- Volume 96, Issue 8, 2015
Volume 96, Issue 8, 2015
- Animal
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- Positive-strand RNA Viruses
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Characterization of the IFN pathway in the teleost fish gonad against vertically transmitted viral nervous necrosis virus
One of the most powerful innate immune responses against viruses is mediated by type I IFN. In teleost fish, it is known that virus infection triggers the expression of ifn and many IFN-stimulated genes, but the viral RNA sensors and mediators leading to IFN production are scarcely known. Thus, we have searched for the presence of these genes in gilt-head sea bream (Sparus aurata) and European sea bass (Dicentrarchus labrax), and evaluated their expression after infection with viral nervous necrosis virus (VNNV) in the brain, the main viral target tissue, and the gonad, used to transmit the virus vertically. In sea bream, a fish species resistant to the VNNV strain used, we found an upregulation of the genes encoding MDA5 (melanoma differentiation-associated gene 5), TBK1 (TANK-binding kinase 1), IRF3 (IFN regulatory factor 3), IFN, Mx [myxovirus (influenza) resistance protein] and PKR (dsRNA-dependent protein kinase receptor) proteins in the brain, which were unaltered in the gonad and could favour the dissemination by gonad fluids or gametes. Strikingly, in European sea bass, a very susceptible species, we also identified, transcripts coding for LGP2 (Laboratory of Genetics and Physiology 2), MAVS (mitochondrial antiviral signalling), TRAF3 (TNF receptor-associated factor 3), TANK (TRAF family member-associated NFκB activator) and IRF7 (IFN regulatory factor 7), and found that all the genes analysed were upregulated in the gonad, but only mda5, lgp2, irf3, mx and pkr were upregulated in the brain. These findings supported the notion that the European sea bass brain innate immune response is unable to clear the virus and pointed to the importance of gonad immunity to control the dissemination of VNNV to the progeny – an aspect that is worth investigating in aquatic animals.
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Discovery of a novel nidovirus in cattle with respiratory disease
The family Coronaviridae represents a diverse group of vertebrate RNA viruses, all with genomes greater than 26 000 nt. Here, we report the discovery and genetic characterization of a novel virus present in cattle with respiratory disease. Phylogenetic characterization of this virus revealed that it clusters within the subfamily Torovirinae, in the family Coronaviridae. The complete genome consists of only 20 261 nt and represents the smallest reported coronavirus genome. We identified seven ORFs, including the canonical nidovirus ORF1a and ORF1b. Analysis of polyprotein 1ab revealed that this virus, tentatively named bovine nidovirus (BoNV), shares the highest homology with the recently described python-borne nidoviruses and contains several conserved nidovirus motifs, but does not encode the NendoU or O-MT domains that are present in other viruses within the family Coronaviridae. In concert with its reduced genome, the atypical domain architecture indicates that this virus represents a unique lineage within the order Nidovirales.
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Delayed IFN response differentiates replication of West Nile virus and Japanese encephalitis virus in human neuroblastoma and glioblastoma cells
More LessWest Nile virus (WNV) and Japanese encephalitis virus (JEV) are important causes of human encephalitis cases, which result in a high mortality ratio and neurological sequelae after recovery. Understanding the mechanism of neuropathogenicity in these viral infections is important for the development of specific antiviral therapy. Here, we focused on human-derived neuronal and glial cells to understand the cellular responses against WNV and JEV infection. It was demonstrated that early IFN-β induction regulated virus replication in glioblastoma tbl98G cells, whereas delayed IFN-β induction resulted in efficient virus replication in neuroblastoma SK-N-SH cells. Moreover, the concealing of viral dsRNA in the intracellular membrane resulted in the delayed IFN response in SK-N-SH cells. These results, which showed different IFN responses between human neuronal and glial cells after WNV or JEV infection, are expected to contribute to our understanding of the molecular mechanisms for neuropathology in these viral infections.
