted ASA and SAS). Both reassortants asymptomatically infect hamsters, similar to SNV. However, unlike SNV, 1 day prior preinfection with the reassortant virus did not prevent ANDV lethality. The ASA reassortant virus, but not SAS, protected hamsters from lethal ANDV infection when administered 3 days prior to ANDV challenge. Similar to SNV preinfection, the potent innate immune stimulator poly I:C administered to hamsters 1 day before ANDV challenge prevented lethal ANDV disease. Combined, these results suggest that the difference in pathogenicity of SNV and ANDV in hamsters involves differences in early host-pathogen interactions and resultant anti-viral immune responses of both the innate and adaptive immune system.
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Evaluation of anticoagulant agents for the treatment of human metapneumovirus infection in mice
Thrombin has been demonstrated to be involved in several viral diseases including human metapneumovirus (hMPV) infections. We previously showed that immediate administration of thrombin inhibitor argatroban post-infection protected mice against hMPV disease. This current work aims at determining whether warfarin and heparin, two other anticoagulants inhibiting thrombin formation and activities, may also be used for treatment against hMPV in vivo. We found that immediate injections of argatroban, warfarin or heparin after virus challenge protected mice against hMPV infection, as evidenced by decreased or no mortality, less weight loss, reduced viral load and attenuated inflammation. However, delayed treatments starting 1 day post-infection with argatroban or warfarin almost did not impact the survival whereas delayed treatment with heparin induced an increased mortality during infection. Moreover, these treatments also did not reduce weight loss, viral replication and inflammation. In agreement with these results, thrombin generation was decreased upon immediate anticoagulant treatments but was unaltered upon delayed treatments. Thus, thrombin generation occurs at the onset of hMPV infection and thrombin inhibition may be only useful for the treatment of this disease when initiated in the early stage. In this case, heparin is not recommended because of its reduced efficacy on mortality in infected mice whereas argatroban and warfarin appear as safe and effective drugs for the treatment of hMPV disease. The antiviral and anti-inflammatory effects of argatroban occur via thrombin-dependent pathways whereas the mechanisms by which warfarin exerts its beneficial effects against hMPV infection were not elucidated and need to be further studied.
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- Positive-strand RNA Viruses
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Deletion of accessory genes 3a, 3b, 5a or 5b from avian coronavirus infectious bronchitis virus induces an attenuated phenotype both in vitro and in vivo
Avian coronavirus infectious bronchitis virus (IBV) infects domestic fowl, resulting in respiratory disease and causing serious losses in unprotected birds. Its control is mainly achieved by using live attenuated vaccines. Here we explored the possibilities for rationally attenuating IBV to improve our knowledge regarding the function of IBV accessory proteins and for the development of next-generation vaccines with the recently established reverse genetic system for IBV H52 based on targeted RNA recombination and selection of recombinant viruses in embryonated eggs. To this aim, we selectively removed accessory genes 3a, 3b, 5a and 5b individually, and rescued the resulting recombinant (r) rIBV-Δ3a, rIBV-Δ3b, rIBV-Δ5a and rIBV-Δ5b. In vitro inoculation of chicken embryo kidney cells with recombinant and wild-type viruses demonstrated that the accessory protein 5b is involved in the delayed activation of the interferon response of the host after IBV infection. Embryo mortality after the inoculation of 8-day-old embryonated chicken eggs with recombinant and wild-type viruses showed that rIBV-Δ3b, rIBV-Δ5a and rIBV-Δ5b had an attenuated phenotype in ovo, with reduced titres at 6 h p.i. and 12 h p.i. for all viruses, while growing to the same titre as wild-type rIBV at 48 h p.i. When administered to 1-day-old chickens, rIBV-Δ3a, rIBV-Δ3b, rIBV-Δ5a and rIBV-Δ5b showed reduced ciliostasis in comparison to the wild-type viruses. In conclusion, individual deletion of accessory genes in IBV H52 resulted in mutant viruses with an attenuated phenotype.
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Human glucose-regulated protein 78 modulates intracellular production and secretion of nonstructural protein 1 of dengue virus
Virus-host interactions play important roles in virus infection and host cellular response. Several viruses, including dengue virus (DENV), usurp host chaperones to support their amplification and survival in the host cell. We investigated the interaction of nonstructural protein 1 (NS1) of DENV with three endoplasmic reticulum-resident chaperones (i.e. GRP78, calnexin and calreticulin) to delineate their functional roles and potential binding sites for protein complex formation. GRP78 protein showed prominent association with DENV NS1 in virus-infected Huh7 cells as evidenced by co-localization and co-immunoprecipitation assays. Further studies on the functional interaction of GRP78 protein were performed by using siRNA-mediated gene knockdown in a DENV replicon transfection system. GRP78 knockdown significantly decreased intracellular NS1 production and delayed NS1 secretion but had no effect on viral RNA replication. Dissecting the important domain of GRP78 required for DENV NS1 interaction showed co-immunoprecipitation of DENV NS1 with a full-length and substrate-binding domain (SBD), but not an ATPase domain, of GRP78, confirming their interaction through SBD binding. Molecular dynamics simulations of DENV NS1 and human GRP78 complex revealed their potential binding sites through hydrogen and hydrophobic bonding. The majority of GRP78-binding sites were located in a β-roll domain and connector subdomains on the DENV NS1 structure involved in hydrophobic surface formation. Taken together, our findings demonstrated the roles of human GRP78 in facilitating the intracellular production and secretion of DENV NS1 as well as predicted potential binding sites between the DENV NS1 and GRP78 complex, which could have implications in the future development of target-based antiviral drugs.
