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PubMed1987

Evidence for a shift in 5'-termini of early viral RNA during the lytic cycle of JC virus.

We have used primer extension and S1 analysis to localize the 5'-termini of JC virus (JCV) early RNAs in infected primary human fetal glial cells at various times postinfection and in stable JCV-transformed hamster fetal glial cells. At early times postinfection (Days 1-5), two early transcripts are initiated at nucleotides 5122 and 5082. A major shift in 5'-ends at later times results in the synthesis of a new series of early mRNAs beginning upstream at nucleotide 35 and downstream at nucleotides 5047, 5037, and 5012. In the transformed hamster cells, however, only one RNA species was detected, starting at nucleotide 5122. The mechanism underlying the shift in the initiation site of JCV early RNAs during a lytic infection remains unclear but appears analogous to that which occurs in the SV40 lytic cycle. Since the shift occurs during DNA replication, when T-antigen is at maximal levels, it is possible that T-antigen binding to JCV DNA and/or alterations in chromatin structure contribute to this event.

Animals↗

PubMed1979

Cloning the argF gene from Escherichia coli K-12 with simian virus 40.

We have inserted a gene coding for ornithine transcarbamylase (OTCase) from Escherichia coli K-12 into the late gene region of simian virus 40 (SV40) DNA and propagated the hybrid molecules as free episomes or by co-infection with an SV40 tsA helper virus. In the first case, the E. coli argF gene was inserted via the EcoRI and BamHI termini in the late gene region of SV40 and the recombinant molecules were used to transfect monkey kidney cells. The hybrid DNA, which was too large to be encapsidated, was replicated for a short time (14 days) but was eventually lost from the surviving cells. In order to allow the argF gene to be packaged into virions, we purified two SV40 vectors containing large deletions of late gene region sequences. One was a 3325 base pair segment from a HaeII + BamHI digest. The argF gene was joined to both vectors at the BamHI site and these linear molecules were used to transfect monkey cells in the presence of SV40 tsA58 DNA as helper. These hybrid DNAs were replicated and packaged into virions. Late in the lytic infection of monkey cells, polyadenylated, cytoplasmic argF transcripts were detected, but significant translation of these trancripts was not observed.

Cloning, Molecular↗

PubMed2006

The Kaposi's sarcoma-associated herpesvirus ORF57 protein: a pleurotropic regulator of gene expression.

Herpesviridae comprises over 120 viruses infecting a wide range of vertebrates including humans and livestock. Herpesvirus infections typically produce dermal lesions or immune cell destruction, but can also lead to oncogenesis, especially with KSHV (Kaposi's sarcoma-associated herpesvirus). All herpesviruses are nuclear replicating viruses that subvert cellular processes such as nucleocytoplasmic transport for their advantage. For virus replication to take over the cell and produce lytic infection requires that virus gene expression outpace that of the host cell. KSHV ORF57 (open reading frame 57) appears to play a major role in this by (i) serving as a nuclear export receptor to carry intronless viral mRNAs out of the nucleus and (ii) inhibiting expression of intron-containing host mRNAs. As most of the virally encoded mRNAs are intronless compared with host cell mRNAs, these two mechanisms are critical to overcoming host gene expression.

Cell Nucleus↗

PubMed1991

Detection of anti-Epstein-Barr virus trans-activator (ZEBRA) antibodies in sera from patients with human immunodeficiency virus.

Patients with AIDS and AIDS-related complex often show symptoms of Epstein-Barr virus (EBV) reactivation. Several EBV-encoded trans-acting factors activate the EBV lytic cycle, and one, ZEBRA (BamHI Z EBV replication activator; also called EB1), switches EBV from its latent to productive cycle. Indirect immunofluorescence studies were done using human cells transfected with a recombinant DNA-harboring cDNA sequence spanning BZLF1 (BamHI Z left frame 1) that was inserted downstream of the adenovirus major late promoter. IgG anti-ZEBRA antibodies were detected in a high proportion of asymptomatic HIV carriers and in AIDS patients but were absent in healthy control individuals. The presence of anti-ZEBRA antibodies in the sera of HIV-positive patients favors the hypothesis that EBV reactivates in such subjects. This finding may be of practical importance in the prognostication of AIDS development.

