- Volume 71, Issue 12, 1990
Volume 71, Issue 12, 1990
- Animal
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Inhibition of Primary Transcription of Vesicular Stomatitis Virus by Prostaglandin A1
More LessProstaglandin A (PGA) exhibits antiviral activity against RNA and DNA viruses. The effect of PGA, on vesicular stomatitis virus (VSV) was investigated. When VSV-infected L-1210 cells were kept in the presence of PGA 2 the amount of all five viral proteins and their respective mRNAs was dose-dependently decreased. To determine whether the effect was on viral transcription or translation, the temperature-sensitive VSV mutant tsG 41 was employed. This is a good model system for the investigation of primary transcription; at the restrictive temperature of 39 °C, tsG 41 is unable to replicate but can transcribe viral mRNA. Mutant mRNA synthesis was strongly inhibited by PGA, at this temperature, indicating that the major effect is on primary transcription. This conclusion is supported by data demonstrating that in vitro transcription of viral genomic RNA was also inhibited by PGA1
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Effect of Protein Kinase C Inhibitors on Interferon-β Production by Viral and Non-viral Inducers
More LessInduction of interferon-β (IFN-β) in human (BG-9), simian (CV-1) and mouse (L-929) cell lines by Sendai virus and by poly(rI). poly(rC) has been studied for its possible dependence on protein kinase C (PKC) through the use of pharmacological inhibitors (K252a and H-7) of PKC. Exposure of BG-9, CV-1 or L-929 cells to K252a (⩾0·025 μm), a staurosporine derivative, 24 h before or after induction of IFN with poly(rI).poly(rC), inhibited by >95% the production of IFN-β. In contrast, virus-induced IFN production was enhanced threefold or more by K252a in BG-9 and L-929 but not in CV-1 cells. A naphthalene sulphona-mide inhibitor of PKC, H-7, at ⩾5 μm, decreased poly(rI). poly(rC)-induced IFN production in BG-9 and CV-1 cells by 75 to 94%, but had no effect on IFN production in L-929 cells. Viral induction of IFN was not affected significantly by H-7 in BG-9, CV-1 and L-929 cells. In contrast to these results, the calmodulin inhibitor, trifluoperazine (5 to 15 μm) did not affect IFN-β production by poly(rI). poly(rC) but significantly enhanced IFN production by Sendai virus in both human and murine cell lines. Thus, in human and simian fibroblasts the induction of IFN-β by poly(rI).poly(rC) appears to be PKC-dependent, whereas viral induction of IFN-β is not. Results with K252a implicate PKC in non-viral induction of IFN in mouse fibroblasts, as well. Direct measurements of PKC activity in BG-9 cells exposed to several concentrations of K252a showed that the membrane PKC activity is significantly more sensitive to inhibition by K252a than is cytosolic PKC activity. In L-929 cells, K252a inhibited membrane PKC activity similarly, but was less effective as an inhibitor of cytosolic enzyme activity than in BG-9. These studies support an intregral role for PKC activity, particularly membrane-associated activity, in non-viral [poly(rI). poly(rC)] induction of IFN-β in human, simian and mouse fibroblasts.
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Characterization of the Infection Cycle of the Orgyia Pseudotsugata Multicapsid Nuclear Polyhedrosis Virus in Lymantria Dispar Cells
More LessTo characterize the infection cycle of the Orgyia pseudotsugata multicapsid nuclear polyhedrosis virus in Lymantria dispar cells, the time course of DNA synthesis and polyhedron production, and the onset and rate of budded virus production were investigated at three different m.o.i. (5,10 and 100). In addition, the time course of expression of three proteins (gp64, p39 and polyhedrin) representative of three temporal classes of baculovirus genes was also analysed using Western blot analysis. DNA synthesis began at 12 to 18 h post-infection (p.i.). The rate of budded virus (BV) production reached maximal levels at 24 to 36 h p.i. and continued at high levels indicating that BV production was not turned off late in infection. Polyhedra were first observed at 48 h p.i. The m.o.i. appeared to influence the magnitude but not timing of early events in the viral infection cycle (gp64 expression and DNA synthesis) and also influenced the initial levels of BV production and the percentage of cells containing occlusion bodies. The m.o.i. had little influence on the final rates of BV production and the time of detection of p39 and polyhedrin on Western blots.