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A single-amino-acid mutation in hepatitis C virus NS5A disrupts physical and functional interaction with the transcription factor HNF-1α
More LessHepatitis C virus (HCV) infection often causes extrahepatic manifestations, such as type 2 diabetes. We previously reported that HCV infection induces the lysosomal degradation of the transcription factor HNF-1α via an interaction with viral NS5A, thereby suppressing GLUT2 gene expression. However, the molecular mechanism of NS5A-induced degradation of HNF-1α is largely unknown. We aimed to identify the determinants necessary for the degradation of HNF-1α induced by NS5A. Coimmunoprecipitation analysis revealed that the POU specific (POUs) domain spanning from aa 91 to 181 of HNF-1α is responsible for the interaction of NS5A. We also found that the region from aa 121 to 126 of NS5A, which is known as the binding motif of the HCV replication factor FKBP8, is important for the degradation of HNF-1α. A NS5A V121A mutation disrupted the NS5A–HNF-1α interaction as well as the degradation of HNF-1α. Our findings suggest that NS5A Val121 is crucial for viral pathogenesis.
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Genetic manipulation of porcine epidemic diarrhoea virus recovered from a full-length infectious cDNA clone
Porcine epidemic diarrhoea virus (PEDV) causes acute diarrhoea and dehydration in swine of all ages, with significant mortality in neonatal pigs. The recent rise of PEDV outbreaks in Asia and North America warrants an urgent search for effective vaccines. However, PEDV vaccine research has been hampered by difficulties in isolating and propagating the virus in mammalian cells, thereby complicating the recovery of infectious PEDV using a full-length infectious clone. Here, we engineered VeroE6 cells to stably express porcine aminopeptidase N (pAPN) and used them as a platform to obtain a high-growth variant of PEDV, termed PEDVAVCT12. Subsequently, the full-length cDNA clone was constructed by assembling contiguous cDNA fragments encompassing the complete genome of PEDVAVCT12 in a bacterial artificial chromosome. Infectious PEDV could be recovered, and the rescued virus displayed phenotypic properties identical to the parental virus. Interestingly, we found that PEDVAVCT12 contained a C-terminal deletion of the spike gene, resulting in disruption of the ORF3 start codon. When a functional ORF3 gene was restored, the recombinant virus could not be rescued, suggesting that ORF3 could suppress PEDV replication in vitro. In addition, a high-growth and genetically stable recombinant PEDV expressing a foreign protein could be rescued by replacing the ORF3 gene with the mCherry gene. Together, the results of this study provide a means to generate genetically defined PEDV as a promising vaccine candidate.
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- Double-strand RNA Viruses
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Evolution of a G6P[6] rotavirus strain isolated from a child with acute gastroenteritis in Ghana, 2012
More LessUnusual human G6P[6] rotavirus A (RVA) strains have been reported sporadically in Europe and Africa, but how they evolved was not fully understood. The whole genome of a Ghanaian G6P[6] strain designated PML1965 (2012) was analysed to understand how it evolved in Africa and to learn how its G6 VP7 gene was related to that of rotaviruses of human and artiodactyl origin. The genotype constellation of RVA/Human-wt/GHA/PML1965/2012/G6P[6] was G6-P-[6]-I2-R2-C2-M2-A2-N2-T2-E2-H2. It shared sublineages with G6P[6] strains previously detected in Italy and Africa in all genome segments except the VP6 gene of a few Burkinabe and Cameroonian strains and both the VP6 and NSP4 genes of Guinea Bissau strains. The VP7 gene of the G6P[6] strains appeared to derive from those of human G6P[9] strains, and they were distantly related to the VP7 genes of artiodactyl G6 or human G6P[14] strains. The time of the most recent common ancestor of the VP7 sequences of G6P[6] strains was estimated to be the year 1998. The evolutionary rates of the VP7 genes in bovine and human G6 rotaviruses were 6.93 × 10− 4 and 3.42 × 10− 3 nucleotide substitutions site− 1 year− 1, respectively, suggesting an accelerated adaptive process in the new host. The sequences of the remaining 10 genome segments of PML1965 clustered with those of G2 and G8 human rotaviruses detected in Africa possessing the DS-1-like genetic background. In conclusion, PML1965 evolved from G2 or G8 RVA strains with DS-1-like background, acquiring the G6 VP7 gene from a human G6P[9] RVA and not from an artiodactyl G6 RVA strain.
