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Volume 94,
Issue 12,
2013
Volume 94, Issue 12, 2013
- Review
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Capsid-binding retrovirus restriction factors: discovery, restriction specificity and implications for the development of novel therapeutics
More LessThe development of drugs against human immunodeficiency virus type 1 infection has been highly successful, and numerous combinational treatments are currently available. However, the risk of the emergence of resistance and the toxic effects associated with prolonged use of antiretroviral therapies have emphasized the need to consider alternative approaches. One possible area of investigation is provided by the properties of restriction factors, cellular proteins that protect organisms against retroviral infection. Many show potent viral inhibition. Here, we describe the discovery, properties and possible therapeutic uses of the group of restriction factors known to interact with the capsid core of incoming retroviruses. This group comprises Fv1, TRIM5α and TRIMCypA: proteins that all act shortly after virus entry into the target cell and block virus replication at different stages prior to integration of viral DNA into the host chromosome. They have different origins and specificities, but share general structural features required for restriction, with an N-terminal multimerization domain and a C-terminal capsid-binding domain. Their overall efficacy makes it reasonable to ask whether they might provide a framework for developing novel antiretroviral strategies.
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- Animal
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- RNA viruses
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Mutation tryptophan to leucine at position 222 of haemagglutinin could facilitate H3N2 influenza A virus infection in dogs
An avian-like H3N2 influenza A virus (IAV) has recently caused sporadic canine influenza outbreaks in China and Korea, but the molecular mechanisms involved in the interspecies transmission of H3N2 IAV from avian to canine species are not well understood. Sequence analysis showed that residue 222 in haemagglutinin (HA) is predominantly tryptophan (W) in the closely related avian H3N2 IAV, but was leucine (L) in canine H3N2 IAV. In this study, reassortant viruses rH3N2-222L (canine-like) and rH3N2-222W (avian-like) with HA mutation L222W were generated using reverse genetics to evaluate the significance of the L222W mutation on receptor binding and host tropism of H3N2 IAV. Compared with rH3N2-222W, rH3N2-222L grew more rapidly in MDCK cells and had significantly higher infectivity in primary canine tracheal epithelial cells. Tissue-binding assays demonstrated that rH3N2-222L had a preference for canine tracheal tissues rather avian tracheal tissues, whereas rH3N2-222W favoured slightly avian rather canine tracheal tissues. Glycan microarray analysis suggested both rH3N2-222L and rH3N2-222W bound preferentially to α2,3-linked sialic acids. However, the rH3N2-222W had more than twofold less binding affinity than rH3N2-222L to a set of glycans with Neu5Aca2–3Galb1–4(Fuca-)-like or Neu5Aca2–3Galb1–3(Fuca-)-like structures. These data suggest the W to L mutation at position 222 of the HA could facilitate infection of H3N2 IAV in dogs, possibly by increasing the binding affinities of the HA to specific receptors with Neu5Aca2–3Galb1–4(Fuca-) or Neu5Aca2–3Galb1–3(Fuca-)-like structures that are present in dogs.
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Kolente virus, a rhabdovirus species isolated from ticks and bats in the Republic of Guinea
Kolente virus (KOLEV) is a rhabdovirus originally isolated from ticks and a bat in Guinea, West Africa, in 1985. Although tests at the time of isolation suggested that KOLEV is a novel rhabdovirus, it has remained largely uncharacterized. We assembled the complete genome sequence of the prototype strain DakAr K7292, which was found to encode the five canonical rhabdovirus structural proteins (N, P, M, G and L) with alternative ORFs (>180 nt) in the P and L genes. Serologically, KOLEV exhibited a weak antigenic relationship with Barur and Fukuoka viruses in the Kern Canyon group. Phylogenetic analysis revealed that KOLEV represents a distinct and divergent lineage that shows no clear relationship to any rhabdovirus except Oita virus, although with limited phylogenetic resolution. In summary, KOLEV represents a novel species in the family Rhabdoviridae.