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Localization of Adenovirus-encoded DNA Replication Proteins in the Nucleus by Immunogold Electron Microscopy
More LessThe distribution of three adenovirus-encoded DNA replication proteins in the nucleus of human 293 cells was studied by immunogold electron microscopy. The infected nuclei contained four morphologically distinct inclusions. They were highly electron-dense granules (type I), compact fibrogranular masses of medium electron density (type II), filamentous masses of low electron density (type III) and large polygonal crystals (type IV). In immunogold labelling studies, antibodies to the adenovirus single-stranded DNA-binding protein (DBP) and antibodies to single-stranded DNA showed extensive binding to the type III inclusions. The antibodies to the adenovirus DNA polymerase (AdPol) and terminal protein (TP) predominantly labelled type II inclusions. Double immunogold labelling studies detected low levels of AdPol and TP in type III inclusions and DBP in type II inclusions. The selective distribution of DNA replication proteins suggests that the type II and III inclusions represent two functionally different entities that may be involved in two different aspects of adenovirus DNA replication, i.e. chain initiation and elongation.
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Characterization of Antibody and Cytotoxic T Lymphocyte Responses to Human Influenza Virus H3 Haemagglutinin Expressed from the Haemagglutinin Locus of Vaccinia Virus
More LessAntibody and cytotoxic T lymphocyte (CTL) responses to the haemagglutinin (HA) of human H3N2 influenza virus were analysed, using recombinant vaccinia viruses containing the influenza HA gene inserted into the HA gene locus of vaccinia virus. The recombinant vaccinia viruses elicited a high haemagglutination inhibiting (HI) antibody response to the homologous influenza virus in mice. In addition, HI antibody generated by the recombinant vaccinia virus reacted with antigenic variants of human H3N2 influenza virus in a manner similar to that elicited by the HA vaccine. Mice with a high response to influenza virus HA vaccine were highly responsive to the HA expressed from the recombinant vaccinia virus, as measured by HI antibody production. The immunogenicity of the influenza virus HA expressed by the recombinant seems to be attributable to the intrinsic immunogenicity of the HA molecule. The recombinants primed mice for an influenza virus H3-specific CTL response and primed CTLs recognized the target cells in a subtype-specific manner. The results indicate that a recombinant vaccinia virus derived by the insertion of a foreign gene into its HA gene locus is a potent live vaccine not only for eliciting a high antibody response but also for priming a specific CTL response.
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Theiler’s Murine Encephalomyelitis Virus-binding Activity on Neural and Non-neural Cell Lines and Tissues
More LessThree categories of cell lines are described with respect to their activity in binding Theiler ’s murine encephalomyelitis virus (TMEV). High, medium and low densities of viral receptors can be detected on cell lines from different species and origins by using an immunological binding assay. Nevertheless, TMEV acts as a fastidious virus that only infects a few cell types productively. No correlation between virion binding and degree of permissiveness to infection could be detected. The presence of viral receptors in both susceptible and resistant strains of mice seemed to have a widespread tissue distribution, the thymus being an exception. When primary cerebral cultures, enriched in neurons, astrocytes or oligodendrocytes, were checked in the immunological assay, a higher density of viral receptors was detected in the neuronal population. The number of virus-binding sites in the BHK-21 cell line is reported here to be 5 × 103 per cell; approximately 15 × 103 and 2·5 × 103 are the estimates of binding sites per cultured neuron and macroglial cell, respectively.
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Analysis of the Fowlpox Virus Genome Region Corresponding to the Vaccinia Virus D6 to A1 Region: Location of, and Variation in, Non-essential Genes in Poxviruses
More LessThe DNA sequence of the fowlpox virus genome corresponding to the vaccinia virus D6 to A1 region has been determined. Translation of this sequence reveals fowlpoxvirus gene homologues corresponding to the D6, D7, D9, DIO, Dll, D12, D13 and A1 genes of vaccinia virus. In contrast, no gene homologue for the non-essential vaccinia virus D8 gene was present in fowlpox virus. Instead, a gene transcribed from the opposite strand to the vaccinia virus D8 gene showing no homology to any previously sequenced poxvirus gene was present. The amino terminus of the fowlpox virus D9 homologue had undergone substantial changes, including frameshifts which would be predicted to inactivate the gene. Insertion of a gene cartridge composed of the vaccinia virus p7 · 5 promoter and the lacZgene into the fowlpox virus D8, D9 and DIO genes in vitro, followed by recombination into fowlpox virus, was carried out. Stable insertion mutants with the correct genotype were obtained for D8 and D9 which, when tested in chickens did not appear to have been attenuated. No stable insertion mutants were obtained for DIO, indicating that this gene probably encodes a function which is essential for virus replication. The D8 and D9 genes of fowlpox virus represent useful insertion sites for the construction of recombinant fowlpox virus vaccines.