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- Small DNA Viruses
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Interaction of human papillomavirus type 16 particles with heparan sulfate and syndecan-1 molecules in the keratinocyte extracellular matrix plays an active role in infection
More LessOncogenic human papillomaviruses (HPVs) attach predominantly to extracellular matrix (ECM) components during infection of cultured keratinocytes and in the rodent vaginal challenge model in vivo. However, the mechanism of virion transfer from the ECM to receptors that mediate entry into host cells has not been determined. In this work we strove to assess the role of heparan sulfate (HS) chains in HPV16 binding to the ECM and determine how HPV16 release from the ECM is regulated. We also assessed the extent to which capsids released from the ECM are infectious. We show that a large fraction of HPV16 particles binds to the ECM via HS chains, and that syndecan-1 (snd-1) molecules present in the ECM are involved in virus binding. Inhibiting the normal processing of snd-1 and HS molecules via matrix metalloproteinases and heparanase dramatically reduces virus release from the ECM, cellular uptake and infection. Conversely, exogenous heparinase activates each of these processes. We confirm that HPV16 released from the ECM is infectious in keratinocytes. Use of a specific inhibitor shows furin is not involved in HPV16 release from ECM attachment factors and corroborates other studies showing only the intracellular activity of furin is responsible for modulating HPV infectivity. These data suggest that our recently proposed model, describing the action of HS proteoglycan processing enzymes in releasing HPV16 from the cell surface in complex with the attachment factor snd-1, is also relevant to the release of HPV16 particles from the ECM to promote efficient infection of keratinocytes.
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Hepatitis B virus X protein activates the ATM–Chk2 pathway and delays cell cycle progression
Genetic instability is intimately associated with tumour development. In particular, liver cancers associated with hepatitis B virus (HBV) exhibit high genetic instability; however, our understanding of the underlying molecular mechanisms remains limited. In this study, we found that γ-H2AX, a marker of DNA double-strand breaks (DSBs), and the levels of phospho-Chk2 (p-Chk2, the activated form) were significantly elevated in HBV-associated hepatocellular carcinomas and neighbouring regenerating nodules. Likewise, introduction of the pHBV or pMyc-HBx plasmids into cells induced accumulation of γ-H2AX foci and increased the p-Chk2 level. In these cells, inhibitory phosphorylation of Cdc25C phosphatase (Ser216) and CDK1 (Tyr15) was elevated; consequently, cell-cycle progression was delayed at G2/M phase, suggesting that activation of the ATM–Chk2 pathway by the HBV X protein (HBx) induces cell-cycle delay. Accordingly, inhibition of ataxia telangiectasia mutated (ATM) by caffeine or siRNA abolished the increase in the p-Chk2 level and restored the delayed CDK1 kinase activity in ChangX cells. We also found that cytoplasmic HBx, but not nuclear HBx, induced reactive oxygen species (ROS) production and led to the accumulation of γ-H2AX foci and the increased p-Chk2 level. Together, these data indicate that HBx-induced ROS accumulation induces DNA damage that activates the ATM–Chk2 pathway. Our findings provide insight into the mechanisms of HBV pathogenesis.
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Inhibition of hepatitis B virus by the CRISPR/Cas9 system via targeting the conserved regions of the viral genome
More LessHepatitis B virus (HBV) remains a global health threat as chronic HBV infection may lead to liver cirrhosis or cancer. Current antiviral therapies with nucleoside analogues can inhibit the replication of HBV, but do not disrupt the already existing HBV covalently closed circular DNA. The newly developed CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated 9) system is a powerful tool to target cellular genome DNA for gene editing. In order to investigate the possibility of using the CRISPR/Cas9 system to disrupt the HBV DNA templates, we designed eight guide RNAs (gRNAs) that targeted the conserved regions of different HBV genotypes, which could significantly inhibit HBV replication both in vitro and in vivo. Moreover, the HBV-specific gRNA/Cas9 system could inhibit the replication of HBV of different genotypes in cells, and the viral DNA was significantly reduced by a single gRNA/Cas9 system and cleared by a combination of different gRNA/Cas9 systems.
