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Volume 89,
Issue 4,
2008
Volume 89, Issue 4, 2008
- Animal
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- RNA viruses
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Morpholino oligomers targeting the PB1 and NP genes enhance the survival of mice infected with highly pathogenic influenza A H7N7 virus
More LessPeptide-conjugated phosphorodiamidate morpholino oligomers (PPMO) are single-stranded nucleic acid-analogue antisense agents that enter cells readily and can reduce gene expression by steric blocking of complementary RNA (cRNA) sequences. Here, we tested a panel of PPMO designed to target conserved sequences in the RNA genome segments encoding polymerase subunits of a highly pathogenic mouse-adapted influenza A virus (SC35M; H7N7). Three PPMO, targeting the translation start site region of PB1 or NP mRNA or the 3′-terminal region of NP viral RNA (vRNA), potently inhibited virus replication in MDCK cells. Primer extension assays showed that treatment with any of the effective PPMO led to markedly reduced levels of mRNA, cRNA and vRNA. Initially, the potential toxicity of a range of intranasally administered PPMO doses was evaluated, by measuring their effect on body weight of uninfected mice. Subsequently, a non-toxic dosing regimen was used to investigate the effect of various PPMO on SC35M infection in a mouse model. Mice administered intranasal treatment of PPMO targeting the PB1-AUG region or NP vRNA, at 3 μg per dose, given once 3 h before and once 2 days after intranasal infection with 10×LD50 of SC35M, showed a 2 log10 reduction of viral titre in the lungs and 50 % survival for the 16 day duration of the experiment, whereas the NP-AUG-targeted PPMO treatment resulted in 30 % survival of an otherwise lethal infection. These data suggest that PPMO provide a useful reagent to investigate influenza virus molecular biology and may constitute a therapeutic strategy against highly pathogenic influenza viruses.
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Ecology of H3 avian influenza viruses in Korea and assessment of their pathogenic potentials
To determine the genetic origins of novel H3 avian influenza viruses of chickens and ducks in Korea, genetic characterization of H3 avian influenza viruses isolated from live poultry markets and migratory aquatic birds in South Korea during 2004–2006 was conducted. Phylogenetic analysis revealed that at least four novel genotypes of H3N2 and two genotypes of H3N6 avian influenza viruses were co-circulating in backyard poultry of Korea. The viruses were reassortants between H9N2 viruses of Korean chickens and unknown influenza viruses of migratory birds. Genetic comparison of H3 viruses from live bird markets with those from wild bird isolates revealed that certain gene segments of wild bird isolates are related closely to those of Korean group H9N2 viruses isolated from live poultry markets in 2003. Furthermore, animal-challenge studies demonstrated that the pathogenicity of certain avian H3 influenza viruses was altered due to reassortment, leading to H3 avian influenza viruses in Korea that can potentially expand their host range to include mammals. These studies emphasize the continuing need to monitor backyard poultry at live poultry markets to better understand interspecies transmission and the emergence of novel influenza viruses that have the potential to infect humans.
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Antibodies induced by the HA2 glycopolypeptide of influenza virus haemagglutinin improve recovery from influenza A virus infection
More LessThe haemagglutinin (HA) of influenza A virus consists of two glycopolypeptides designated HA1 and HA2. Antibodies recognizing HA1 inhibit virus haemagglutination, neutralize virus infectivity and provide good protection against infection, but do not cross-react with the HA of other subtypes. Little is known regarding the biological activities of antibodies against HA2. To study the role of antibodies directed against HA2 during influenza virus infection, two vaccinia virus recombinants (rVVs) were used expressing chimeric molecules of HA, in which HA1 and HA2 were derived from different HA subtypes. The KG-11 recombinant expressed HA1 from A/PR/8/34 (H1N1) virus and HA2 from A/NT/60 (H3N2) virus, whilst KG-12 recombinant expressed HA1 from A/NT/60 virus and HA2 from A/PR/8/34 virus. Immunization of BALB/c mice with rVV expressing HA2 of the HA subtype homologous to the challenge virus [A/PR/8/34 (H1N1) or A/Mississippi/1/85 (H3N2)] did not prevent virus infection, but nevertheless resulted in an increase in mice survival and faster elimination of virus from the lungs. Passive immunization with antibodies purified from mice immunized with rVVs confirmed that antibodies against HA2 were responsible for the described effect on virus infection. Based on the facts that HA2 is a rather conserved part of the HA and that antibodies against HA2, as shown here, may moderate virus infection, future vaccine design should deal with the problem of how to increase the HA2 antibody response.