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A 39000 M r Immunodominant Protein of Fowlpox Virus Contains Multiple Copies of a 12 Amino Acid Repeat Sequence
More LessThe nucleotide sequence of an unusual fowlpox virus gene which maps immediately upstream from the fowlpox virus 4b gene has been determined. The 34000 M r protein predicted to be encoded by the gene contains 11 copies of a 12 amino acid serine-rich repeat sequence. The seven amino-terminal copies of the repeat sequence are perfectly conserved but variation exists in the four carboxy-terminal copies. Three peptides were synthesized which contained either one copy of the repeat sequence, two copies of the repeat sequence or a hydrophilic amino-terminal region of the protein. All three peptides when injected with adjuvant into rabbits gave rise to antibodies which reacted strongly on Western blots of purified fowlpox virus proteins with a 39000 M r protein. When directly compared in Western blots the antipeptide sera were shown to recognize a protein comigrating with one of the two immunodominant proteins recognized by chicken anti-fowlpox virus sera taken 2 weeks postinfection. The virion protein is removed by treatment with sodium deoxycholate suggesting that it is located at or near the surface of the virus.
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Glycosylation Governs the Binding of Antipeptide Antibodies to Regions of Hypervariable Amino Acid Sequence within Recombinant gp120 of Human Immunodeficiency Virus Type 1
More LessAntibodies raised to an overlapping series of peptides following the amino acid sequence of the external envelope glycoprotein (gpl20) of human immunodeficiency virus type 1 (HIV-1) recognize eight regions in recombinant gpl20 molecules. If the recombinant molecules are glycosylated, three of these regions show a reduced capacity to bind antibody. Of the other five regions, two are strain-specific and carbohydrate restricts antibody binding to their N-terminal flanks, and three can be recognized by antibodies in recombinant gpl20 from an unrelated strain of HIV-1. Antibodies in sera from HIV-l-infected patients bind at high levels to peptides from five regions of gpl20. Of these regions, two coincide with those recognized by antibodies raised to peptides. Four of the five epitopes recognized by the rat antipeptide sera whose ability to bind antibody is influenced most by glycosylation, and three of the five regions which induce high levels of antibodies in patients’ sera, contain putative glycosylation sites which are variable between strains of HIV-1. Such sites flank the putative neutralization and CD4-binding regions of gpl20. It is suggested that changes in the number and position of carbohydrate moieties following mutation can alternately mask and reveal epitopes. Masking an epitope can render a virus resistant to neutralization, whereas virus which binds antibody without being neutralized is able to gain entry to cells bearing antibody and complement receptors. Changes in the glycosylation pattern of gpl20 may therefore contribute to the control of HIV-1 spread within its host.
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Liposomes Modulate Human Immunodeficiency Virus Infectivity
We have investigated the effects of the fusion of liposomes with human immunodeficiency virus type 1 (HIV-1Lva) on the ability of the virus to infect CD4+ and CD4− cells. Fluorescence dequenching measurements indicated that HIV-1 fuses with liposomes composed of either cardiolipin (CL) or N-[2,3-(dioley- loxy) propyl]- N,N,N -trimethyl ammonium chloride (DOTMA) but not appreciably with dioleoylphospha- tidylcholine (DOPC) liposomes. Pre-incubation of HIV-1 with DOTMA liposomes enhanced virus production (measured by p24 gag antigen production in the culture medium and in situ) in CD4+ A3.01 and H9 cells in a concentration-dependent manner, but did not mediate the infection of the CD4− cell line, K562. Pre-incubation of HIV-1 with between 10 and 30 | μ m- DOTMA liposomes, and subsequent incubation with A3.01 cells, resulted in the production of about 30-fold greater levels of virus than controls. The presence of DOTMA liposomes during the incubation of A3.01 cells with HIV-1 enhanced the infectivity of the virus up to 90-fold compared to controls. Conversely, preincubation of HIV-1 with CL liposomes inhibited infection of A3.01 cells, dependent on the concentration of liposomes; DOPC liposomes did not alter the infectivity of the virus under any of the incubation conditions. Our results thus indicate that fusion of HIV-1 with liposomes alters the ability of the virus to infect its target cells.