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Recurrent positive selection and heterogeneous codon usage bias events leading to coexistence of divergent pigeon circoviruses
More LessThe capsid genes from 14 pigeon circovirus (PiCV) sequences, collected from Taiwan between 2009 and 2010, were sequenced and compared with 14 PiCV capsid gene sequences from GenBank. Based on pairwise comparison, PiCV strains from Taiwan shared 73.9–100 % nucleotide identity and 72–100 % amino acid identity with those of the 14 reported PiCV sequences. Phylogenetic analyses revealed that Taiwanese PiCV isolates can be grouped into two clades: clade 1 comprising isolates from Belgium, Australia, USA, Italy and China, and clade 2 showing close relation to isolates from Germany and France. Recurrent positive selection was detected in clade 1 PiCV lineages, which may contribute to the diversification of predominant PiCV sequences in Taiwan. Further observations suggest that synonymous codon usage variations between PiCV clade 1 and clade 2 may reflect the adaptive divergence on translation efficiency of capsid genes in infectious hosts. Variation in selective pressures acting on the evolutionary divergence and codon usage bias of both clades explains the regional coexistence of virus sequences congeners prevented from competitive exclusion within an island such as Taiwan. Our genotyping results also provide insight into the aetiological agents of PiCV outbreak in Taiwan and we present a comparative analysis of the central coding region of PiCV genome. From the sequence comparison results of 28 PiCVs which differs in regard to the geographical origin and columbid species, we identified conserved regions within the capsid gene that are likely to be suitable for primer selection and vaccine development.
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The human papillomavirus type 16 L1 protein directly interacts with E2 and enhances E2-dependent replication and transcription activation
The human papillomavirus (HPV) E2 protein is a multifunctional protein essential for the control of virus gene expression, genome replication and persistence. E2 is expressed throughout the differentiation-dependent virus life cycle and is functionally regulated by association with multiple viral and cellular proteins. Here, we show for the first time to our knowledge that HPV16 E2 directly associates with the major capsid protein L1, independently of other viral or cellular proteins. We have mapped the L1 binding region within E2 and show that the α-2 helices within the E2 DNA-binding domain mediate L1 interaction. Using cell-based assays, we show that co-expression of L1 and E2 results in enhanced transcription and virus origin-dependent DNA replication. Upon co-expression in keratinocytes, L1 reduces nucleolar association of E2 protein, and when co-expressed with E1 and E2, L1 is partially recruited to viral replication factories. Furthermore, co-distribution of E2 and L1 was detected in the nuclei of upper suprabasal cells in stratified epithelia of HPV16 genome-containing primary human keratinocytes. Taken together, our findings suggest that the interaction between E2 and L1 is important for the regulation of E2 function during the late events of the HPV life cycle.
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Seroreactivity against Merkel cell polyomavirus and other polyomaviruses in chronic lymphocytic leukaemia, the MCC-Spain study
Claudia Robles, Delphine Casabonne, Yolanda Benavente, Laura Costas, Eva Gonzalez-Barca, Marta Aymerich, Elias Campo, Adonina Tardon, José J. Jiménez-Moleón, Gemma Castaño-Vinyals, Trinidad Dierssen-Sotos, Angelika Michel, Lena Kranz, Nuria Aragonés, Marina Pollan, Manolis Kogevinas, Michael Pawlita and Silvia de SanjoseMerkel cell polyomavirus (MCPyV) has been suspected to cause chronic lymphocytic leukaemia (CLL) but previous data are inconsistent. We measured seroreactivities of nine polyomaviruses (MCPyV, BKPyV, JCPyV, LPyV, KIPyV, WUPyV, HPyV-6, HPyV-7 and TSPyV) in 359 CLL cases and 370 controls using bead-based multiplex serology technology. We additionally tested two herpesviruses (HSV-1 and CMV). Associations between disease and viral seroreactivities were assessed using logistic regression. All human viruses showed high seroprevalences (69–99 %) against structural proteins in controls but significantly lower viral seroprevalences in cases (58–94 %; OR range = 0.21–0.70, P value < 0.05), except for MCPyV (OR = 0.79, 95 % CI = 0.54–1.16). Lower seroreactivity levels were observed among CLL subjects, with significant differences already observed at early stages of disease, unrelated to treatment status. Seroreactivities against polyomavirus related oncoproteins were almost null. Our data suggest no association for MCPyV polyomavirus with CLL development and an unlikely association for other polyomaviruses tested.
