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1
Delboy, Mark. "PROTEASOME-DEPENDENT ENTRY OF HERPES SIMPLEX VIRUS." VCU Scholars Compass, 2010. http://scholarscompass.vcu.edu/etd/47.
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Herpes simplex virus entry into cells is a multistep process that engages the host cell machinery. The proteasome is a large, ATP-dependent, multisubunit protease that plays a critical role in the maintenance of cell homeostasis. A battery of assays were used to demonstrate that proteasome inhibitors blocked an early step in herpes simplex virus entry that occurred after capsid penetration into the cytosol but prior to capsid arrival at the nuclear periphery. Proteasome-dependent viral entry was not reliant on host or viral protein synthesis. MG132, a peptide aldehyde that competitively inhibits the degradative activity of the proteasome, had a reversible inhibitory effect on herpes simplex virus capsid transport. Herpes simplex virus can use endocytic or nonendocytic pathways to enter cells. These distinct entry routes were both dependent on proteasome-mediated proteolysis. In addition, herpes simplex virus successfully entered cells in the absence of a functional host ubiquitin-activating enzyme, suggesting that viral entry is ubiquitin independent. Herpes simplex virus immediate-early protein ICP0 is a multifunctional regulator of herpes simplex virus infection. Late in infection ICP0 interacts dynamically with cellular proteasomes. ICP0 has a RING finger domain with E3 ubiquitin ligase activity that is necessary for its IE functions. The fundamental and functional properties of ICP0 that is present in the virion tegument layer have not been well characterized. For these reasons, I sought to characterize tegument ICP0 and determine the role of tegument ICP0 during proteasome-dependent entry of herpes simplex virus. Protein compositions of wild-type and ICP0 null virions were similar, suggesting that the absence of ICP0 does not grossly impair virion assembly. Virions with mutations in the RING finger domain contained greatly reduced levels of tegument ICP0, suggesting that the domain influences the incorporation of ICP0. Virion ICP0 was resistant to removal by detergent and salt and was associated with capsids, features common to inner tegument proteins. ICP0 mutations that resulted in the absence of ICP0 in the tegument layer, allow herpes simplex virus to enter cells independently of the proteasome activity. I propose that proteasomal degradation of virion and/or host proteins is regulated by ICP0 to allow for efficient delivery of incoming herpes simplex virus capsids to the nucleus.
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Wu, Zetang. "Silencing Suppression by Herpes Simplex Virus Type 1." The Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1213287215.
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Simmonds, Peter. "Detection of antibody responses to infection with herpes simplex virus and human immunodeficiency virus." Thesis, University of Edinburgh, 1988. http://hdl.handle.net/1842/26933.
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Targett-Adams, Paul. "Characterisation of the HSV-1 DNA packaging protein encoded by the UL25 gene." Thesis, University of Glasgow, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.368523.
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Yirrell, D. L. "Double infections with HSV in the mouse." Thesis, University of Bristol, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.234887.
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Dalrymple, M. A. "The regulation of herpes simplex virus immediate early gene expression." Thesis, University of Glasgow, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.378173.
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Grapes, Matthew Giles Robert. "Analysis of transcriptional activation by the HSV-1 protein VP16 and its EHV-1 homologue." Thesis, Imperial College London, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.325048.
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Leslie, Jenny. "An investigation into factors that influence the incorporation of proteins into the HSV-1 tegument." Thesis, University of Glasgow, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.297029.
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Leddon, Jennifer. "Oncolytic Herpes Simplex Virus Therapy for the Treatment of Pediatric Rhabdomyosarcoma." University of Cincinnati / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1427980753.
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Collins, Terry Cordell. "The effect of HSV-2 infection on the expression of cellular mitochondrial aspartate aminotransferase." Thesis, University of Glasgow, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.266539.
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Boutell, Christopher John. "Characterisation of the herpes simplex virus type 1 (HSV-1) triplex proteins." Thesis, University of Glasgow, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326428.
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Ramaswamy, Meghna. "The epidemiology and natural history of genital herpes simplex virus (HSV) infection." Thesis, University College London (University of London), 2006. http://discovery.ucl.ac.uk/1445811/.