Adult↗

PubMed1978

Infection of mouse liver by human adenovirus type 5.

CBA mice, inoculated intravenously with large doses of adenovirus type 5, showed raised levels of serum aspartate aminotransferase (SAAT; EC 2.6.I.I) and died within a few days from histologically demonstrable hepatic necrosis. After inoculation of I LD50, virus was rapidly taken up by the tissues where infectivity then declined greatly. Organ titres then increased about 100-fold by 48 h p.i. but, in the liver, which showed intranuclear inclusion bodies, and by electron microscopy, scattered intranuclear and intracytoplasmic adenovirions, the increase was 10000- to 100000-fold. P antigen was detected by single radial diffusion in liver extracts, and by immunofluorescence in 80% of liver cells at 36 h p.i. Hexon, penton base and fibre antigens appeared later and in fewer cells. The maximum amount of hexon, of demonstrable type 5 specificity, was shown by radioimmunoassay to be equivalent to up to 5 x 1011 whole adenovirions/g liver. It is concluded that human adenovirus type 5 undergoes an abortive but lytic infection in most liver cells but that replication may proceed to completion in a few.

Adenoviridae Infections↗

PubMed1997

Application and evaluation of the phage resistance- and bacteriocin-encoding plasmid pMRC01 for the improvement of dairy starter cultures.

The conjugative 63-kb lactococcal plasmid pMRC01 encodes bacteriophage resistance and production of and immunity to a novel broad-spectrum bacteriocin, designated lacticin 3147 (M.P. Ryan, M.C. Rea, C. Hill, and R.P. Ross, Appl. Environ. Microbiol. 62:612-619, 1996). The phage resistance is an abortive infection mechanism which targets the phage-lytic cycle at a point after phage DNA replication. By using the genetic determinants for bacteriocin immunity encoded on the plasmid as a selectable marker, pMRC01 was transferred into a variety of lactococcal starter cultures to improve their phage resistance properties. Selection of resulting transconjugants was performed directly on solid media containing the bacteriocin. Since the starters exhibited no spontaneous resistance to the bacteriocin as a selective agent, this allowed the assessment of the transfer of the naturally occurring plasmid into a range of dairy starter cultures. Results demonstrate that efficient transfer of the plasmid was dependent on the particular recipient strain chosen, and while high-frequency transfer (10(-3) per donor) of the entire plasmid to some strains was observed, the plasmid could not be conjugated into a number of starters. In this study, transconjugants for a number of lactococcal starter cultures which are phage resistant and bacteriocin producing have been generated. This bacteriocin-producing phenotype allows for control of nonstarter flora in food fermentations, and the phage resistance property protects the starter cultures in industry. The 63-kb plasmid was also successfully transferred into Lactococcus lactis MG1614 cells via electroporation.

Bacteriocins↗

PubMed1977

Selective inhibition of Bacillus subtilis sporulation by acridine orange and promethazine.

Two structurally similar compounds were found to inhibit sporulation in Bacillus subtilis 168. A dye, acridine orange, and an antischizophrenic drug, promethazine, blocked spore formation at concentrations subinhibitory to vegetative growth, while allowing synthesis of serine protease, antibiotic, and certain catabolite-repressed enzymes. The sporulation process was sensitive to promethazine through T2, whereas acridine orange was inhibitory until T4. The drug-treated cells were able to support the replication of phages phie and phi29, although the lytic cycles were altered slightly. The selective inhibition of sporulation by these compounds may be related to the affinity of some sporulation-specific genes to intercalating compounds.

Acridines↗

PubMed2005

Host gene expression changes and DNA amplification during temperate phage induction.