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Early and late promoters of BK polyomavirus, Merkel cell polyomavirus, Trichodysplasia spinulosa-associated polyomavirus and human polyomavirus 12 are among the strongest of all known human polyomaviruses in 10 different cell lines
More LessRecently, 11 new human polyomaviruses (HPyVs) have been isolated and named KI, WU, Merkel cell polyomavirus (MCPyV), HPyV6, − 7, − 9, − 10 and − 12, Trichodysplasia spinulosa-associated polyomavirus (TSPyV), STLPyV and NJPyV-2013. Little is known about cell tropism of the novel HPyVs, and cell cultures allowing virus propagation are lacking. Because viral tropism partially depends on the interaction of cellular transcription factors with the viral promoter, we monitored the promoter activity of all known HPyVs. Therefore, we compared the relative early and late promoter activity of the BK polyomavirus (BKPyV) (WW strain) with the corresponding activities of the other HPyVs in 10 different cell lines derived from brain, colon, kidney, liver, lung, the oral cavity and skin. Our results show that the BKPyV, MCPyV, TSPyV and HPyV12 early promoters displayed the strongest activity in most cell lines tested, while the remaining HPyV had relative low early promoter activity. HPyV12 showed the highest late promoter activity of all HPyVs in most cell lines, but also the BKPyV, MCPyV and TSPyV late promoters belonged to the stronger ones among HPyVs. The HPyVs with weak early promoter activity had in general also weak late promoter activity, except for HPyV10 whose late promoter was relatively strong in six of the 10 cell lines. A 20 bp deletion in the promoter of an HPyV12 variant significantly affected both early and late promoter activity in most cell lines. In conclusion, our findings suggest which cell lines may be suitable for virus propagation and may give an indication of the cell tropism of the HPyVs.
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- Large DNA Viruses
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An investigation of herpes simplex virus type 1 latency in a novel mouse dorsal root ganglion model suggests a role for ICP34.5 in reactivation
More LessAfter a primary lytic infection at the epithelia, herpes simplex virus type 1 (HSV-1) enters the innervating sensory neurons and translocates to the nucleus, where it establishes a quiescent latent infection. Periodically, the virus can reactivate and the progeny viruses spread back to the epithelium. Here, we introduce an embryonic mouse dorsal root ganglion (DRG) culture system, which can be used to study the mechanisms that control the establishment, maintenance and reactivation from latency. Use of acyclovir is not necessary in our model. We examined different phases of the HSV-1 life cycle in DRG neurons, and showed that WT HSV-1 could establish both lytic and latent form of infection in the cells. After reactivating stimulus, the WT viruses showed all markers of true reactivation. In addition, we showed that deletion of the γ134.5 gene rendered the virus incapable of reactivation, even though the virus was clearly able to replicate and persist in a quiescent form in the DRG neurons.
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Subcapsular sinus macrophages limit acute gammaherpesvirus dissemination
More LessLymphocyte proliferation, mobility and longevity make them prime targets for virus infection. Myeloid cells that process and present environmental antigens to lymphocytes are consequently an important line of defence. Subcapsular sinus macrophages (SSMs) filter the afferent lymph and communicate with B-cells. How they interact with B-cell-tropic viruses is unknown. We analysed their encounter with murid herpesvirus-4 (MuHV-4), an experimentally accessible gammaherpesvirus related to Kaposi's sarcoma-associated herpesvirus. MuHV-4 disseminated via lymph nodes, and intranasally or subcutaneously inoculated virions readily infected SSMs. However, this infection was poorly productive. SSM depletion with clodronate-loaded liposomes or with diphtheria toxin in CD169–diphtheria toxin receptor transgenic mice increased B-cell infection and hastened virus spread to the spleen. Dendritic cells provided the main route to B-cells, and SSMs slowed host colonization, apparently by absorbing virions non-productively from the afferent lymph.
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Pseudorabies virus US3 triggers RhoA phosphorylation to reorganize the actin cytoskeleton
More LessThe conserved alphaherpesvirus serine/threonine kinase US3 causes dramatic changes in the actin cytoskeleton, consisting of actin stress fibre breakdown and protrusion formation, associated with increased virus spread. Here, we showed that US3 expression led to RhoA phosphorylation at serine 188 (S188), one of the hallmarks of suppressed RhoA signalling, and that expression of a non-phosphorylatable RhoA variant interfered with the ability of US3 to induce actin rearrangements. Furthermore, inhibition of cellular protein kinase A (PKA) eliminated the ability of US3 to induce S188 RhoA phosphorylation, pointing to a role for PKA in US3-induced RhoA phosphorylation. Hence, the US3 kinase leads to PKA-dependent S188 RhoA phosphorylation, which contributes to US3-mediated actin rearrangements. Our data suggest that US3 efficiently usurps the antagonistic RhoA and Cdc42/Rac1/p21-activated kinase signalling branches to rearrange the actin cytoskeleton.