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Protection of cats against lethal influenza H5N1 challenge infection
Highly pathogenic avian influenza virus (HPAIV) H5N1 of Asian origin continues to circulate in poultry and wild birds, causing considerable concern for veterinary and public health in Asia, Europe and Africa. Natural transmission of HPAIV H5N1 from poultry to humans, resulting in infections associated with high mortality, and from poultry or wild birds to large felids and domestic cats has been reported. Experimental infection of cats with HPAIV H5N1 derived from a human patient resulted in lethal disease. The role of cats in the adaptation of HPAIV H5N1 to mammals and vaccination regimens for the eventual protection of cats, however, remain to be elucidated. Here, it was shown that cats can be protected against a lethal high-dose challenge infection by an inactivated, adjuvanted heterologous H5N6 avian influenza virus vaccine. The challenge HPAIV H5N1 was derived from a naturally infected cat. In non-vaccinated cats, low-dose exposure resulted in asymptomatic infections with minimal virus excretion. As diseased cats can transmit the infection to naïve contact animals, the epidemiological role of H5N1-infected cats in endemically infected areas as a link between wild birds, poultry and humans needs close inspection, and vaccination of cats should be considered to reduce possible human exposure.
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Specificity and functional interaction of the polymerase complex proteins of human and avian metapneumoviruses
Human metapneumovirus (HMPV) and avian metapneumovirus (AMPV) have a similar genome organization and protein composition, but a different host range. AMPV subgroup C (AMPV-C) is more closely related to HMPV than other AMPVs. To investigate the specificity and functional interaction of the polymerase complex proteins of human and avian metapneumoviruses, a minireplicon system was generated for AMPV-C and used in combination with minireplicon systems for HMPV lineages A1 and B1. Viral RNA-like molecules representing HMPV-A1 and -B1, AMPV-A and -C and human respiratory syncytial virus were replicated efficiently by polymerase complexes of HMPV-A1 and -B1 and AMPV-C, but not by polymerase complexes of bovine parainfluenza virus 3. Upon exchange of HMPV and AMPV-C polymerase complex components, all chimeric polymerase complexes were functional; exchange between HMPVs did not result in altered polymerase activity, whereas exchange between HMPVs and AMPV-C did. Recombinant HMPV-B1 viruses in which polymerase genes were exchanged with those of HMPV-A1 replicated with normal kinetics in vitro, whilst replacement with AMPV-C genes resulted in moderate differences in virus replication. In hamsters, recombinant HMPV-B1 viruses in which individual polymerase genes were exchanged with those of AMPV-C were attenuated, irrespective of the results obtained with minireplicon systems or in vitro replication assays. This study provides insight into the specificity and functional interaction of polymerase complex proteins of human and avian metapneumoviruses, but neither minireplicon systems nor in vitro replication kinetics were found to be predictive for attenuation in permissive animals.
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Measles virus inhibits human immunodeficiency virus type 1 reverse transcription and replication by blocking cell-cycle progression of CD4+ T lymphocytes
More LessAcute measles virus (MV) infection results in a decrease in plasma human immunodeficiency virus type 1 (HIV-1) RNA levels in co-infected children. An in vitro peripheral blood mononuclear cell (PBMC) culture system was used to assess the mechanisms by which MV blocks HIV-1 replication. MV inhibited proliferation of CD4+ T lymphocytes, the target cell for HIV-1 replication. In the presence of MV, cells did not progress to G1b and S phases, steps critical for the completion of HIV-1 reverse transcription and productive replication. This block in cell-cycle progression was characterized by an increased proportion of CD4+ and HIV-1-infected cells retained in the parental generation in PBMCs co-cultured with MV and HIV-1, and decreased levels of cyclins and RNA synthesis. Early HIV-1 replication was also inhibited in the presence of MV, as measured by reduced expression of a luciferase reporter gene and lower levels of both early (LTR) and late (LTR–gag) DNA intermediates of HIV-1 reverse transcription in the presence of CCR5-tropic HIV-1. The effects of MV on lymphoproliferation and p24 antigen production were reproduced by n-butyrate and hydroxyurea, drugs that block the cell cycle in G1a and G1/S, respectively. It was concluded that MV inhibits HIV-1 productive replication in part by blocking the proliferation of CD4+ T lymphocytes.