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Measurement of Antibody-dependent Infection Enhancement of Four Dengue Virus Serotypes by Monoclonal and Polyclonal Antibodies
More LessAlthough its underlying mechanisms are poorly understood, data comparing each of the four dengue virus serotypes suggest that in vitro antibody-dependent infection enhancement is a reproducible and measurable phenomenon related to other serological measures of antibody-virus binding. Information characterizing infection enhancement may provide clues to disease pathogenesis for dengue and other viruses that exhibit antibody-enhanced infection. We propose criteria for the detection and quantification of in vitro antibody- dependent enhancement of flavivirus infection based on observations using all four dengue virus serotypes, macrophage-like cell lines and human peripheral blood monocytes, and various immune sera and monoclonal antibodies. It is proposed that antibody-dependent infection enhancement is defined by the following findings: (i) significantly increased virus production is measured in quantitative assays at different points on the growth curve; (ii) assays of the virus output of cells infected with mixtures of constant amounts of virus and serial dilutions of the pre-existing antibody source produce characteristic ‘enhancement profiles’ of rising and falling virus output over at least a 10−3-fold dilution range; (iii) for each enhancing antibody source the dilution producing maximal infection enhancement is related to other serological measures of binding to the envelope, or another virus component; (iv) infection enhancement is detected with different antibody sources and virus strains (when available) tested over a range of m.o.i.; (v) other causes of enhanced virus production are ruled out.
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Genetic Variation of Japanese Encephalitis Virus in Nature
More LessForty-six strains of Japanese encephalitis (JE) virus from a variety of geographic areas in Asia were examined by primer-extension sequencing of the RNA template. A 240 nucleotide sequence from the pre-M gene region was selected for study because it provided sufficient information for determining genetic relationships among the virus isolates. Using 12% divergence as a cutoff point for virus relationships, the 46 isolates fell into three distinct genotypic groups. One genotypic group consisted of JE virus isolates from northern Thailand and Cambodia. A second group was composed of isolates from southern Thailand, Malaysia, Sarawak and Indonesia. The remainder of the isolates, from Japan, China, Taiwan, the Philippines, Sri Lanka, India and Nepal, made up a third group. The implications of these findings in relation to the epidemiology of JE are discussed. Results of this study demonstrate that the comparison of short nucleotide sequences can provide insight into JE virus evolution, transmission and, possibly, pathogenesis.
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Epitope Analysis of the Envelope and Non-structural Glycoproteins of Murray Valley Encephalitis Virus
More LessPrevious studies have shown that antibodies produced against strategic flavivirus epitopes play an important role in recovery and immunity. Definition of the conformation and location of these epitopes and the degree of their conservation among flaviviruses is important to understanding the humoral response to flavivirus infection. In this study we have examined epitopes recognized by 14 monoclonal antibodies (MAbs) produced to the envelope (E) and nonstructural (NS1) proteins of Murray Valley encephalitis virus (MVE). These antibodies were analysed for specificity, neutralization, haemagglutination inhibition (HI) and competitive binding. We have identified six distinct epitopes on the E protein which are located in four non-overlapping domains. MAbs to epitopes in one domain neutralized virus, were specific for MVE and Japanese encephalitis virus, and reacted with epitopes resistant to reduction. Two other E domains, one specific to MVE and the other shared by all flaviviruses, also contained neutralization sites and were stabilized by disulphide bonds. The fourth domain on E was conserved among the flaviviruses, sensitive to SDS denaturation and did not induce neutralizing antibody. Studies with MVE NS1 MAbs revealed that they were mostly type-specific, unreactive with conserved epitopes, and unreactive in HI and neutralization tests. The six epitopes identified on NS1 did not overlap and represent antigenic domains either resistant or sensitive to reduction. Immunoblotting of viral proteins in MVE-infected C6/36 cells revealed two distinct forms of NS1 and high M r proteins of 97K and 108K that represented disulphide-linked heterodimers of E and NS1.