Salmonella enterica serovar Typhimurium LT2 harbors four temperate prophages. The lytic cycle of these phages was induced with hydrogen peroxide or mitomycin C. Microarray analysis was used to monitor the increase in phage genome copy number and the changes in RNA expression. Phage gene transcription was classified temporally, and host genes that responded to hydrogen peroxide, mitomycin C, or phage induction were also identified. A region of the serovar Typhimurium LT2 host genome encompassing hundreds of genes, flanking the Fels-1 lambdoid prophage, was amplified manyfold during lytic induction, presumably due to Fels-1 runoff replication prior to excision, a phenomenon termed escape replication. An excisionase (xis) mutant of Fels-1 also induced escape replication but did not get packaged. Gifsy-1, a lambdoid prophage that does not normally produce escape replication, did so after deletion of either its integrase or excisionase genes. Escape replication is probably widespread; large regions of host genome amplification were also observed after phage induction in serovar Typhimurium strains SL1344 and 14028s at the suspected integration site of prophage genomes.

DNA Nucleotidyltransferases↗

PubMed1980

New chimeric splice junction in adenovirus type 2-simian virus 40 hybrid viral mRNA.

We have examined hybrid viral RNAs synthesized in both human and monkey cells infected by three nondefective adenovirus type 2 (Ad2)-simian virus 40 (SV40) hybrid viruses; Ad2+ND1, Ad2+ND2, and Ad2+ND4. Most of the hybrid viral RNA molecules appeared to be initiated within adenoviral sequences, but were polyadenylated on their 3' end at the early SV40 mRNA polyadenylation site. The Ad2+ND4 stock of virus was not homogeneous, but consisted of two principle populations of viral DNA. Both populations contained a segment of SV40 DNA extending from the SV40 map positions 0.63 to 0.11 in a left-to-right orientation at adenovirus map position 0.82. One population contained an intact SV40 segment, whereas the other (representing 80 to 85% of the population) has a 500-base pair deletion mapping from approximately 0.60 to 0.50 SV40 map units. This deletion encompassed the SV40 DNA segment which encodes the early SV40 splice sites. Cells infected by the mixed Ad2+ND4 population induced the synthesis of at least three major SV40 RNA species among the hybrid viral transcripts. The most abundant of these hybrid mRNA's appeared only late in the lytic cycle, after the onset of viral DNA replication. It contained an RNA splice junction which extended from a donor (5') nucleotide within the adenoviral RNA sequences to an acceptor (3') splice site within the early region of SV40 at 0.46 SV40 map units. This SV40 acceptor splice site was remarkable in that its use has not been detected in the spliced viral mRNA's of SV40-infected or -transformed cells.

Adenoviridae↗

PubMed1997

Immediate early and early lytic cycle proteins are frequent targets of the Epstein-Barr virus-induced cytotoxic T cell response.

Epstein-Barr virus (EBV), a human gamma-herpesvirus, can establish both nonproductive (latent) and productive (lytic) infections. Although the CD8+ cytotoxic T lymphocyte (CTL) response to latently infected cells is well characterized, very little is known about T cell controls over lytic infection; this imbalance in our understanding belies the importance of virus-replicative lesions in several aspects of EBV disease pathogenesis. The present work shows that the primary CD8+ CTL response to EBV in infectious mononucleosis patients contains multiple lytic antigen-specific reactivities at levels at least as high as those seen against latent antigens; similar reactivities are also detectable in CTL memory. Clonal analysis revealed individual responses to the two immediate early proteins BZLF1 and BRLF1, and to three (BMLF1, BMRF1, and BALF2) of the six early proteins tested. In several cases, the peptide epitope and HLA-restricting determinant recognized by these CTLs has been defined, one unusual feature being the number of responses restricted through HLA-C alleles. The work strongly suggests that EBV-replicative lesions are subject to direct CTL control in vivo and that immediate early and early proteins are frequently the immunodominant targets. This contrasts with findings in alpha- and beta-herpesvirus systems (herpes simplex, cytomegalovirus) where viral interference with the antigen-processing pathway during lytic infection renders immediate early and early proteins much less immunogenic. The unique capacity of gamma-herpesvirus to amplify the viral load in vivo through a latent growth-transforming infection may have rendered these agents less dependent upon viral replication as a means of successfully colonizing their hosts.