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Effect of NS3 and NS5B proteins on classical swine fever virus internal ribosome entry site-mediated translation and its host cellular translation
More LessA full-length NS3 (NS3F) and a truncated NS3 protein (NS3H) with an RNA helicase domain possess RNA helicase activity. Using an in vitro system with a monocistronic reporter RNA or DNA, containing the CSFV 5′-UTR, we observed that both NS3F and NS3H enhanced internal ribosome entry site (IRES)-mediated and cellular translation in a dose-dependent manner, but NS3 protease (NS3P) that lacks a helicase domain did not. NS3F was stronger than NS3H in promoting both translations. These results showed that viral RNA helicase could promote viral and cellular translation, and higher RNA helicase activity might be more efficient. The NS5B protein, the viral replicase, did not significantly affect the IRES-directed or cellular translation alone. NS5B significantly enhanced the stimulative effect of NS3F on both IRES-mediated and cellular translation, but did not affect that of NS3H or NS3P. This suggests that NS5B and NS3 interact via the protease domain during the enhancement of translation.
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Thiopurines inhibit bovine viral diarrhea virus production in a thiopurine methyltransferase-dependent manner
More LessThe family Flaviviridae comprises positive-strand RNA viral pathogens of humans and livestock with few treatment options. We have previously shown that azathioprine (AZA) has in vitro activity against bovine viral diarrhea virus (BVDV). While the mechanism of inhibition is unknown, AZA and related thiopurine nucleoside analogues have been used as immunosuppressants for decades and both AZA metabolites and cellular genes involved in AZA metabolism have been extensively characterized. Here, we show that only certain riboside metabolites have antiviral activity and identify the most potent known antiviral AZA metabolite as 6-methylmercaptopurine riboside (6MMPr). The antiviral activity of 6MMPr is antagonized by adenosine, and is specific to BVDV and not to the related yellow fever virus. An essential step in the conversion of AZA to 6MMPr is the addition of a methyl group onto the sulfur atom attached to position six of the purine ring. Intracellularly, the methyl group is added by thiopurine methyltransferase (TPMT), an S-adenosyl methionine-dependent methyltransferase. Either chemically bypassing or inhibiting TPMT modulates antiviral activity of AZA metabolites. TPMT exists in several variants with varying levels of activity and since 6MMPr is a potent antiviral, the antiviral activity of AZA may be modulated by host genetics.
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Mutagenesis of the West Nile virus NS2B cofactor domain reveals two regions essential for protease activity
More LessThe flavivirus NS2B/NS3 protease has received considerable attention as a target for the development of antiviral compounds. While substrate based inhibitors have been the primary focus to date, an approach focussing on NS2B cofactor displacement could prove to be an effective alternative. To understand better the role of the NS2B cofactor in protease activation, we conducted an alanine mutagenesis screen throughout the 42-residue central cofactor domain (NS2B51–92) of West Nile virus (WNV). Two sites critical for proteolytic activity were identified (NS2B59–62 and NS2B75–87), where the majority of substitutions were found to significantly decrease proteolytic activity of a recombinant WNV NS2B/NS3 protease. These findings provide mechanistic insights into the structural and functional role that the cofactor may play in the substrate-bound and free protease complexes as well as providing novel sites for targeting new antiviral inhibitors.
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Identification of residues in the receptor-binding domain (RBD) of the spike protein of human coronavirus NL63 that are critical for the RBD–ACE2 receptor interaction
Human coronavirus NL63 (NL63), a member of the group I coronaviruses, may cause acute respiratory diseases in young children and immunocompromised adults. Like severe acute respiratory syndrome coronavirus (SARS-CoV), NL63 also employs the human angiotensin-converting enzyme 2 (hACE2) receptor for cellular entry. To identify residues in the spike protein of NL63 that are important for hACE2 binding, this study first generated a series of S1-truncated variants, examined their associations with the hACE2 receptor and subsequently mapped a minimal receptor-binding domain (RBD) that consisted of 141 residues (aa 476–616) towards the C terminus of the S1 domain. The data also demonstrated that the NL63 RBD bound to hACE2 more efficiently than its full-length counterpart and had a binding efficiency comparable to the S1 or RBD of SARS-CoV. A further series of RBD variants was generated using site-directed mutagenesis and random mutant library screening assays, and identified 15 residues (C497, Y498, V499, C500, K501, R518, R530, V531, G534, G537, D538, S540, E582, W585 and T591) that appeared to be critical for the RBD–hACE2 association. These critical residues clustered in three separate regions (designated RI, RII and RIII) inside the RBD, which may represent three receptor-binding sites. These results may help to delineate the molecular interactions between the S protein of NL63 and the hACE2 receptor, and may also enhance our understanding of the pathogenesis of NL63 and SARS-CoV.