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Genital infection with herpes simplex virus type 2 (HSV -2) is increasingly common worldwide. The aims of this thesis were to investigate the epidemiology and natural history of genital herpes among GUM attendees with symptomatic genital herpes, and among HIV-l infected individuals. In our study of GUM attendees in the UK, we demonstrated HSV -1 to account for 9% of first episodes of genital herpes. These findings are in contrast with observations made elsewhere in the UK, where HSV -1 has accounted for >50% of first-episode cases. As most individuals with genital HSV -2 infection remain clinically misdiagnosed, the need for improved diagnostic methods to detect genital HSV infection is warranted. We compared the performance of virus culture and PCR in patients clinically diagnosed with genital herpes. PCR increased HSV detection in patients with both early and late presentations and in first and recurrent diseases. PEG precipitation was the most sensitive specimen preparation method of choice. A HSV positive PCR was also associated with heterosexuals, early presentation, and visible genital ulceration. HSV -1 and HSV -2 genital infections were also associated with white and black ethnicity respectively. This suggests that host susceptibility and behavioural factors may influence the epidemiological patterns of genital herpes. Current data support the use of HSV type-specific serology and PCR to diagnose HSV infections. In addition to PCR, we evaluated the performance of type-specific serology (HerpeSelect EIA, Focus Technologies, Cypress, California, USA) for the diagnosis of HSV infection. Our findings indicated that increasing the assay cut-off from 1.1 to 3.1 increased specificity and maintained sensitivity. By performing an inhibition EIA using an inhibition value of ~60% we minimised false positive results from Ugandan and Kenyan sera. Recent data has implicated HSV-2 as a co-factor in HIV transmission. We therefore investigated the seroepidemiology of HSV infection among 850 HIV-infected individuals. HSV-2 seroprevalence was 63% and increased with age and was associated with female gender, heterosexuals and black ethnicity. A follow-up of 123 HSV-2 seronegative persons revealed a HSV -2 seroconversion rate of 10% which was associated with HPV infection and gonorrhoea. Only 21 % of the seroconverters received a clinical diagnosis of genital herpes, and this was more likely in persons diagnosed HIV -1 positive before 1997 (preHAART era). To investigate the effects of HAART on HSV-specific immunity, we studied the kinetics of HAART-induced reconstitution of HSV-specific T-cell responses in HIV-l infected persons at different stages of clinical disease using an ELISPOT assay. Successful HAART proved to resolve HSV-specific immunity restoration which coincided with HAART-induced CD4 gain. HSV-specific IFN-y responses correlated with CD4 counts. Responses similar to those of HIV -negative healthy controls were seen at CD4 counts >450 cells/mm3.
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Orzalli, Megan Jenkins. "Inhibition of Nuclear DNA Sensing by Herpes Simplex Virus 1." Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:10779.
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The detection of immunostimulatory DNA is well documented to occur at several cellular sites, but there is limited evidence of nuclear innate DNA sensing. Prior to this study, the detection of herpesviral DNA was thought to be restricted to the cytosol so as to limit the sensing of host DNA in the nucleus. However, given the nuclear lifecycle of these viruses, we hypothesized that viral DNA could be sensed in the nucleus of infected cells. To test this hypothesis we examined the activation of interferon regulatory factor 3 (IRF-3) in response to herpes simplex virus 1 (HSV-1) infection of primary human foreskin fibroblasts (HFF). Using a mutant defective for expression of all viral genes, we observed that the release of viral DNA into the nucleus is necessary to activate IRF-3 signaling. Furthermore, we determined this response to be dependent on nuclear-localized interferon inducible protein 16 (IFI16) and the cytoplasmic stimulator of interferon genes (STING) adaptor protein.
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Caplinger, John N. "MematineHCI and Amino-Alkyl-Cyclohexanes (621,625) Inhibit HSV-1 in SK-N-SH Neuronal Cells." Youngstown State University / OhioLINK, 2001. http://rave.ohiolink.edu/etdc/view?acc_num=ysu1007757941.
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Arone, Blanco Maria. "Effects of herpes simplex virus 1 (HSV-1) infection on nuclear amyloid aggregation." Thesis, KTH, Skolan för kemi, bioteknologi och hälsa (CBH), 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-231319.