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Antigenicity and transmissibility of a novel clade 2.3.2.1 avian influenza H5N1 virus
A genetic variant of the H5N1 influenza virus, termed subclade 2.3.2.1, was first identified in Bulgaria in 2010 and has subsequently been found in Vietnam and Laos. Several cases of human infections with this virus have been identified. Thus, it is important to understand the antigenic properties and transmissibility of this variant. Our results showed that, although it is phylogenetically closely related to other previously characterized clade 2.3 viruses, this novel 2.3.2.1 variant exhibited distinct antigenic properties and showed little cross-reactivity to sera raised against other H5N1 viruses. Like other H5N1 viruses, this variant bound preferentially to avian-type receptors, but contained substitutions at positions 190 and 158 of the haemagglutinin (HA) protein that have been postulated to facilitate HA binding to human-type receptors and to enhance viral transmissibility among mammals, respectively. However, this virus did not appear to have acquired the capacity for airborne transmission between ferrets. These findings highlight the challenges in selecting vaccine candidates for H5N1 influenza because these viruses continue to evolve rapidly in the field. It is important to note that some variants have obtained mutations that may gain transmissibility between model animals, and close surveillance of H5N1 viruses in poultry is warranted.
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A single amino acid in the F2 subunit of respiratory syncytial virus fusion protein alters growth and fusogenicity
More LessRespiratory syncytial virus (RSV) causes severe lower respiratory tract infection in children, especially in infants less than 1 year of age. There are currently no licensed vaccines against RSV. rA2ΔM2-2 is a promising live-attenuated vaccine candidate that is currently being evaluated in the clinic. Attenuation of rA2ΔM2-2 is achieved by a single deletion of the M2-2 gene, which disrupts the balance between viral transcription and replication. Whilst performing a manufacturing feasibility study in a serum-free adapted Vero cell line, differences in growth kinetics and cytopathic effect (CPE) were identified between two rA2ΔM2-2 vaccine candidates. Comparative sequence analysis identified four amino acid differences between the two vaccine viruses. Recombinant rA2ΔM2-2 viruses carrying each of the four amino acid differences identified a K66E mutation in the F2 fragment of the fusion (F) protein as the cause of the growth and CPE differences. Syncytium-formation experiments with RSV F protein carrying mutations at aa 66 suggested that a change in charge at this residue within the F2 fragment can have a significant impact on fusion.
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A role for endoplasmic reticulum exit sites in foot-and-mouth disease virus infection
Picornaviruses replicate their genomes in association with cellular membranes. While enteroviruses are believed to utilize membranes of the early secretory pathway, the origin of the membranes used by foot-and-mouth disease virus (FMDV) for replication are unknown. Secretory-vesicle traffic through the early secretory pathway is mediated by the sequential acquisition of two distinct membrane coat complexes, COPII and COPI, and requires the coordinated actions of Sar1, Arf1 and Rab proteins. Sar1 is essential for generating COPII vesicles at endoplasmic reticulum (ER) exit sites (ERESs), while Arf1 and Rab1 are required for subsequent vesicle transport by COPI vesicles. In the present study, we have provided evidence that FMDV requires pre-Golgi membranes of the early secretory pathway for infection. Small interfering RNA depletion of Sar1 or expression of a dominant-negative (DN) mutant of Sar1a inhibited FMDV infection. In contrast, a dominant-active mutant of Sar1a, which allowed COPII vesicle formation but inhibited the secretory pathway by stabilizing COPII coats, caused major disruption to the ER–Golgi intermediate compartment (ERGIC) but did not inhibit infection. Treatment of cells with brefeldin A, or expression of DN mutants of Arf1 and Rab1a, disrupted the Golgi and enhanced FMDV infection. These results show that reagents that block the early secretory pathway at ERESs have an inhibitory effect on FMDV infection, while reagents that block the early secretory pathway immediately after ER exit but before the ERGIC and Golgi make infection more favourable. Together, these observations argue for a role for Sar1 in FMDV infection and that initial virus replication takes place on membranes that are formed at ERESs.