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Analysis of the mechanism of antibody-dependent enhancement of feline infectious peritonitis virus infection: aminopeptidase N is not important and a process of acidification of the endosome is necessary
Infection of the monocyte/macrophage lineage with feline infectious peritonitis virus (FIPV) is enhanced in the presence of anti-FIPV antibodies (antibody-dependent enhancement or ADE). We investigated the following unclear points concerning ADE of FIPV infection: (i) involvement of the virus receptor, feline aminopeptidase N (fAPN), in ADE activity in FIPV infection; (ii) necessity of acidification of the endosome in cellular invasion of FIPV. Virus receptor-blocking experiments using anti-fAPN antibodies at 4 or 37 °C and experiments using fAPN-negative U937 cells revealed that fAPN is not involved in ADE of FIPV infection. Experiments using lysosomotropic agents clarified that acidification of the endosome is necessary for cellular invasion by FIPV, regardless of the presence or absence of antibodies. These findings may be very important for understanding the mechanism of ADE of FIPV infection.
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Widespread recombination within human parechoviruses: analysis of temporal dynamics and constraints
More LessHuman parechoviruses (HPeVs), members of the family Picornaviridae, are classified into six types. To investigate the dynamics and likelihood of recombination among HPeVs, we compared phylogenies of two distant regions (VP1 and 3Dpol) of 37 HPeV isolates (types 1 and 3–5) and prototype sequences (types 1–6). Evidence for frequent recombination between HPeV1, 4, 5 and 6 was found. The likelihood of recombination was correlated with the degree of VP1 divergence and differences in isolation dates, both indicative of evolutionary times of divergence. These temporal dynamics were found to be most similar to those of human enterovirus species B variants. In contrast, HPeV3 remained phylogenetically distinct from other types throughout the genome. As HPeV3 is equally divergent in nucleotide sequence from the other HPeV types, its genetic isolation may reflect different biology and changed cellular tropisms, arising from the deletion of the RGD motif, and likely use of a non-integrin receptor.
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Occurrence, function and evolutionary origins of ‘2A-like’ sequences in virus genomes
2A is an oligopeptide sequence mediating a ribosome ‘skipping’ effect, producing an apparent ‘cleavage’ of polyproteins. First identified and characterized in picornaviruses, ‘2A-like’ sequences are found in other mammalian viruses and a wide range of insect viruses. Databases were analysed using a motif conserved amongst 2A/2A-like sequences. The newly identified 2A-like sequences (30 aa) were inserted into a reporter polyprotein to determine their cleavage activity. Our analyses showed that these sequences fall into two categories. The majority mediated very high (complete) cleavage to separate proteins and a few sequences mediated cleavage with lower efficiency, generating appreciable levels of the uncleaved form. Phylogenetic analyses of 2A-like sequences and RNA-dependent RNA polymerases (RdRps) indicated multiple, independent, acquisitions of these sequences at different stages during virus evolution. Within a virus family, 2A sequences are (probably) homologous, but diverge due to other evolutionary pressures. Amongst different families, however, 2A/2A-like sequences appear to be homoplasic.
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Naturally arising point mutations in non-essential domains of equine infectious anemia virus Rev alter Rev-dependent nuclear-export activity
More LessEquine infectious anemia virus (EIAV) exhibits a high rate of genetic variation in vivo, and results in a clinically variable disease in infected horses. In vivo populations of EIAV have been characterized by the presence of distinct, genetic subpopulations of Rev that differ in phenotype and fluctuate in dominance in a manner coincident with each clinical stage of disease. This study examined the specific mutations that arose in vivo and altered the phenotype. The Rev protein was found to be highly conserved, and only 10 aa mutations were observed at a frequency greater than 10 % in the sample population. Nine of these mutations were capable of significantly altering Rev activity, either as single mutations in the context of the founder variant, or in the context of cumulatively fixed mutations. The results indicated that limited genetic variation outside the essential functional domains of Rev can alter the phenotype and may confer a selective advantage in vivo.