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Thermostable hepatitis C virus JFH1-derived variant isolated by adaptation to Huh7.5.1 cells
Hepatitis C virus (HCV) infection and propagation in cultured cells have mainly been investigated using the infectious clinical clone JFH1. However, its infectivity is not high enough for infection to be detected easily. In this study, we attempted to isolate HCV-JFH1 variants adapted to human hepatoma Huh7.5.1 cells. By performing serial passages of the wild-type HCV-JFH1 in Huh7.5.1 cells, we obtained a variant that was capable of inducing severe cytopathic effects and showed approximately 700-fold higher infectivity than the wild-type HCV-JFH1. Further, when highly permissive Huh7.5.1–8 cells were infected with this variant, viral particles were produced at >1011 copies ml−1, making this variant one of the most efficient HCV production systems. Two adaptive mutations were noted in the variant genome: a1994c (K74T) in the core protein region and t3014c (I414T) in the E2 protein region. Both mutations contributed to enhanced infectivity and their combination showed synergistic effects in this regard. An examination of recombinant viruses carrying K74T, I414T and K74T/I414T mutations revealed that none of the mutations had an effect on the steps after viral entry (genome replication, particle assembly and egress), but led to the viral infection becoming less dependent on scavenger receptor class B type I, changes of the infectious particles to a broader and lower range of densities, and enhanced thermal stability of the infectious viruses. Thus, this Huh7.5.1-adapted HCV-JFH1 variant with higher and stable infectivity should be a valuable tool for studying the molecular mechanisms behind the life cycle of HCV and for antiviral screening.
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A novel picornavirus-like genome from transcriptome sequencing of sugar beet cyst nematode represents a new putative genus
Analysis of transcriptome sequence data from eggs and second-stage juveniles (J2s) of sugar beet cyst nematode (SBCN, Heterodera schachtii) identified the full-length genome of a positive-sense single-stranded RNA virus, provisionally named sugar beet cyst nematode virus 1 (SBCNV1). The SBCNV1 sequence was detected in both eggs and J2s, indicating its possible vertical transmission. The 9503-nucleotide genome sequence contains a single long open reading frame, which was predicted to encode a polyprotein with conserved domains for picornaviral structural proteins proximal to its amino terminus and RNA helicase, cysteine proteinase and RNA-dependent RNA polymerase (RdRp) conserved domains proximal to its carboxyl terminus, hallmarks of viruses belonging to the order Picornavirales. Phylogenetic analysis of the predicted SBCNV1 RdRp amino acid sequence indicated that the SBCNV1 sequence is most closely related to members of the family Secoviridae, which includes genera of nematode-transmitted plant-infecting viruses. SBCNV1 represents the first fully sequenced viral genome from SBCN.
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- Large DNA Viruses
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Differences in the effects of mutations in GP131, a guinea pig cytomegalovirus homologue of pentameric complex component UL130, on macrophage and epithelial cell infection
As congenital cytomegalovirus (CMV) infection is the major cause of developmental abnormalities in children, the development of effective vaccines is critical to public health. Recent studies have demonstrated that the pentameric complex (Pentamer) of glycoproteins, which is required for human CMV infection of endothelial and epithelial cells, could be a potent vaccine antigen. As guinea pig CMV (GPCMV) infects congenitally and encodes homologues of all Pentamer components, GPCMV models are considered to be useful for the development of vaccine strategies. Here, to clarify the precise requirement of GP131, one of the GPCMV Pentamer components, for the infection of epithelial cells and macrophages, we prepared several mutants with a charged amino acid-to-alanine alteration in GP131 and found some differences in the effects of the mutations on the infection of the two cell types, suggesting the existence of cell type-dependent recognition or function of Pentamer in GPCMV infection.
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HSV-1 DNA polymerase 3′-5′ exonuclease-deficient mutant D368A exhibits severely reduced viral DNA synthesis and polymerase expression
More LessHerpesviruses, including herpes simplex virus-1, encode and express a DNA polymerase that is required for replication of their dsDNA genomes. The catalytic subunit of this enzyme contains a 3′-5′ exonuclease that is involved in proofreading during replication. Although certain mutations that severely impair exonuclease activity are not lethal to the virus, it was reported that virus containing the substitution of alanine for aspartate 368 (D368A), which ablates exonuclease activity, could not be recovered, raising the possibility that this activity is essential for viral replication. To investigate this issue, we produced virus containing this mutation (D368A Pol) using a complementing cell line. D368A Pol virus was unable to form plaques on non-complementing cells. Viral DNA synthesis and polymerase activity were severely inhibited in D368A-infected cells, as was expression of the enzyme, suggesting that effects on polymerase expression rather than on exonuclease activity per se largely explain the lethal phenotype of this mutation.
