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PubMed1984

Highly lytic and persistent lentiviruses naturally present in sheep with progressive pneumonia are genetically distinct.

Ovine and caprine lentiviruses share the capacity to induce slowly progressive and inflammatory diseases of the central nervous system (leukoencephalitis or visna), lungs (progressive pneumonia or maedi), and joints (arthritis) in their natural hosts. Studies on their replication indicated that ovine lentiviruses and caprine arthritis-encephalitis virus (CAEV) recently isolated in the United States establish persistent infection in ovine and caprine fibroblasts, whereas older prototype ovine lentiviruses such as Icelandic visna virus or American progressive pneumonia virus irreversibly lyse fibroblast cultures. Since all of the recent isolates were found to be persistent, Narayan et al. (J. Gen. Virol. 59:345-356, 1982) concluded that the highly lytic viruses were only tissue-culture-adapted strains. In the present report, we isolated new ovine lentiviruses from French sheep with naturally occurring progressive pneumonia which are either highly lytic (five isolates), as are the Icelandic strains of visna virus, or persistent (one isolate), as are CAEV or American persistent ovine lentiviruses. Protein and nucleic acid content analyses of these new highly lytic (type I) and persistent (type II) isolates indicated that type I and type II ovine lentiviruses were genetically distinct, type I and type II viruses being closely related to the Icelandic strains of visna virus and to CAEV, respectively. We conclude that (i) highly lytic ovine lentiviruses, such as the Icelandic prototype strains of visna virus and persistent lentiviruses more related to CAEV, are naturally present in the ovine species, and (ii) irreversible cell lysis induced by highly lytic viruses does not result from a tissue culture adaptation of field isolates that were originally persistent but is instead the consequence of a genetic content distinct from that of persistent viruses.

Animals↗
PubMed1995

Lytic infection of Escherichia coli biofilms by bacteriophage T4.

Escherichia coli 3000 XIII formed biofilms on the surface of polyvinylchloride coupons in a modified Robbins device. Bacteriophage T4D+ infected cells in the biofilm and replicated. It is commonly held that bacteriophage cannot infect surface-attached bacteria (biofilms) because such bacteria are protected by an exopolymeric matrix that binds macromolecules and prevents their diffusion into the biofilm. To our knowledge this is the first observation that a bacteriophage can infect and multiply within cells growing as a biofilm.

Bacteriolysis↗
PubMed2003

Negative regulation of mitotic promoting factor by the checkpoint kinase chk1 in simian virus 40 lytic infection.

Lytic infection of African green monkey kidney (CV-1) cells by simian virus 40 (SV40) is characterized by stimulation of DNA synthesis leading to bypass of mitosis and replication of cellular and viral DNA beyond a 4C DNA content. To define mechanisms underlying the absence of mitosis, the expression levels of upstream regulatory molecules of mitosis-promoting factor (MPF) were compared in parallel synchronized cultures of SV40-infected and uninfected CV-1 cells. The DNA replication/damage checkpoint kinase Chk1 was phosphorylated in both uninfected and SV40-infected cultures arrested at G(1)/S by mimosine, consistent with checkpoint activation. Following release of uninfected cultures from G(1)/S, Chk1 phosphorylation was lost even though Chk1 protein levels were retained. In contrast, G(1)/S-released SV40-infected cultures exhibited dephosphorylation of Chk1 in S phase, followed by an increase in Chk1 phosphorylation coinciding with entry of infected cells into >G(2). Inhibitors of Chk1, UCN-01 and caffeine, induced mitosis and abnormal nuclear condensation and increased the protein kinase activity of MPF in SV40-infected CV-1 cells. These results demonstrate that SV40 lytic infection triggers components of a DNA damage checkpoint pathway. In addition, chemical inhibition of Chk1 activity suggests that Chk1 contributes to the absence of mitosis during SV40 lytic infection.

Alkaloids↗
PubMed1995

Epstein-Barr virus replication within pulmonary epithelial cells in cryptogenic fibrosing alveolitis.