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The block to membrane fusion differs with the site of ligand insertion in modified retroviral envelope proteins
More LessEfforts to achieve cell type-specific transduction of retroviral vectors for gene therapy have centred on modification of the envelope protein (Env). Typically, addition of a ligand to Env gives binding to the new or target receptor, but little or no infection, and affects the subunit association of the modified Env. We previously discovered two point mutations that increase targeted infection by over 1000-fold when added to an Env modified by N-terminal insertion of the receptor-binding domain from amphotropic murine leukemia virus Env. Here, we asked whether these mutations would similarly increase transduction by Env modified with a clinically relevant ligand, human interleukin-13 (IL-13L). Addition of the point mutations stabilized the weak subunit association observed in some IL-13L-modified Env proteins, but infection via the target IL-13 receptor still did not occur. Fluorescence-based cell–cell fusion assays and studies with a membrane-curving agent revealed that defects in membrane fusion differed with the site of ligand insertion. When IL-13 was inserted into the N terminus of Env, membrane fusion was blocked prior to membrane-lipid mixing, regardless of whether flanking flexible linkers were added. Unexpectedly, insertion of IL-13 in the proline-rich region showed evidence of initiation of fusion and fusion-peptide exposure, but fusion was blocked at a subsequent step prior to fusion-pore formation. Thus, the site of ligand insertion influenced initiation of membrane fusion and its progression. These observations suggest that a novel site for ligand insertion must be identified before clinically useful targeted transduction will be achieved.
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Characterization of interleukin-1β mRNA expression in chicken macrophages in response to avian reovirus
More LessInhibitors of viral disassembly or RNA and protein synthesis, viral disassembly intermediates (infectious subviral particles, ISVP), binary ethylenimine-inactivated virions, and viral particles lacking genomic double-stranded (ds) RNA (empty particles) were used to assess the expression of interleukin-1β (IL-1β) mRNA in chicken (chIL-1β) macrophages in response to avian reovirus. The results demonstrate that two distinct expression patterns of chIL-1β mRNA mediated by different steps in viral replication were found. Viral disassembly was required for the induction of a rapid, transient expression pattern of chIL-1β mRNA that was rapidly induced at 30 min, with maximal levels reached by 2 h, and fell to a low level within 6 h post-inoculation, while viral RNA synthesis rather than protein translation, which was subsequent to membrane penetration, was required to induce a stable, sustained expression pattern of chIL-1β mRNA that occurred at and after 6 h post-inoculation. In addition, the induction of chIL-1β mRNA expression by the empty particles and ISVP was extremely weak, compared with the active dsRNA+ virions or binary ethylenimine-inactivated virions, suggesting that the presence of dsRNA, even if transcriptionally inactive, may be an important factor in this response.
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- DNA viruses
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Diversity of the a sequence of herpes simplex virus type 1 developed during evolution
More LessHerpes simplex virus type 1 (HSV-1) is a ubiquitous human pathogen. The a sequence of HSV-1 is the cis-acting site required for the cleavage and encapsidation of unit-length HSV-1 DNA from concatemeric forms. The consensus a sequence consists of (i) DR1 (direct repeat 1), (ii) Ub, (iii) a DR2 array [a repeat of various copy numbers of DR2 elements (11 or 12 bp)], (iv) a DR4 stretch and (v) Uc. In the present study, the nucleotide sequences of the a sequences of 26 HSV-1 isolates were determined and the DR4 stretches were classified into three groups. The state of a set of 20 DNA polymorphisms in the genomes of these HSV-1 isolates was determined previously. A correct classification rate of 100 % was achieved when discriminant analysis was performed between the DR4 stretch (criterion variable) and the set of 20 DNA polymorphisms (predictor variables), suggesting a close association of the DR4 stretch with HSV-1 diversification. DR2 elements of 9, 13 and 14 bp were detected in addition to those of 11 and 12 bp, and a correct classification rate of 93 % was achieved when discriminant analysis was performed between the DR2 array and the set of 20 DNA polymorphisms. Some DR2 elements of one HSV-1 isolate had the same nucleotide sequences as part of the adjacent DR4 stretch, and these variations were adequately explained by postulating recombination involving DR2 elements; hence, the DR2 array was deduced to be prone to recombination.