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Characterization of self-assembled virus-like particles of ferret hepatitis E virus generated by recombinant baculoviruses
Ferret hepatitis E virus (HEV), a novel hepatitis E-like virus, has been identified in ferrets in The Netherlands. Due to the lack of a cell-culture system for ferret HEV, the antigenicity, pathogenicity and epidemiology of this virus have remained unclear. In the present study, we used a recombinant baculovirus expression system to express the 112-N-terminus and 47-C-terminus-amino-acid-truncated ferret HEV ORF2 protein in insect Tn5 cells, and found that a large amount of a 53 kDa protein (F-p53) was expressed and efficiently released into the supernatant. Electron microscopic analysis revealed that F-p53 was self-assembled into virus-like particles (ferret HEV-LPs). These ferret HEV-LPs were estimated to be 24 nm in diameter, which is similar to the size of G1, G3, G4 and rat HEV-LPs derived from both the N-terminus- and C-terminus-truncated constructs. Antigenic analysis demonstrated that ferret HEV-LPs were cross-reactive with G1, G3, G4 and rat HEVs, and rat HEV and ferret HEV showed a stronger cross-reactivity to each other than either did to human HEV genotypes. However, the antibody against ferret HEV-LPs does not neutralize G3 HEV, suggesting that the serotypes of these two HEVs are different. An ELISA for detection of anti-ferret HEV IgG and IgM antibodies was established using ferret HEV-LPs as antigen, and this assay system will be useful for monitoring ferret HEV infection in ferrets as well as other animals. In addition, analysis of ferret HEV RNA detected in ferret sera collected from a breeding colony in the USA revealed the genetic diversity of ferret HEV.
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The non-primate hepacivirus 5′ untranslated region possesses internal ribosomal entry site activity
More LessThe 5′ untranslated region (5′UTR) of the recently described non-primate hepacivirus (NPHV) contains a region with sequence homology to the internal ribosomal entry site (IRES) of hepatitis C virus (HCV) and GB virus B (GBV-B). Here, we demonstrated internal translation initiation by the NPHV 5′UTR in a bicistronic vector. An RNA stem–loop upstream of the NPHV IRES was structurally distinct from corresponding regions in HCV and GBV-B, and was not required for IRES function. Insertion of the NPHV stem–loop into the corresponding region of the HCV 5′UTR within the HCV subgenomic replicon significantly impaired RNA replication, indicating that long-range interactions between the 5′UTR and cis-acting downstream elements within the NPHV genome are not interchangeable with those of HCV. Despite similarities in IRES structure and function between hepaciviruses, replication elements in the NPHV 5′UTR appear functionally distinct from those of HCV.
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The human immunodeficiency virus type 1 Vpr protein upregulates PVR via activation of the ATR-mediated DNA damage response pathway
More LessViral infection may induce the cell-surface expression of PVR (CD155) that, upon recognition by its cognate activating DNAM-1 receptor present on cytotoxic lymphocytes, may promote antiviral immune responses. Here we show that expression of the human immunodeficiency virus type 1 (HIV-1) Vpr protein in Jurkat T cells increases cell-surface and total PVR levels. Analysis of mutated Vpr variants indicated that Vpr uses the same protein surfaces, and hence probably the same mechanisms, to upregulate PVR and arrest the cell cycle in the G2 phase. Moreover, we found that PVR upregulation by Vpr relied on the ability of the protein to activate the ATR kinase that triggers the DNA damage response pathway and G2 arrest. Finally, we showed that Vpr contributes to PVR up-modulation in HIV-infected CD4+ T lymphocytes and inhibits the PVR downregulating activity of the viral Nef protein.
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Deep sequencing identifies two genotypes and high viral genetic diversity of human pegivirus (GB virus C) in rural Ugandan patients
Human pegivirus (HPgV), formerly ‘GB virus C’ or ‘hepatitis G virus’, is a member of the genus Flavivirus (Flaviviridae) that has garnered significant attention due to its inhibition of HIV, including slowing disease progression and prolonging survival in HIV-infected patients. Currently, there are six proposed HPgV genotypes that have roughly distinct geographical distributions. Genotypes 2 and 3 are the most comprehensively characterized, whereas those genotypes occurring on the African continent, where HPgV prevalence is highest, are less well studied. Using deep sequencing methods, we identified complete coding HPgV sequences in four of 28 patients (14.3 %) in rural Uganda, east Africa. One of these sequences corresponds to genotype 1 and is the first complete genome of this genotype from east Africa. The remaining three sequences correspond to genotype 5, a genotype that was previously considered exclusively South African. All four positive samples were collected within a geographical area of less than 25 km2, showing that multiple HPgV genotypes co-circulate in this area. Analysis of intra-host viral genetic diversity revealed that total single-nucleotide polymorphism frequency was approximately tenfold lower in HPgV than in hepatitis C virus. Finally, one patient was co-infected with HPgV and HIV, which, in combination with the high prevalence of HIV, suggests that this region would be a useful locale to study the interactions and co-evolution of these viruses.