BACKGROUND: Cryptogenic fibrosing alveolitis (synonymous with idiopathic pulmonary fibrosis) is a clinically heterogeneous condition in which the precipitating factor is unclear. Both environmental and infective factors have been implicated. An association between Epstein-Barr virus (EBV) and cryptogenic fibrosing alveolitis was suggested over a decade ago by a study based on EBV serology, but the significance of this has been unclear. METHODS: Lung tissue obtained surgically from patients (n = 20) with cryptogenic fibrosing alveolitis was investigated for evidence of EBV replication and compared with lung tissue from 21 control patients. Fourteen of the 20 patients had received no specific therapy for cryptogenic fibrosing alveolitis at the time of biopsy. Monoclonal antibodies directed against the EBV viral antigens, EBV viral capsid antigen (VCA) and gp 340/220 antigen, which are expressed during the lytic phase of the EBV life cycle, were studied. RESULTS: Fourteen (70%) of the 20 patients with cryptogenic fibrosing alveolitis were positive for both EBV VCA and gp 340/220 compared with two (9%) of the 21 controls. In the patients with cryptogenic fibrosing alveolitis viral replication was localised to pulmonary epithelial cells using epithelial cell markers, and immunohistochemical analysis confirmed the staining to be within type II alveolar cells. CONCLUSIONS: This is the first report of in vivo EBV replication within epithelial cells of the lower respiratory tract in an immunocompetent human host. Furthermore, this suggests that EBV may be an immune trigger or contribute to lung injury in cryptogenic fibrosing alveolitis, thus offering a potential new avenue of treatment.

Adult↗
PubMed2006

Coronavirus infection of the central nervous system: host-virus stand-off.

Several viruses infect the mammalian central nervous system (CNS), some with devastating consequences, others resulting in chronic or persistent infections associated with little or no overt pathology. Coronavirus infection of the murine CNS illustrates the contributions of both the innate immune response and specific host effector mechanisms that control virus replication in distinct CNS cell types. Despite T-cell-mediated control of acute virus infection, host regulatory mechanisms, probably designed to protect CNS integrity, contribute to the failure to eliminate virus. Distinct from cytolytic effector mechanisms expressed during acute infection, non-lytic humoral immunity prevails in suppressing infectious virus during persistence.

Animals↗
PubMed2005

Complete genome sequence of bacteriophage T5.

The 121,752-bp genome sequence of bacteriophage T5 was determined; the linear, double-stranded DNA is nicked in one of the strands and has large direct terminal repeats of 10,139 bp (8.3%) at both ends. The genome structure is consistently arranged according to its lytic life cycle. Of the 168 potential open reading frames (ORFs), 61 were annotated; these annotated ORFs are mainly enzymes involved in phage DNA replication, repair, and nucleotide metabolism. At least five endonucleases that believed to help inducing nicks in T5 genomic DNA, and a DNA ligase gene was found to be split into two separate ORFs. Analysis of T5 early promoters suggests a probable motif AAA{3, 4 T}nTTGCTT{17, 18 n}TATAATA{12, 13 W}{10 R} for strong promoters that may strengthen the step modification of host RNA polymerase, and thus control transcription of phage DNA. The distinct protein domain profile and a mosaic genome structure suggest an origin from the common genetic pool.

Bacteriophages↗
PubMed2003

A mathematical model for the investigation of the Th1 immune response to Chlamydia trachomatis.

Chlamydia are bacterial pathogens of humans and animals causing the important human diseases trachoma, sexually transmitted chlamydial disease and pneumonia. Of the human chlamydial diseases, sexually transmitted disease caused by Chlamydia trachomatis is a major public health concern. Chlamydia trachomatis replicates intracellularly and is characterised by a complex developmental cycle. Chlamydia is susceptible to humoral and cell-mediated immunity. Here we investigate the Th1 cell-mediated immune response against Chlamydia-infected cells as the response changes over the chlamydial developmental cycle. We suggest a form for the immune response over one developmental cycle by modelling the change in the number of intracellular chlamydial particles and assume peptides are presented in proportion to the number of replicating forms of chlamydial particles. We predict, perhaps non-intuitively, that persistent Chlamydia should be induced and forced not to return to the lytic cycle. We also suggest that extending the length of the time of the lytic cycle will effectively decrease the required efficacy of the Th1 response to eliminate the pathogen. We produce plots of active disease progression, control and clearance for varying levels of Th1 effectiveness.

Chlamydia Infections↗
PubMedDate not supplied

The generation of human monocyte/macrophage cell lines.

The development of continuous murine macrophage-like cell lines has permitted direct and somatic cell genetic approaches to a variety of functions of murine mononuclear phagocytes. However, few, if any, human cell lines exist that have the general characteristics of macrophages, although a promonocyte line, U937, has been reported which can be induced to differentiate into non-dividing cells with macrophage-like properties. Although murine macrophage-like lines have been obtained by transformation with simian virus 40 (SV40), this technique has not, in general, been useful in producing human cell lines, presumably because SV40 causes a lytic infection in human cells. We have therefore developed a method for transfecting primary human monocytes with SV40 DNA deleted in the origin of replication. Using this method, we have now, we believe for the first time, generated transformed human cell lines with macrophage characteristics. Three cell lines from three transfections of human monocytes expressed macrophage enzymes, phagocytic function, surface receptors including HLA-DR and DS and alloantigen presenting activity.