Amino Acid Sequence↗

PubMed1988

Adeno-associated virus general transduction vectors: analysis of proviral structures.

We used two kinds of adeno-associated virus (AAV) vectors to transduce the neomycin resistance gene into human cells. The first of these (dl52-91) retains the AAV rep genes; the second (dl3-94) retains only the AAV terminal repeats and the AAV polyadenylation signal (428 base pairs). Both vectors could be packaged into AAV virions and produced proviral structures that were essentially the same. Thus, the AAV sequences that are required in cis for packaging (pac), integration (int), rescue (res), and replication (ori) of viral DNA are located within a 284-base-pair sequence that includes the terminal repeat. Most of the G418r cell lines (73%) contained proviruses which could be rescued (Res+) when the cells were superinfected with the appropriate helper viruses. Some produced high yields of viral DNA; other rescued at a 50-fold lower level. Most of the lines that were Res+ (79%) contained a tandem repeat of the AAV genome (2 to 20 copies) which was integrated randomly with respect to cellular DNA. Junctions between two consecutive AAV copies in a tandem array contained either one or two copies of the AAV terminal palindrome. Junctions between AAV and cellular sequences occurred predominantly at or within the AAV terminal repeat, but in some cases at internal AAV sequences. Two lines were seen that contained free episomal copies of AAV DNA. Res+ clones contained deleted proviruses or tandem repeats of a deleted genome. Occasionally, flanking cellular DNA was also amplified. There was no superinfection inhibition of AAV DNA integration. Our results suggest that AAV sequences are amplified by DNA replication either before or after integration and that the mechanism of replication is different from the one used during AAV lytic infections. In addition, we have described a new AAV general transduction vector, dl3-94, which provides the maximum amount of room for insertion of foreign DNA and integrates at a high frequency (80%).

Cell Line↗

PubMed1996

Similarities and dissimilarities of phage genomes.

Genomic similarities and contrasts are investigated in a collection of 23 bacteriophages, including phages with temperate, lytic, and parasitic life histories, with varied sequence organizations and with different hosts and with different morphologies. Comparisons use relative abundances of di-, tri-, and tetranucleotides from entire genomes. We highlight several specific findings. (i) As previously shown for cellular genomes, each viral genome has a distinctive signature of short oligonucleotide abundances that pervade the entire genome and distinguish it from other genomes. (ii) The enteric temperate double-stranded (ds) phages, like enterobacteria, exhibit significantly high relative abundances of GpC = GC and significantly low values of TA, but no such extremes exist in ds lytic phages. (iii) The tetranucleotide CTAG is of statistically low relative abundance in most phages. (iv) The DAM methylase site GATC is of statistically low relative abundance in most phages, but not in P1. This difference may relate to controls on replication (e.g., actions of the host SeqA gene product) and to MutH cleavage potential of the Escherichia coli DAM mismatch repair system. (v) The enteric temperate dsDNA phages form a coherent group: they are relatively close to each other and to their bacteria] hosts in average differences of dinucleotide relative abundance values. By contrast, the lytic dsDNA phages do not form a coherent group. This difference may come about because the temperate phages acquire more sequence characteristics of the host because they use the host replication and repair machinery, whereas the analyzed lytic phages are replicated by their own machinery. (vi) The nonenteric temperate phages with mycoplasmal and mycobacterial hosts are relatively close to their respective hosts and relatively distant from any of the enteric hosts and from the other phages. (vii) The single-stranded RNA phages have dinucleotide relative abundance values closest to those for random sequences, presumably attributable to the mutation rates of RNA phages being much greater than those of DNA phages.

Bacteriophages↗

PubMed2001

Perspectives on inducing efficient immune control of HIV-1 replication--a new goal for HIV therapeutics?