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RanBPM regulates Zta-mediated transcriptional activity in Epstein–Barr virus
Epstein–Barr virus (EBV) expresses two immediate-early proteins, Rta and Zta, which are key transcription factors that can form a complex with MCAF1 at Zta-responsive elements (ZREs) to synergistically activate several viral lytic genes. Our previous research indicated that RanBPM interacts with Rta and enhances Rta sumoylation. Here we showed that RanBPM binds to Zta in vitro and in vivo, and acts as an intermediary protein in Rta–Zta complex formation. The Rta–RanBPM–Zta complex was observed to bind with ZREs in the transcriptional activation of key viral genes, such as BHLF1 and BHRF1, while the introduction of RanBPM short hairpin RNA (shRNA) subsequently reduced the synergistic activity of Zta and Rta. RanBPM was found to enhance Zta-dependent transcriptional activity via the inhibition of Zta sumoylation. Interestingly, Z-K12R, a sumoylation-defective mutant of Zta, demonstrated transcriptional activation capabilities that were stronger than those of Zta and apparently unaffected by RanBPM modulation. Finally, RanBPM silencing inhibited the expression of lytic proteins. Taken together, these results shed light on the mechanisms by which RanBPM regulates Zta-mediated transcriptional activation, and point to an important role for RanBPM in EBV lytic progression.
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A replication defect of pseudorabies virus induced by targeted α-helix distortion in the syntaxin-like bundle of glycoprotein H (V275P) is corrected by an adjacent compensatory mutation (V271A)
Glycoprotein gH is essential for herpesvirus-induced membrane fusion during entry and cell-to-cell spread. Structural analyses of gH homologues revealed a conserved syntaxin-like bundle motif composed of three α-helices. Previous studies showed that targeted disruption of any of these helices strongly impaired maturation, cell surface expression and fusion activity of pseudorabies virus gH, as well as formation and spread of infectious virus. After passaging of one corresponding mutant (pPrV-gH-V275P) these replication defects were widely corrected by an adjacent spontaneous amino acid substitution (V271A). Although the doubly mutated gH was still non-functional in fusion assays, its targeted reinsertion into the cloned virus genome (pPrV-gH-V275P-V271A) led to a 200-fold increase in plaque sizes and 10 000-fold higher virus titres, compared with pPrV-gH-V275P. Thus, our results demonstrate that structural requirements for gH function in in vitro assays and virus replication are different, and that minor amounts of mature gH in virions are sufficient for productive replication.
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Latent infection of myeloid progenitors by human cytomegalovirus protects cells from FAS-mediated apoptosis through the cellular IL-10/PEA-15 pathway
More LessLatent infection of primary CD34+ progenitor cells by human cytomegalovirus (HCMV) results in their increased survival in the face of pro-apoptotic signals. For instance, we have shown previously that primary myeloid cells are refractory to FAS-mediated killing and that cellular IL-10 (cIL-10) is an important survival factor for this effect. However, how cIL-10 mediates this protection is unclear. Here, we have shown that cIL-10 signalling leading to upregulation of the cellular factor PEA-15 mediates latency-associated protection of CD34+ progenitor cells from the extrinsic death pathway.
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Modification of promoter spacer length in vaccinia virus as a strategy to control the antigen expression
Vaccinia viruses (VACVs) with distinct early promoters have been developed to enhance antigen expression and improve antigen-specific CD8 T-cell responses. It has not been demonstrated how the length of the spacer between the coding region of the gene and its regulatory early promoter motif influences antigen expression, and whether the timing of gene expression can modify the antigen-specific CD4 T-cell response. We generated several recombinant VACVs based on the attenuated modified vaccinia Ankara (MVA) strain, which express GFP or the Leishmania LACK antigen under the control of an optimized promoter, using different spacer lengths. Longer spacer length increased GFP and LACK early expression, which correlated with an enhanced LACK-specific memory CD4 and CD8 T-cell response. These results show the importance of promoter spacer length for early antigen expression by VACV and provide alternative strategies for the design of poxvirus-based vaccines.
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Volumes and issues
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Volume 105 (2024)
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