Cell Line↗
PubMed1981

Kinetics of inhibition of papovavirus DNA synthesis by superinfection with adenovirus 2 and non-defective adenovirus 2-simian virus 40 hybrid viruses.

Simian Virus 40 (SV40) DNA synthesis is inhibited in monkey cells by superinfection with adenovirus 2 (Ad2) and various non-defective Ad2-SV40 hybrid viruses. Similarly, BKV (a human papovavirus) DNA synthesis is inhibited in human cells by superinfection with Ad2. Kinetic studies indicate that inhibition begins during the early phase of the Ad2 lytic cycle. Superinfection with Ad2 does not significantly alter the formation of SV40 T antigen. Superinfection with Ad2 late in SV40 lytic cycle is less efficient in the inhibition of SV40 DNA synthesis, and the onset of Ad2 DNA synthesis is delayed, compared to superinfection early in the SV40 lytic cycle. These findings suggest that the Ad2 and SV40 genomes may compete to bind an early AD2 protein which is essential for Ad2 replication, but which blocks SV40 replication.

Adenoviruses, Human↗
PubMed1989

Simian virus 40 host range/helper function mutations cause multiple defects in viral late gene expression.

Simian virus 40 (SV40) deletion mutants dlA2459 and dlA2475 express T antigens that lack the normal carboxy terminus. These mutants are called host range/helper function (hr/hf) mutants because they form plaques at 37 degrees C on BSC-1 and Vero monkey kidney cell lines but not on CV-1p monkey kidney cells. Wild-type SV40 can provide a helper function to permit growth of human adenoviruses in monkey kidney cells; the hr/hf mutants cannot. Progeny yields of hr/hf mutants are also cold sensitive in all cell lines tested. Patterns of viral macromolecular synthesis in three cell lines (Vero, BSC-1, and CV-1) at three temperatures (40, 37, and 32 degrees C) were examined to determine the nature of the growth defect of hr/hf mutants. Mutant viral DNA replication was similar to that of the wild type in all three cell lines, indicating that the mutations affect late events in the viral lytic cycle. In mutant-infected Vero cells, in which viral yields were highest, late mRNA levels were similar to those observed during wild-type infection. Levels of viral late mRNA from mutant-infected CV-1 and BSC-1 cells at 32 and 37 degrees C were reduced relative to those of wild-type-infected cells. The steady-state level of the major viral capsid protein, VP1, in mutant-infected CV-1 cells was reduced to the same extent as was late mRNA. The synthesis of agnoprotein could not be detected in mutant-infected CV-1 cells but was readily detected in CV-1 cells infected by wild-type SV40. Primer extension analyses indicated that most late mRNAs from mutant-infected CV-1 cells utilize start sites downstream from the major wild-type cap site (nucleotide 325) and the agnoprotein initiation codon (nucleotide 335). These results indicate that deletion of the carboxyl-terminal domain of T antigen affects viral late mRNA production, both quantitatively and qualitatively. The agnoprotein is detected late in the wild-type SV40 lytic cycle and is thought to play a role in the assembly or maturation of virions. Reduced hr/hf progeny yields could result from decreased capsid protein synthesis and, in the absence of detectable levels of agnoprotein, from inefficient use of available capsid proteins.

Amino Acid Sequence↗
PubMed1997

Effect of enforced expression of human bcl-2 on Japanese encephalitis virus-induced apoptosis in cultured cells.