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Delayed induction of proinflammatory cytokines and suppression of innate antiviral response by the novel Middle East respiratory syndrome coronavirus: implications for pathogenesis and treatment
The high mortality associated with the novel Middle East respiratory syndrome coronavirus (MERS-CoV) has raised questions about the possible role of a cytokine storm in its pathogenesis. Although recent studies showed that MERS-CoV infection is associated with an attenuated IFN response, no induction of inflammatory cytokines was demonstrated during the early phase of infection. To study both early and late cytokine responses associated with MERS-CoV infection, we measured the mRNA levels of eight cytokine genes [TNF-α, IL-1β, IL-6, IL-8, IFN-β, monocyte chemotactic protein-1, transforming growth factor-β and IFN-γ-induced protein (IP)-10] in cell lysates of polarized airway epithelial Calu-3 cells infected with MERS-CoV or severe acute respiratory syndrome (SARS)-CoV up to 30 h post-infection. Among the eight cytokine genes, IL-1β, IL-6 and IL-8 induced by MERS-CoV were markedly higher than those induced by SARS-CoV at 30 h, whilst TNF-α, IFN-β and IP-10 induced by SARS-CoV were markedly higher than those induced by MERS-CoV at 24 and 30 h in infected Calu-3 cells. The activation of IL-8 and attenuated IFN-β response by MERS-CoV were also confirmed by protein measurements in the culture supernatant when compared with SARS-CoV and Sendai virus. To further confirm the attenuated antiviral response, cytokine response was compared with human HCoV-229E in embryonal lung fibroblast HFL cells, which also revealed higher IFN-β and IP-10 levels induced by HCoV-229E than MERS-CoV at 24 and 30 h. Whilst our data supported recent findings that MERS-CoV elicits attenuated innate immunity, this represents the first report to demonstrate delayed proinflammatory cytokine induction by MERS-CoV. Our results provide insights into the pathogenesis and treatment of MERS-CoV infections.
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VP1 B–C and D–E loops of bovine enterovirus cluster B can effectively display foot-and-mouth disease virus type O-conserved neutralizing epitope
More LessOn the basis of generation of an infectious cDNA clone for the BHM26 strain of bovine enterovirus cluster B (BEV-B), 22 sites on different loops of the BHM26 capsid were selected according to an alignment of its sequence with the structural motifs of BEV-A strain VG-5-27 for insertion of the foot-and-mouth disease virus (FMDV) type O-conserved neutralizing epitope 8E8. Two recombinant viruses, rBEV-A1 and rBEV-DE, in which the FMDV epitope was inserted into the VP1 B–C or D–E loops, were rescued by transfection of BHK-21 cells with the in vitro-transcribed RNA of the recombinant BHM26 genome-length cDNA constructs. The two epitope-inserted viruses were genetically stable and exhibited growth properties similar to those of their parental virus in BHK-21 and IBRS-2 cells, which are susceptible to both BEV and FMDV. However, the two recombinant BEVs (rBEVs) had a significantly lower growth titre than those of the parental virus BHM26 in MDBK and Marc145 cells, which are susceptible to BEV but not to FMDV. These results indicated that insertion of the FMDV epitope into the VP1 B–C or D–E loops of the BEV particle altered the replication properties of BEV. In addition, the two rBEVs were sensitive to neutralization by the FMDV type O-specific mAb 8E8, and anti-FMDV IgG antibodies were induced in mice by intramuscular inoculation with the rBEV-A1 and rBEV-DE viruses. Our results demonstrate that the VP1 B–C and D–E loops of the BEV-B particle can effectively display a foreign epitope, making this an attractive approach for the design of BEV-vectored and epitope-based vaccines.
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Development of chimaeric West Nile virus attenuated vaccine candidate based on the Japanese encephalitis vaccine strain SA14-14-2
Mosquito-borne flaviviruses include a large group of important human medical pathogens. Several chimaeric flaviviruses have been constructed, and show potential for vaccine development. Although Japanese encephalitis virus (JEV) live vaccine SA14-14-2 has been widely used with ideal safety and efficacy profiles, no chimaeric flavivirus based on the JEV vaccine has been described to date. Based on the reverse genetic system of the JEV vaccine SA14-14-2, a novel live chimaeric flavivirus carrying the protective antigens of West Nile virus (WNV) was constructed and recovered in this study. The resulting chimaera (ChinWNV) replicated efficiently in both mammalian and mosquito cells and possessed genetic stability after in vitro serial passaging. ChinWNV exhibited a small-plaque phenotype, and its replication was significantly restricted in mouse peripheral blood and brain compared with parental WNV. Importantly, ChinWNV was highly attenuated with regard to both neurovirulence and neuroinvasiveness in mice. Furthermore, a single ChinWNV immunization stimulated robust WNV-specific adaptive immune responses in mice, conferring significant protection against lethal WNV infection. Our results demonstrate that chimaeric flaviviruses based on the JEV vaccine can serve as a powerful platform for vaccine development, and that ChinWNV represents a potential WNV vaccine candidate that merits further development.