OBJECTIVES: A goal for long-term therapy of HIV infection is immune control of virus replication rather than the somewhat unrealistic aim of complete viral elimination. This paper will review the evidence that the control of viral infection can be achieved by an active CD8+ T-cell-mediated response. DESIGN: This review will draw on both experimental and clinical sources to discuss the potential mechanisms of the immune control. RESULTS: Data indicate that HIV infection can be effectively controlled by HIV-specific CD8+ T-cell-mediated responses. In infected individuals, the development of active cytotoxic T lymphocytes (CTLs, as measured by lytic activity) is associated with the control of viral replication. Within the simian immunodeficiency virus infection model in rhesus macaques, strong CTL responses are similarly associated with effective viral control. In addition, depletion by antibodies of CD8+ T cells within infected macaques results in rapid increases in viral load. However, in most HIV-infected individuals, the CD8+ T-cells response is inefficient at low antigen dose, probably due to the lack of an effective H V-specific CD4+ T-cell response. If this CD4+ T-cell response is lost due to viral induced anergy, rather than clonal deletion, such responses may be generated by interruptions in antiretroviral treatment, and/or therapeutic immunization in chronically infected patients. A strong immune response stimulated at low-antigen dose early during viral rebound may be critical in preventing accumulation of toxic viral products that might inhibit effective CD4+ T-cell responses. CONCLUSION: Immune control of HIV infection is a realistic goal. Understanding both the basic immune mechanisms of in vivo viral replication and identifying practical therapeutic regimens to activate HIV CD4+ and CD8+ T-cell responses may allow the development of efficient immune control of HIV replication in chronically infected patients.

Acquired Immunodeficiency Syndrome↗

PubMed1989

Epstein-Barr virus replication in interferon-treated cells.

The Burkitt's lymphoma-derived cell line Daudi is latently infected with the Epstein-Barr virus (EBV). These cells are very sensitive to the growth inhibitory and differentiation-inducing effects of human interferon-alpha (IFN) and we have examined the possibility that these responses are due to induction of EBV replication. Our results indicate that only a very small proportion of cells (less than 0.3%) are induced by IFN treatment to express EBV lytic genes at the RNA or protein level, whereas cell growth inhibition is complete under the same conditions. In contrast, when EBV replication is chemically induced the large increase in lytic gene transcripts, including that of the BZLF1 trans-activator gene, is partially inhibited by concomitant IFN treatment. The increase in viral DNA copy number in chemically induced Daudi cells is also partially inhibited by IFN but no effect of IFN on the level of viral DNA is observed in uninduced cells.

Burkitt Lymphoma↗

PubMed2006

Interaction of retinoblastoma protein family members with large T-antigen of primate polyomaviruses.

The retinoblastoma gene product pRb and other members of the Rb family of pocket proteins have a central role in the regulation of cell cycle progression. Soon after its discovery, pRb was found to interact with the transforming oncoproteins of DNA tumor viruses and this led to rapid advances in our understanding of the mechanisms of viral transformation and cell cycle progression. DNA viruses of the polyomavirus family have small, circular, double-stranded DNA genomes contained within non-enveloped icosahedral capsids and are highly tumorigenic in experimental animals. At least three types of polyomavirus infect humans: JC virus (JCV), BK virus (BKV) and Simian Vacuolating virus-40. The early region of these viruses encodes the transforming proteins large T-antigen and small t-antigen, which are involved in viral replication and also promote transformation of cells in culture and oncogenesis in vivo. Binding of T-antigen to pRb promotes the activation of the E2F family of transcription factors, which induce the expression of cellular genes required for S phase. In the context of lytic infection, this cell cycle progression is necessary for viral replication because polyomaviruses rely on S phase-specific host factors for their DNA synthesis. In the context of cellular transformation and tumorigenesis, T-antigen/pRB interaction is an indispensable event.

Animals↗

PubMed1980

Biological characterization of the virus causing leukoencephalitis and arthritis in goats.