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Huntington’s disease (HD) and Spinocerebellar ataxia (SCA) are incurable neurodegenerative diseases that affect the central nervous system. Amyloids, highly organized protein aggregates, are a hallmark for many neurodegenerative diseases. The presence and accumulation of amyloids are toxic and constitute the major cause of neuron cell death. Both genetic and environmental factors contribute to the onset and progression of these diseases. However, despite intensive research, the underlying cause remains unclear. The role of viral infection as an environmental factor in the context of neurodegenerative diseases has not received much attention. The purpose of this study is to investigate the effects of Herpes Simplex Virus 1 (HSV-1) infection on nuclear amyloid aggregation in model cell lines of HD and SCA. The research process consists mainly of laboratory work which involved the use of several molecular techniques used in the field of biotechnology. The work comprises cultivating cells, infecting cells with HSV-1, Fluorescence microscopy, Western Blot and isolation and detection of amyloids. Western Blot is used for the analysis of specific proteins associated with protein aggregation in HD and SCA. The techniques used for detecting amyloids are Dot Blot and Antibody-staining of amyloids in cells. The results from Western Blot showed that aggregates changed in the presence of the virus. This pattern is observed for both HD and SCA1 cell lines. A big effort is done in this study to optimize Dot Blot as it is method that could be applied in every lab. Normalization of samples proved to be the most challenging part with Dot Blot. No definitive conclusions can be drawn from the Dot Blot results as reproducibility and sensitivity were lacking. This work addresses some of the difficulties encountered when working with detection of amyloids especially Dot Blot. Antibody-staining of amyloids showed that amyloids were formed in the presence of virus in comparison to non-infected. To conclude, aggregates changed, and amyloids were formed in the presence of virus. These results point to the fact that HSV-1 infection could be involved in the process of nuclear amyloid aggregation. The data presented in this thesis will need further investigation and characterization to identify the precise role of viral-induced amyloid formation in HD and SCA patient cells.Huntingtons sjukdom (HD) och Spinocerebellära ataxier (SCA) är obotliga neurodegenerativa sjukdomar som påverkar det centrala nervsystemet. Amyloid, proteinaggregat som har en viss konformation är ett kännemärke för många neurodegenerativa sjukdomar. Ackumulering av dessa amyloider är toxiskt och är den främsta orsaken till att nervceller dör. Både genetiska faktorer och miljöfaktorer bidrar till uppkomsten och progressionen av dessa sjukdomar. Trots intensiv forskning är den bakomliggande orsaken emellertid fortfarande oklar. Virusinfektion som en potentiell miljöfaktor har i detta sammanhang inte fått mycket uppmärksamhet. Syftet med denna studie är att undersöka effekterna av Herpes Simplex Virus 1 (HSV-1) infektion på amyloid aggregering i modellcellinjer av HD och SCA. Forskningsarbetet bestod i huvudsakligen av experimentellt arbete med hjälp av flera molekylära tekniker inom bioteknikområdet som cell odling, infektering av celler med HSV-1, fluorescensmikroskopi, Western Blot och isolering och detektion av amyloider. Western Blot användes for att analysera specifika proteiner associerade med protein aggregering i HD och SCA. Amyloider detekterades med Dot Blot och med antikroppar specifika för amyloider. Resultat från Western Blot visade att amyloiderna förändras i virusinfekterade celler. Detta mönster observerades i både HD and SCA1 cellinjer. En stor bemöda görs i denna studie för att optimera Dot Blot eftersom det är en metod som kan användas i alla laboratorier. Normalisering visade sig vara det svåraste med detektion av amyloider. Inga definitiva slutsatser kan dras från dessa experiment, eftersom reproducerbarhet och känslighet var bristande. Detta arbete tar upp några av de svårigheter som uppstod vid arbetande med detektion av amyloider speciellt Dot Blot. Detektion av amyloider med antikropp visade att amyloider bildades till stor utsträckning i infekterade cellinjer i jämförelse med icke-infekterade. Sammanfattningsvis, amyloider förändrades och amyloider bildades i närvaro av virus. Dessa resultat indikerar på att HSV-1 infektion skulle kunna vara involverad i processen av amyloid aggregering. De presenterade uppgifter i detta examensarbete är preliminära och behöver följas upp med ytterligare studier för att identifiera virusens exakta roll i amyloid bildning i HD och SCA patient celler.
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Stoner, Terri Dorene. "Indole-3-Carbinol Inhibition of Herpes Simplex Virus Replication." Kent State University / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=kent1228328838.
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Hutchinson, Lloyd M. "Glycoprotein K of herpes simplex virus (HSV), role in viral egress and HSV-induced cell-cell fusion." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape16/PQDD_0016/NQ30094.pdf.