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- Retrovirus
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Characterization of the membrane-bound form of the chimeric, B/C recombinant HIV-1 Env, LT5.J4b12C
More LessHuman immunodeficiency virus 1 (HIV-1) diversity is a significant challenge in developing a vaccine against the virus. B/C recombinants have been found in India and other places but are the predominant clade prevalent in China. HIV-1 envelopes (Envs) are the target of broadly neutralizing antibodies (bNAbs) which develop spontaneously in some HIV-1 infected patients. It has been previously reported with efficiently cleaved clade A, B and C Envs that preferential binding of Envs to bNAbs as opposed to non-NAbs, a desirable property for immunogens, is correlated with efficient cleavage of the Env precursor polypeptide into constituent subunits. These Envs are suitable for designing immunogens as soluble proteins, virus-like particles or for delivery by viral vectors/plasmid DNA. However, a B/C recombinant Env with similar properties has not been reported. Here we show that the chimeric, recombinant B/C clade Env LT5.J4b12C is efficiently cleaved on the plasma membrane and selectively binds to bNAbs.
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- Insect
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- DNA Virus
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Virus innexin expression in insect cells disrupts cell membrane potential and pH
More LessCertain parasitoid wasps are associated with Polydnaviruses, symbiotic viruses that encode virulence factors which are essential to successful parasitization by the wasp of a caterpillar host. Members of one group of Polydnaviruses, the Ichnoviruses, encode a multi-gene family known as Vinnexins. Vinnexins are homologues of insect gap junction genes, and form functional gap junctions that may affect host cell physiology. However, the role of Vinnexins in host pathology and the mechanism by which these affect their caterpillar host are largely unknown. In this article, we generated recombinant baculoviruses to express vinnexins in Spodoptera frugiperda (Sf9) cells. To measure cell physiological changes caused by Vinnexins, cells were probed with a membrane potential-sensitive probe, DiBac4(3), and a pH indicator, carboxyfluorescein diacetate (CFDA). In addition, we utilized carbenoxolone and ouabain, respectively, to probe the role of gap junctions and hemi-channels, and Na+/K+-ATPase in establishing membrane potential in studied cells. Our results indicate that Vinnexins induce cell membrane depolarization and cytoplasmic alkalization to a degree specific to each tested Vinnexin, and that neither Vinnexin hemi-channels nor Na+/K+-ATPase appear to underlie these effects directly. These results hint that members of the Vinnexin protein family may affect host bio-electrical phenomena to disrupt host cell physiology, and that the individual proteins of the family may differentially affect host physiology.
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- Prokaryotic Virus
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Isolation and characterization of a novel phage Xoo-sp2 that infects Xanthomonas oryzae pv. oryzae
Bacterial leaf blight (BLB) caused by Xanthomonas oryzae pv. oryzae (Xoo) is a serious bacterial disease in rice-growing regions worldwide. Phage therapy has been proposed as a potential measure to treat bacterial infections. In this study, a novel phage, Xoo-sp2, which infects Xoo was isolated from soil. The characteristics of Xoo-sp2, including the morphology, one-step growth curve and host range, were analysed. The genome of phage Xoo-sp2 was sequenced and annotated. The results demonstrated that Xoo-sp2 is a siphovirus and has a broad lytic spectrum, infecting 9 out of 10 representative Xoo strains. Genome analysis showed that the Xoo-sp2 genome consists of a linear double-stranded DNA molecule of length 60 370 bp. Annotation of the whole genome indicated that Xoo-sp2 encodes 79 putative open reading frames (ORFs). Comparative genomics analysis of Xoo-sp2 showed that it shares significant similarity only with Pseudomonas and Stenotrophomonas phages (with maximum identity reaching 80 % along 69 % of the genome), and thus represents a novel Xanthomonas phage. Xoo-sp2 significantly inhibited Xoo growth in liquid culture. An experiment with potted plants indicated that Xoo-sp2 could efficiently control BLB in living rice. In summary, our work characterized a novel Xanthomonas phage and demonstrated its potential as a prophylactic agent in the control of BLB in rice.
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Volumes and issues
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Volume 106 (2025)
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Volume 105 (2024)
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Volume 104 (2023)
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Volume 103 (2022)
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Volume 102 (2021)
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Volume 101 (2020)
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Volume 100 (2019)
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Volume 99 (2018)
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Volume 98 (2017)
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Volume 97 (2016)
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Volume 96 (2015)
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Volume 95 (2014)
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Volume 94 (2013)
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Volume 10 (1971)
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Volume 7 (1970)
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Volume 6 (1970)
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Volume 5 (1969)
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Volume 4 (1969)
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Volume 3 (1968)
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Volume 2 (1968)
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Volume 1 (1967)
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