This study describes the biological properties of a strain of virus isolated from tissues of a goat with leukoencephalomyelitis-arthritis. The agent is a retrovirus, having a virion-associated reverse transcriptase enzyme and an antigenic determinant(s) which cross-reacts with the p30 of visna-maedi viruses. Morphogenesis of the virus is also similar to visna virus in terms of virus assembly and the multinucleated giant cell formation which accompanies replication of the latter virus. Despite its cytopathogenic property the goat agent was not lytic in goat cell culture, causing instead a productive infection which persisted through multiple subcultures of the cells. The virus replicated incompletely in sheep cell cultures but could be rescued from the latter, weeks after inoculation, by co-cultivation with goat cells. Our data suggest that this strain of goat leukoencephalitis virus is a variant of the ovine retroviruses with a host range limited to the goat.

Animal Diseases↗

PubMed1988

Differences in cell-type-specific blocks to immediate early gene expression and DNA replication of human, simian and murine cytomegalovirus.

We have previously described blocks to the viral lytic cycle at two different levels in cytomegalovirus (CMV)-infected non-permissive cells. BALB/c-3T3 cells express only the predominant immediate early (IE) nuclear phosphoproteins (IE68 or IE94) of human CMV (HCMV) or simian CMV (SCMV) and do not replicate the input viral genomes. However, in human teratocarcinoma stem cells and 293 cells, expression of the HCMV IE68 gene (but not the SCMV IE94 gene) is blocked at the transcriptional level. Here we report the results of an extensive comparison of the level of permissiveness for HCMV, SCMV and murine CMV (MCMV) in a variety of additional cell types of human, monkey and mouse origin. We also describe a subtle change in the tryptic peptide pattern of the IE68 polypeptide produced in BALB/c-3T3 cells compared to permissive human foreskin fibroblasts. Neither the IE68 nor IE94 proteins could be detected by biochemical labelling procedures in infected mouse Ltk- or F9 teratocarcinoma stem cells, although IE94 was synthesized after retinoic acid-induced differentiation of the F9 cells. Synthesis of [35S]methionine-labelled IE94 protein, but not that of HCMV IE68, was detected in infected Vero cells and in human peripheral blood leukocyte cultures. The failure to synthesize detectable IE68 protein in infected Vero cells appeared to be unrelated to a lack of entry of viral DNA and to a lack of appropriate transcription factors. Indeed, immunofluorescence assays showed that the IE68 antigen was expressed efficiently in DNA-transfected Vero cells and in a small fraction of infected Vero cells. Overall, two clear host range trends emerged. First, whilst all three viruses showed a tendency for repression of IE expression in transformed cell lines, the effect was severe for HCMV and only minimal for SCMV. Secondly, progression of infection to the viral DNA synthesis level in non-transformed fibroblast cell types occurred in a much wider range of host species cell types for SCMV and MCMV than for HCMV.

Animals↗

PubMed1987

DNA-binding proteins of herpes simplex virus type 1-infected BHK cell nuclear matrices.

The nuclear matrix is involved in the replicative cycle of herpes simplex virus type 1 (HSV-1) and in at least some cases viral DNA has been shown to be closely associated with this structure. In this communication, we report the presence of five DNA-binding proteins in the nuclear matrix of HSV-1-infected BHK cells. These proteins (p114, p89, p77, p37 and p29) were detected by probing with 32P-labelled HSV DNA after Western blotting of nuclear matrix proteins. Three were identified as virion components: p89 as VP12, p77 as VP13 and p37 as the capsid protein VP22a. These polypeptides were detected in cells and nuclei and found to be associated with the nuclear matrix late during the lytic cycle, long after the onset of viral DNA replication. The nuclear matrix-binding capacity of VP22a depended on viral DNA replication, since after DNA polymerase inhibition it was still synthesized and transported into the nucleus but was no longer associated with the nuclear matrix. After inhibition of viral DNA synthesis, VP13 was no longer found in cells, nuclei or nuclear matrices. These results suggest a possible involvement in anchoring viral progeny DNA to the nuclear matrix.

Animals↗