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Ahmed, Md Firoz. "Studies of viral and cellular proteins involved in herpes simplex virus type-1 egress." Thesis, University of Cambridge, 2019. https://www.repository.cam.ac.uk/handle/1810/288270.
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The egress pathway of herpes simplex virus-1 (HSV-1) is a complicated process mediated by co-ordinated activity of several virus glycoproteins. The virions are first assembled and enveloped at trans-Golgi-network (TGN) or endosome membranes and then travel through a guided pathway that is directed towards the cell adherent points for secretion. Once secreted the vast majority of virions remain associated with the extracellular membrane of cells and very few free virions are released into the culture medium (< 1%). The mechanisms that mediate both the targeted secretion of newly assembled virions at cell contact points and post-secretion attachment of virions with the extracellular surface of cells are poorly understood, and were the topics of this research. In this thesis, an HSV-1 passage mutant of increased virion secretion phenotype had been studied. Genome sequencing of the mutant virus identified mutations in three viral envelope proteins. Study of recombinant viruses that were constructed based on those three mutations revealed that a single amino acid change in glycoprotein I (gI) of glycine to arginine at residue 39 is responsible for the increased release of virus. The result suggests the principal effect of this mutation is to modify the secretory pathway used by virions during their release from infected cells. Data also suggests a role of gC in the attachment of virions to the extracellular surface of cells after egress. In the context of HSV-1 envelopment and egress glycoprotein E (gE), which forms a heterodimeric complex with gI (gE/gI), is known to be important. The gE/gI complex has been shown to interact with many tegument proteins and have a redundant role in secondary envelopment. The gE/gI complex has been also proposed to colocalise with various cellular components and sort the nascent virions to cell contact points. However, there is little understanding of the cellular proteins that gE/gI interact with, or the mechanisms that mediate targeted secretion of virions. This research has identified a novel interactome of gE/gI by mass-spectrometric analysis utilising stable isotope labelling with amino acids in cell culture (SILAC) medium. Among the cellular interactome obtained, Nipsnap1 was validated by co-precipitation assays from both infected and transfected cells, and furthermore using cell free systems, suggesting gE and Nipsnap1 directly interact. Nipsnap1 and its homologue Nipsnap2 have been proposed to contribute in vesicle transport and membrane fusion in cells. Using CRISPR-Cas9 technology these proteins were knocked out in a keratinocyte cell line (HaCaT) to investigate their role in HSV-1 egress. However, little or no effect on HSV-1 egress could be observed upon loss of either or both of these proteins suggesting the biological significance of gE-Nipsnap1 interaction may not be directly linked to any egress function of gE/gI. Two further interesting 'hits' from the gE/gI interactome were interferon-induced transmembrane protein type-2 (IFITM2), a virus restriction factor, and Myoferlin that has a putative role in endocytic vesicle recycling. This study could validate gE-Myoferlin interaction and co-localisation in infected or transfected cells however, functional significance of this interaction remains to be determined. Overall, the research of this thesis has provided a better understanding of the role of the gE/gI complex in HSV-1 egress and investigated the role of some interesting cellular proteins in the context of virion egress.
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Mbopi-Keou, Francois-Xavier. "The role of Herpes simplex virus type 2 (HSV-2) as a cofactor in HIV transmission." Thesis, Open University, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.247049.
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Deback, Claire. "Variabilité génétique des virus herpès simplex : épidémiologie moléculaire et résistance aux antiviraux." Paris 6, 2009. http://www.theses.fr/2009PA066155.
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La variabilité génétique des virus herpes simplex 1 (HSV-1) et 2 (HSV-2) a été étudiée sur le plan épidémiologique et sur celui de leur résistance aux antiviraux. Dans une première partie, nos travaux portent sur la pneumopathie herpétique (HSV BPn). Lors d’une étude clinique prospective chez des patients intubés et ventilés, 42 patients (21%) ont présenté une HSV BPn Une association significative a été montrée entre la présence d’HSV-1 dans l’oropharynx et l’ HSV BPn. L’analyse moléculaire montre que les HSV BPn font suite à la réactivation d’HSV-1 dans l’oropharynx, sans transmission nosocomiale. Dans une seconde partie, un test de sensibilité aux antiviraux des HSV par PCR en temps réel a été mis au point. Ce test est corrélé avec la technique de réduction des plages de lyse pour l’aciclovir et le foscarnet, mais ne l’est pas pour le cidofovir (CDV). L’analyse phénotypique et génotypique des souches d’HSV-2 isolées de patients ayant présenté une résistance clinique au cidofovir, a révélé que des mutations de l’ADN polymérase, cible du CDV, n’étaient pas en cause, faisant envisager la possibilité d’une autre cible virale.