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Insertion of DNA Sequences at a Unique Restriction Enzyme Site Engineered for Vector Purposes into the Genome of Herpes Simplex Virus Type 1
More LessWe describe the construction of a novel herpes simplex virus (HSV) vector containing a unique XbaI restriction enzyme cloning site in an intergenic position in the short unique genome region. Sequences can be inserted at this site with high efficiency by ligation with XbaI-digested vector DNA. A series of plasmids has been designed for use with this vector. These allow protein coding sequences to be placed under the control of various transcriptional regulation signals and then isolated as XbaI fragments ready for insertion into the vector. The XbaI fragments also contain the β- galactosidase gene thereby facilitating selection of recombinant virus by screening for blue plaques. A variant of the vector has been made based on the temperature-sensitive (ts) mutant tsK, which expresses only immediate early (IE) genes at non-permissive temperatures. Chloramphenicol acetyltransferase was used as a reporter gene to assess the fidelity of expression of sequences cloned into this position. Under these circumstances IE and early HSV promoters were shown to behave as expected in both wild-type and ts vectors.
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The Herpes Simplex Virus Type 1 Alkaline Nuclease is Not Essential for Viral DNA Synthesis: Isolation and Characterization of a lacZ Insertion Mutant
More LessHerpes simplex virus type 1 (HSV-1) encodes a novel enzyme activity, the alkaline nuclease, whose precise role in the viral replication cycle remains obscure. The alkaline nuclease gene corresponds to the UL12 open reading frame, which is predicted to encode a protein of 626 amino acid residues. We describe the isolation and characterization of a null mutant of the gene for the viral alkaline nuclease in which 917 bp from the N- terminal half of the gene (corresponding to residues 70 to 375) were deleted and replaced by the insertional mutagen ICP6::lacZ. The resulting mutant virus, AN- 1, was propagated in helper cells (S22) which express the wild-type version of the alkaline nuclease gene. Mutant AN-1 growth in Vero cells is severely restricted, although small amounts of infectious virus are produced. On the other hand, wild-type levels of viral DNA and late viral proteins are expressed in virus AN- 1-infected Vero cells. These results indicate that the HSV-1 alkaline nuclease gene product is not essential for viral DNA synthesis but may play a role in the processing or packaging of viral DNA into infectious virions. Possible roles in the viral infectious cycle will be discussed.
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Identification and Characterization of the Virion Protein Products of Herpes Simplex Virus Type 1 Gene UL47
More LessWe have identified two encoded proteins with an antiserum raised against a synthetic oligopeptide corresponding to amino acids 671 to 684 of the predicted protein product of gene UL47 of herpes simplex virus type 1 (HSV-1). They have apparent Mrs of 82000 and 81000 and are both major virion components located in the tegument. The 82/8IK proteins were first detected in infected cells in minor amounts 6 h after infection at 37 °C but were later (from 10 h until 24 h after infection) present in large amounts. UL47 regulation was investigated using phosphonoacetic acid (PAA), an inhibitor of DNA synthesis: the amounts of the 82/8IK protein synthesized were compared with those of 65KDBP, an early gene product, and 21K/22K, a true late gene product. The data showed that UL47 is regulated as a true late gene.
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Inactivation of the Shutoff Gene (UL41) of Herpes Simplex Virus Types 1 and 2
More LessGene UL41 of herpes simplex virus type 1 (HSV-1) and the corresponding gene of HSV-2, which control the virion-mediated early suppression of cellular protein synthesis, have been inactivated by inserting a β- galactosidase expression cassette into their coding regions. The resulting recombinants grew well in tissue culture, although with the type 2 recombinant viral protein synthesis was slightly delayed. As a result of inactivation of UL41 host protein synthesis was not suppressed in the presence of actinomycin or early in normal infection, although it declined at a late stage. Polyribosomes were not broken down early in infection, cellular DNA synthesis was not inhibited and in the presence of cycloheximide stable alpha (immediate early) mRNA accumulated, in marked contrast to that of the parent HSV-2 strain. Comparison of the proteins of purified virions of HSV-1 and shutoff-defective recombinant virus revealed discrepancies consistent with the presence of the UL41 gene product in the enveloped virion.