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Human cytomegalovirus serum neutralizing antibodies block virus infection of endothelial/epithelial cells, but not fibroblasts, early during primary infection
A panel of human sera exhibited a ≥128-fold higher neutralizing potency against a human cytomegalovirus (HCMV) clinical isolate propagated and tested in endothelial (or epithelial) cells than against the same virus infecting human fibroblasts. In a group of 18 primary infections, the reverse geometric mean titre was in the range of 10–15 in human fibroblasts within the first 3 months after the onset of infection, whereas the endothelial cell infection-neutralizing activity was already present within the first 10 days, reaching median levels of 122, 320 and 545 at respectively 30, 60 and 90 days after onset, then declining slowly. This difference was also confirmed in the majority of reactivated and remote HCMV infections, as well as in a hyperimmune globulin preparation. The antibody response to HCMV pUL131A, pUL130 and pUL128 locus products, which are required for endothelial/epithelial cell infection, provided a potential molecular basis for such a differential neutralizing activity. In addition, monoclonal/monospecific antibodies raised against the pUL131A, pUL130 and pUL128 proteins were found to display an inhibitory activity on HCMV plaque formation and HCMV leukocyte transfer from HCMV-infected cells. Hence, conventional determination of the neutralizing activity of human sera in fibroblasts is misleading. Antibodies to pUL131A, pUL130 and pUL128 appear to display a major HCMV-neutralizing and dissemination-inhibiting activity.
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Epstein–Barr virus nuclear antigen (EBNA) 3A induces the expression of and interacts with a subset of chaperones and co-chaperones
More LessViral nuclear oncoproteins EBNA3A and EBNA3C are essential for the efficient immortalization of B cells by Epstein–Barr virus (EBV) in vitro and it is assumed that they play an essential role in viral persistence in the human host. In order to identify cellular genes regulated by EBNA3A expression, cDNA encoding EBNA3A was incorporated into a recombinant adenoviral vector. Microarray analysis of human diploid fibroblasts infected with either adenovirus EBNA3A or an empty control adenovirus consistently showed an EBNA3A-specific induction of mRNA corresponding to the chaperones Hsp70 and Hsp70B/B′ and co-chaperones Bag3 and DNAJA1/Hsp40. Analysis of infected fibroblasts by real-time quantitative RT-PCR and Western blotting confirmed that EBNA3A, but not EBNA3C, induced expression of Hsp70, Hsp70B/B′, Bag3 and DNAJA1/Hsp40. This was also confirmed in a stable, inducible expression system. EBNA3A activated transcription from the Hsp70B promoter, but not multimerized heat-shock elements in transient transfection assays, consistent with specific chaperone and co-chaperone upregulation. Co-immunoprecipitation experiments suggest that EBNA3A can form a complex with the chaperone/co-chaperone proteins in both adenovirus-infected cells and EBV-immortalized lymphoblastoid cell lines. Consistent with this, induction of EBNA3A resulted in redistribution of Hsp70 from the cytoplasm to the nucleus. EBNA3A therefore specifically induces (and then interacts with) all of the factors necessary for an active Hsp70 chaperone complex.
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Essential role of PKCδ in histone deacetylase inhibitor-induced Epstein–Barr virus reactivation in nasopharyngeal carcinoma cells
Histone deactylase inhibitors (HDACi) are common chemotherapeutic agents that stimulate Epstein–Barr virus (EBV) reactivation; the detailed mechanism remains obscure. In this study, it is demonstrated that PKCδ is required for induction of the EBV lytic cycle by HDACi. Inhibition of PKCδ abrogates HDACi-mediated transcriptional activation of the Zta promoter and downstream lytic gene expression. Nuclear translocation of PKCδ is observed following HDACi stimulation and its overexpression leads to progression of the EBV lytic cycle. Our study suggests that PKCδ is a crucial mediator of EBV reactivation and provides a novel insight to study the regulation of the EBV lytic cycle.
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