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Heid, Andreas. "Baculovirus-vermittelte transiente Genexpression in Herpes-simplex-Virus-Typ-1(HSV-1)-infizierten Säugerzellen." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=970212208.
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Maric, Martina. "Identification of cellular factors involved in herpes simplex virus type 1 nucelar egress." Diss., University of Iowa, 2012. https://ir.uiowa.edu/etd/3346.
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The herpesvirus life cycle involves a step where newly formed capsids leave the nucleus by translocating across the intact nuclear envelope (NE). Little is known about the role of cellular factors during nuclear egress. We sought to identify novel cellular proteins that interact with the conserved herpes simplex virus-1 (HSV-1) pUL34 by performing a yeast two-hybrid screen. pUL34 was chosen due to its crucial and multifunctional role during nuclear egress. From 42 cellular factors that interacted with pUL34 in yeast, twelve were further evaluated in mammalian cells by co-localization studies using immunofluorescence. No specific co-location between the tested cellular factors and pUL34 was observed in infected cells, thus the screen failed to convincingly identify novel pUL34 interactors. In the second part of the thesis we addressed the functional significance of the cellular protein torsinA (TA) in the HSV-1 life cycle. We became interested in TA due to its role in maintaining normal NE morphology. We showed that perturbing the normal function of TA through overexpression impaired HSV-1 replication and caused a defect in capsid nuclear egress. In mouse embryonic fibroblasts that failed to express TA (TA-/-MEFs), HSV-1 replication was also inhibited, but a defect in capsid nuclear egress was not apparent. Strikingly, infection in TA-null MEFs induced a NE breakdown, the extent of which was dependent on viral products involved in nuclear egress. The viral growth defect and NE envelope breakdown, however, seem to be TA-null cell line specific rather than a functional consequence of TA loss as indicated by TA-/-MEFs reconstituted with TA and 293T with reduced TA levels. In conclusion, overexpression and loss of TA have different effects on the HSV-1 life cycle.
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Lau, Sheung-Yee Kathy. "The trafficking of viral and host membrane proteins during HSV-1 assembly." Thesis, University of Cambridge, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708835.
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Owen, Danielle. "Investigating the structure and function of HSV-1 tegument proteins, UL7 and UL51." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/278659.
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Herpes simplex virus-1 (HSV-1) has a large double-stranded DNA genome encased within an icosahedral capsid. The capsid is surrounded by a protein-rich layer, termed tegument, and a membranous envelope containing viral glycoproteins. HSV-1 genome replication and encapsidation occurs in the nucleus, after which, DNA-loaded capsids enter the cytoplasm where they undergo tegumentation and assembly. This thesis presents a structural and functional investigation of two HSV-1 tegument proteins, UL7 and UL51 that are conserved across all herpesviruses. Deletion of UL7 or UL51 results in impaired viral replication, a small plaque phenotype and an accumulation of unenveloped capsids in the cytoplasm, the latter of which is indicative of a defect in tegumentation and/or secondary envelopment. Similar phenotypes have been observed upon deletion of homologous proteins in pseudorabies virus and human cytomegalovirus, suggesting a conserved role for these proteins. This thesis presents evidence for the formation of a UL7-UL51 complex in transfected and infected cells. Pull-down experiments using recombinant UL7 and UL51 protein purified from E. coli demonstrated that the interaction is direct, and mapped the UL7-binding region within UL51. The interaction was shown to be conserved between UL7 and UL51 homologues from murid herpesvirus, ORF42 and ORF55, respectively. The UL7-UL51 complex was purified from E.coli and, after optimisation of the purification protocol and the UL51 construct, a pure protein sample was obtained that was suitable for crystallisation trials. Two conditions were identified that produced reproducible crystals. These crystals proved to be thin and fragile, preventing their analysis by X-ray diffraction. Optimisation of the crystallisation conditions to produce more robust crystals and/or in situ diffraction measurements may yet yield X-ray diffraction data for the complex. Host-cell binding partners for UL7 and UL51 were identified by yeast-two-hybrid screen and quantitative proteomics (SILAC). An interaction between UL51 and the G-Box domain of the centriole protein CPAP was identified by Y2H screen, and validated by immunoprecipitation from transfected cells and in pull-down experiments using recombinant proteins purified from E. coli. The CPAP-binding region within UL51 was mapped and shown to resemble a motif present in the cellular protein STIL that mediates an interaction between STIL and CPAP. Two UL51 point-mutations within the putative CPAP-binding motif blocked the interaction between UL51 and the CPAP G-box domain. A mutant HSV-1 virus carrying these UL51 mutations was generated, but no difference was evident between single-step growth curves of wild-type HSV-1 and the UL51 mutant. Host-cell proteins pontin and reptin were identified as putative UL7/UL51 interaction partners in two SILAC screens. Purified GST-tagged UL7-UL51 complex was able to interact with pontin and reptin. However, it is likely that the interaction is non-specific since pontin and reptin were also found to bind a misfolded protein in a similar manner.