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- Retroviruses
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Generation of a replication-competent simian–human immunodeficiency virus, the neutralization sensitivity of which can be enhanced in the presence of a small-molecule CD4 mimic
Simian–human immunodeficiency virus (SHIV) carrying the envelope from the clade B clinical human immunodeficiency virus type 1 (HIV-1) isolate MNA, designated SHIV MNA, was generated through intracellular homologous recombination. SHIV MNA inherited biological properties from the parental HIV-1, including CCR5 co-receptor preference, resistance to neutralization by the anti-V3 loop mAb KD-247 and loss of resistance in the presence of the CD4-mimic small-molecule YYA-021. SHIV MNA showed productive replication in rhesus macaque PBMCs. Experimental infection of a rhesus macaque with SHIV MNA caused a transient but high titre of plasma viral RNA and a moderate antibody response. Immunoglobulin in the plasma at 24 weeks post-infection was capable of neutralizing SHIV MNA in the presence but not in the absence of YYA-021. SHIV MNA could serve a model for development of novel therapeutic interventions based on CD4-mimic-mediated conversion of envelope protein susceptible to antibody neutralization.
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- DNA viruses
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An immunodominant HLA-A*1101-restricted CD8+ T-cell response targeting hepatitis B surface antigen in chronic hepatitis B patients
More LessHepatitis B virus (HBV) infection is a worldwide public health problem. HBV-specific CD8+ CTLs are vital for viral clearance. Identification of immunodominant CTL epitopes from HBV-associated antigens is necessary for therapeutic vaccine development. We showed that the HLA-A*1101 allele is one of the most common alleles in both healthy individuals and chronic hepatitis B (CHB) patients in the Chongqing area, China. However, less than 10 % of epitopes of HBV-associated antigens have been identified in an HLA-A*1101 context. Here, we describe an immunodominant CD8+ T-cell response targeting a hepatitis B surface antigen determinant (HBs295–304) restricted by HLA-A*1101 in both healthy individuals and CHB patients. Moreover, HBs295–304 is more immunogenic for CTL induction than a known naturally HLA-A*1101-processed epitope from hepatitis B core antigen (HBc88–96). Therefore, the newly identified epitope, HBs295–304, will benefit the development of immunotherapeutic approaches for HBV infection.
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In vitro replication competence of a hepatitis B genotype D/A recombinant virus: dissimilar biological behaviour regarding its parental genotypes
Hepatitis B virus (HBV) DNA recombinants contribute to ~30 % of the overall full-length sequences already deposited in GenBank. However, their biological behaviour has not been analysed so far. In this study, the in vitro replication kinetics of the first D/A recombinant from the American continent differed from its parental genotypes, exhibiting higher extracellular levels of HBV DNA and hepatitis B e antigen. Southern blots of intracellular core-associated HBV DNA were in agreement with such results. Because this recombinant was obtained from an Argentinian injecting drug user belonging to a vulnerable community, these results are of singular relevance for regional public health. Further in vivo studies are urgently needed to determine the pathogenicity of these replicative competent clones.