Infection by Japanese encephalitis virus (JEV), a mosquito-borne flavivirus, causes acute encephalitis in humans and induces severe cytopathic effects in different types of cultured cells. This study attempted to determine whether apoptosis contributes to virus-induced cell death in a culture system by characterizing JEV lytic infection in baby hamster kidney BHK-21 cells, murine neuroblastoma N18 cells, and human neuronal progenitor NT2 cells. According to our results, the replication of JEV, and not the UV-inactivated virions per se, triggered apoptosis in these cell lines, as evidenced by nuclear condensation, DNA fragmentation ladder, and in situ end labeling of DNA strand breaks with terminal transferase (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling assay). Different strains of JEV, regardless of whether they are neurovirulent to mice, could induce apoptosis of the infected cells. In addition, enforced expression of the human protooncogene bcl-2 in BHK-21 cells, which did not influence virus production, appeared to delay the process of JEV-induced apoptosis, despite the fact that most infected cells were inevitably killed after prolonged cultures. However, Bcl-2 proteins expressed in N18 cells failed to block JEV-induced apoptosis, although they did prevent Sindbis virus-induced apoptosis from occurring in the same cells. This finding suggests that these two viruses may utilize similar but not identical mechanisms to kill their infected cells. The results presented here thus demonstrate that apoptosis can be a general mechanism for JEV-induced cell death and that enforced bcl-2 expression may be inadequate in protecting all cell types from JEV-induced apoptosis in cell cultures.

Animals↗
PubMed2002

Functional interaction between JC virus late regulatory agnoprotein and cellular Y-box binding transcription factor, YB-1.

Human polyomavirus JC virus (JCV) is a causative agent of progressive multifocal leukoencephalopathy which results from lytic infection of glial cells. Although significant progress has been made in understanding the regulation of JCV gene transcription, the mechanism(s) underlying the viral lytic cycle remains largely unknown. We recently reported that the JCV late auxiliary Agnoprotein may have a regulatory role in JCV gene transcription and replication. Here, we investigated its regulatory function in viral gene transcription through its physical and functional interaction with YB-1, a cellular transcription factor which contributes to JCV gene expression in glial cells. Time course studies revealed that Agnoprotein is first detected at day 3 postinfection and that its level increased during the late stage of the infection cycle. Agnoprotein is mainly localized to the cytoplasmic compartment of the infected cell, with high concentrations found in the perinuclear region. While the position of Agnoprotein throughout the infection cycle remained relatively unaltered, the subcellular distribution of YB-1 between the cytoplasm and nucleus changed. Results from coimmunoprecipitation and glutathione S-transferase pull-down experiments revealed that Agnoprotein physically interacts with YB-1 and that the amino-terminal region of Agnoprotein, between residues 1 and 36, is critical for this association. Further investigation of this interaction by functional assays demonstrated that Agnoprotein negatively regulates YB-1-mediated gene transcription and that the region corresponding to residues 1 to 36 of Agnoprotein is important for the observed regulatory event. Taken together, these data demonstrate that the interaction of the viral late regulatory Agnoprotein and cellular Y-box binding factor YB-1 modulates transcriptional activity of JCV promoters.

Binding Sites↗
PubMed2005

Herpesvirus pan encodes a functional homologue of BHRF1, the Epstein-Barr virus v-Bcl-2.

BACKGROUND: Epstein-Barr virus (EBV) latently infects about 90% of the human population and is associated with benign and malignant diseases of lymphoid and epithelial origin. BHRF1, an early lytic cycle antigen, is an apoptosis suppressing member of the Bcl-2 family. In vitro studies imply that BHRF1 is dispensable for both virus replication and transformation. However, the fact that BHRF1 is highly conserved not only in all EBV isolates studied to date but also in the analogous viruses Herpesvirus papio and Herpesvirus pan that infect baboons and chimpanzees respectively, suggests BHRF1 may play an important role in vivo. RESULTS: Herpesvirus papio BHRF1 has been shown to function in an analogous manner to EBV BHRF1 in response to DNA damaging agents in human keratinocytes. In this study we show that the heterologous expression of the previously uncharacterised Herpesvirus pan BHRF1 in the human Burkitt's lymphoma cell line Ramos-BL provides similar anti-apoptotic functions to that of EBV BHRF1 in response to apoptosis triggered by serum withdrawal, etoposide treatment and ultraviolet (UV) radiation. We also map the amino acid changes onto the recently solved structure of the EBV BHRF1 and reveal that these changes are unlikely to alter the 3D structure of the protein. CONCLUSIONS: These findings show that the functional conservation of BHRF1 extends to a lymphoid background, suggesting that the primate virus proteins interact with cellular proteins that are themselves highly conserved across the higher primates. Further weight is added to this suggestion when we show that the difference in amino acid sequences map to regions on the 3D structure of EBV BHRF1 that are unlikely to change the conformation of the protein.

Antineoplastic Agents↗
PubMed2001

Protein-DNA interaction and CpG methylation at rep*/vIL-10p of latent Epstein-Barr virus genomes in lymphoid cell lines.