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Equine Herpesvirus Type 1 Unique Short Fragment Encodes Glycoproteins with Homology to Herpes Simplex Virus Type 1 gD, gI and gE
More LessThe nucleotide sequence of a 6·4 kbp portion of the 10·6 kbp BamHI fragment D contained in the unique short region of the equine herpesvirus type 1 (EHV-1) genome has been determined. Analysis of this sequence revealed five open reading frames (ORFs), four complete and one incomplete, which were encoded by the same sense strand. Comparison of the EHV-1 DNA sequence with that encoding glycoproteins of other alphaherpesviruses has revealed no significant homologies. Comparison at the amino acid level, however, has demonstrated regions of significant sequence similarity between the three complete EHV-1 ORFs 2, 3 and 4, and the herpes simplex virus type 1 (HSV-1) glycoprotein gD encoded by the US6 gene, the HSV-1 glycoprotein gI encoded by the US7 gene and the HSV-1 glycoprotein gE encoded by the US8 gene, respectively. The interrupted ORF 5 was found to display partial homology with the HSV-1 US9- encoded protein, but no homology was found between the protein encoded by ORF 1 and other proteins. The three collinear EHV-1 ORFs encoding putative glycoproteins with homology to the HSV-1 glycoproteins were therefore designated EHV-1 gD, gI and gE, respectively. Moreover, further similarities were found between EHV-1 gD and pseudorabies virus (PRV) gp50, between EHV-1 gI and PRV gp63 and varicella- zoster virus (VZV) gpIV, and between EHV-1 gE and PRV gI and VZV gpI. It is concluded that EHV-1, PRV, HSV-1 and VZV encode homologous glycoprotein genes in the small unique components of their genomes and that the genetic organization of these regions is conserved.
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Herpesviral Deoxythymidine Kinases Contain a Site Analogous to the Phosphoryl-binding Arginine-rich Region of Porcine Adenylate Kinase; Comparison of Secondary Structure Predictions and Conservation
More LessTwelve herpesviral deoxythymidine kinases were examined for regions of sequence similarity by multiple alignment. Six highly conserved sites were observed. Site 1 corresponded to a glycine-rich loop that forms part of the ATP-binding pocket in porcine adenylate kinase (PAK), and site 5 corresponded to a region in PAK, located on one lobe of the cleft, that contains arginine residues that bind substrate phosphoryl groups. Site 3, consisting of the motif -DRH-, is thought to be involved in thymine/deoxythymidine recognition; site 4, which is nearby, probably participates in this function as well. The functions of sites 2 and 6 have not been identified. Secondary structure predictions were made by the Gamier method and averaged for each position in the multiple alignment. The structure predicted for all six sites was typically a short flexible region (turn or coil) at or adjacent to the site, flanked by rigid structures (helix or sheet) on either side.
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The Mechanism of the Antiherpetic Activity of Zinc Sulphate
More LessThe molecular mechanism of the effects of zinc ions against herpes simples virus (HSV) infection was investigated. Zinc sulphate (100 µm) in the culture medium of an HSV-infected African green monkey kidney cell line did not block viral DNA synthesis and, at this concentration, only moderate cytotoxic effects were observed in uninfected cells. Nevertheless, virus yields were reduced to less than 1 %0 of the control. Thus the long standing hypothesis that zinc might block multiplication of HSV by selective intranuclear inhibition of the viral DNA polymerase apparently has lost its validity. Inhibition of virus growth in the absence of severe cytotoxicity must therefore result from other effects of ZnSO4. Free virus is inactivated by 15 mm-ZnSO4 within a few hours of its addition. The inactivated virus is defective in the glycoprotein- dependent functions of penetration and, to some extent, adsorption. Electron micrographs show massive deposition of zinc onto virion components. In a virion, transmembrane transport of zinc ions is not expected and the established antiviral effect is therefore explained by an inhibition of virion glycoprotein function after non-specific accumulation of zinc into many virion membrane components.
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