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Role of the line probe assay INNO-LiPA HBV DR and ultradeep pyrosequencing in detecting resistance mutations to nucleoside/nucleotide analogues in viral samples isolated from chronic hepatitis B patients
Despite the effectiveness of nucleoside/nucleotide analogues in the treatment of chronic hepatitis B (CHB), their long-term administration is associated with the emergence of resistant hepatitis B virus (HBV) mutants. In this study, mutations resulting in antiviral resistance in HBV DNA samples isolated from 23 CHB patients (nine treatment naïve and 14 treated previously) were studied using a line probe assay (INNO-LiPA HBV DR; Innogenetics) and ultradeep pyrosequencing (UDPS) methods. Whilst the INNO-LiPA HBV DR showed no resistance mutations in HBV DNA samples from treatment-naive patients, mutations mediating lamivudine resistance were detected in three samples by UDPS. Among patients who were treated previously, 19 mutations were detected in eight samples using the INNO-LiPA HBV DR and 29 mutations were detected in 12 samples using UDPS. All mutations detected by the INNO-LiPA HBV DR were also detected by UDPS. There were no mutations that could be detected by INNO-LiPA HBV DR but not by UDPS. A total of ten mutations were detected by UDPS but not by INNO-LiPA HBV DR, and the mean frequency of these mutations was 14.7 %. It was concluded that, although INNO-LiPA HBV DR is a sensitive and practical method commonly used for the detection of resistance mutations in HBV infection, UDPS may significantly increase the detection rate of genotypic resistance in HBV at an early stage.
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Perturbation of biogenesis and targeting of Epstein–Barr virus-encoded miR-BART3 microRNA by adenosine-to-inosine editing
More LessEpstein–Barr virus (EBV) encodes at least 44 mature microRNAs (miRNAs), some of which are abundantly expressed in nasopharyngeal carcinoma cells. EBV-encoded miR-BART6 miRNA is known to undergo adenosine-to-inosine (A-to-I) RNA editing, which impacts on processing and function. Whether additional EBV miRNAs might be A-to-I edited remains to be determined. In this study, we have reported on A-to-I editing of EBV miR-BART3. The A-to-I editing enzyme was expressed abundantly in EBV-infected epithelial carcinoma cells. pri-miR-BART3 was found to be edited at four sites in these cells and in nasopharyngeal carcinoma samples. Whereas editing of the second site located within the seed region prevented the targeting of DICE1 mRNA, editing of the third site effectively crippled the biogenesis of mature miR-BART3. Thus, A-to-I editing perturbs biogenesis and targeting of miR-BART3 and may contribute to its differential expression and function in EBV-infected epithelial cells.
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Molecular identification of a novel gammaherpesvirus in the endangered Darwin’s fox (Lycalopex fulvipes)
We report the detection and characterization of a novel gammaherpesvirus in the critically endangered Darwin’s fox (Lycalopex fulvipes; syn. Pseudalopex fulvipes) on Chiloé Island, Chile. Out of 28 analysed blood samples stored in alcohol, four were positive for this herpesvirus using a previously described pan-herpesvirus PCR assay targeting the herpesvirus DNA polymerase. Positive samples were subsequently characterized by means of a PCR targeting a 500 bp fragment of the glycoprotein B of the gammaherpesviruses. This novel herpesvirus was most closely related to other gammaherpesviruses from terrestrial carnivores, and is tentatively named Darwin’s fox gammaherpesvirus. No apparent lesions were observed in the surveyed foxes. This is the first report of a gammaherpesvirus infecting a canid worldwide, and also of one infecting a carnivore from South America.
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Microtubule depolymerization activates the Epstein–Barr virus lytic cycle through protein kinase C pathways in nasopharyngeal carcinoma cells
More LessElevated levels of antibodies against Epstein–Barr virus (EBV) and the presence of viral DNA in plasma are reliable biomarkers for the diagnosis of nasopharyngeal carcinoma (NPC) in high-prevalence areas, such as South-East Asia. The presence of these viral markers in the circulation suggests that a minimal level of virus reactivation may have occurred in an infected individual, although the underlying mechanism of reactivation remains to be elucidated. Here, we showed that treatment with nocodazole, which provokes the depolymerization of microtubules, induces the expression of two EBV lytic cycle proteins, Zta and EA-D, in EBV-positive NPC cells. This effect was independent of mitotic arrest, as viral reactivation was not abolished in cells synchronized at interphase. Notably, the induction of Zta by nocodazole was mediated by transcriptional upregulation via protein kinase C (PKC). Pre-treatment with inhibitors for PKC or its downstream signalling partners p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) abolished the nocodazole-mediated induction of Zta and EA-D. Interestingly, the effect of nocodazole, as well as colchicine and vinblastine, on lytic gene expression occurred only in NPC epithelial cells but not in cells derived from lymphocytes. These results establish a novel role of microtubule integrity in controlling the EBV life cycle through PKC and its downstream pathways, which represents a tissue-specific mechanism for controlling the life-cycle switch of EBV.
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Volumes and issues
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Volume 106 (2025)
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