The viral interleukin-10 promoter (vIL-10p), overlapping the rep* element in the Epstein-Barr virus (EBV) genome, is a promoter element active mostly in the late phase of the lytic cycle and immediately upon infection of B cells. rep* was, through transfection experiments with small plasmids, characterised as a cis element supporting oriP replicative function. In this study, in vivo protein binding and CpG methylation at rep*/vIL-10p were analysed in five cell lines that harbour strictly latent EBV genomes. Contrary to the invariably unmethylated dyad symmetry element (DS) of oriP, rep*/vIL-10p was highly methylated and showed only traces of protein binding in all examined cell lines. This result is in agreement with vIL-10p being an inactive promoter of EBV genomes, and makes it less likely that rep* functions as a replicative element of latent EBV genomes.

Base Sequence↗
PubMed1990

Evidence for poliovirus-induced cytoplasmic alkalinization in HeLa cells.

During the early period after poliovirus infection of HeLa cells, cellular Na+/K+ ATPase activity is transiently activated. We investigated the possibility that Na+/K+ ATPase activation is a consequence of Na+/H+ antiporter activation. Increased uptake of the weak organic acid 5,5-dimethyloxazolidine-2,4-dione by infected cells around 2 h after infection suggested cytoplasmic alkalinization equivalent to pH 7.7 during the biosynthetic phase of viral replication. Consistent with the involvement of Na+/H+ antiporter activation in this phenomenon, it was found to be [Na+]-dependent and inhibited by 5-(N-ethyl-N-isopropyl)amiloride (EIPA). However, the pH increase was not associated with an increase in amiloride-sensitive Na+ uptake by infected cells predicted by this mechanism. By contrast, the alkalinization could be abolished with the anion-exchange inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), implicating an anion-exchange mechanism, such as Cl-/HCO3- exchange, in this process. In addition to abolishing virus-induced intracellular alkalinization, both EIPA and DIDS moderately inhibited viral replication. Manipulation of intracellular pH with nigericin in the incubation medium revealed that maximum viral replication required a pH of about 7.7 and that replication was significantly inhibited even at pH 7.3. Thus, the pH increase in infected cells appeared to be physiologically relevant. These findings represent the first demonstration of a biologically meaningful pH increase in cells infected with a lytic virus.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2001

Rapid degradation of bacteriophage lambda O protein by ClpP/ClpX protease influences the lysis-versus-lysogenization decision of the phage under certain growth conditions of the host cells.

The initiator of bacteriophage lambda DNA replication, the O protein, is rapidly degraded in Escherichia coli by the ClpP/ClpX protease encoded by the host. Although the biochemical mechanism of this degradation has been investigated intensively, a physiological role for this process remained unknown since little effect of dysfunction of clpP and clpX genes on the lytic development of the phage was observed. Here we demonstrate that activities of clpP and clpX genes influence the lysis-versus-lysogenization decision of bacteriophage lambda under certain growth conditions of the host cells. This decision is influenced specifically by ClpP/ClpX-mediated O degradation and resultant inhibition of early lambda DNA replication because mutations in clpP and clpX genes have little effect on stability of other lambda proteins involved in the regulation of the phage developmental switch.

Adenosine Triphosphatases↗
PubMed1992

The interleukin-10 homolog encoded by Epstein-Barr virus enhances the reactivation of virus-specific cytotoxic T cell and HLA-unrestricted killer cell responses.

We determined what influence the Epstein-Barr virus (EBV)-encoded homologue of IL-10 (viral or vIL-10) had on immune responses important for the control of EBV infection. We produced recombinant vIL-10 in a B cell line. A 17-kDa recombinant protein was secreted and had the same molecular weight as vIL-10 secreted by EBV-infected B cells. Functional activity of recombinant vIL-10 was shown by the inhibition of interferon-gamma production by activated leukocytes. Cytotoxic T cells and HLA-unrestricted activated killer cells are both important arms of the immune response to EBV. vIL-10, either expressed by B cell stimulators or added exogenously, enhanced the in vitro reactivation of allo- and EBV-specific cytotoxic T cells. vIL-10 also enhanced the activation of HLA-unrestricted killer cells by EBV-transformed B cells. In contrast, the interleukin-2-mediated activation of these killers was unaffected. Since vIL-10 is expressed during the lytic cycle of EBV, we conclude that the expression of vIL-10 may enhance immune responses to EBV-infected cells during periods of virus replication in vivo. In this way, the virus may limit its own replication and maintain the apathogenic virus carrier state that is characteristic of EBV.

B-Lymphocytes↗