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Chatterjee, Somik. "STRUCTURE-FUNCTION ANALYSIS OF THE VIRULENCE PROTEIN ICP34.5 FROM HERPES SIMPLEX VIRUS TYPE 2." Kent State University / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=kent1248108386.
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Ren, Yudan. "Glycoprotein M and ESCRT in herpes simplex virus type 1 assembly." Thesis, University of Cambridge, 2012. https://www.repository.cam.ac.uk/handle/1810/241516.
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Herpes simplex virus type 1 (HSV-1) has a large linear double-stranded DNA genome in an icosahedral capsid shell, a cell-derived lipid envelope and a proteinaceous tegument layer. There are over fifty viral proteins and many host proteins identified in HSV-1 virions. The final formation of mature virus particles requires the membrane wrapping of tegumented capsids in the cytoplasm, a process termed secondary envelopment. This process involves the coordination of numerous viral and cellular proteins and results in double-membrane structures with enveloped virions contained within cellular vesicles. Mature viruses are then released through the fusion of these virion-containing vesicles and plasma membranes. This thesis describes investigation into the functions of viral glycoprotein M (gM) and the cellular Endosomal Sorting Complexes Required for Transport (ESCRT) in secondary envelopment. Firstly, it has been reported that gH/L can be efficiently internalised and targeted to the TGN by the co-expression of gM in transfection assays. In order to examine the role of gM in guiding the localisation of viral proteins in infected cells, a HSV-1 gM deletion virus (∆gM), and its revertant virus were constructed. The major phenotype demonstrated was that the absence of gM caused the internalisation of cell surface gH/L to be inhibited and higher levels of gH/L to be observed on the cell surface. Further, lower levels of gH/L were detected in purified ∆gM virions, which was in agreement with the delayed entry kinetics, smaller plaque sizes and greater replication deficits at low multiplicity of infection observed in ∆gM infected cells. Over all the results presented in this thesis demonstrate that in infected cells the efficient incorporation of gH/L into virions relies on the function of gM in HSV-1. Secondly, during HSV-1 secondary envelopment the budding and scission of the viral envelope from the host membrane share topological similarities with the formation of intraluminal vesicle in multivesicular bodies, retrovirus budding, and abscission at the end of cytokinesis, processes that require the cellular ESCRT machinery. There are four multiprotein ESCRT complexes and many associated proteins involved in their regulation. It has been previously shown that the ESCRT-III complex and a functional ATPase VPS4 are required for HSV-1 secondary envelopment, but different from the strategy utilised by HIV-1, the recruitment of ESCRT during HSV-1 infection is independent of TSG101 and/or ALIX. Data presented in this thesis demonstrate that CHMP4A/B/C proteins of the ESCRT-III complex are specifically crucial for HSV-1 secondary envelopment. Simultaneous depletion of CHMP4A/B/C proteins significantly inhibited HSV-1 replication. Ultrastructure analysis revealed that there were virtually no extracellular virions in CHMP4A/B/C depleted samples while more free capsids were observed in the cytoplasm, although the nuclear capsids and primary envelopment events appeared to be normal. In order to identify interactions between HSV-1 and ESCRT proteins, 22 HSV-1 tegument proteins were cloned and tested against a panel of ESCRT and ESCRT-associated proteins in yeast two-hydrid assays. Analysis of positive hits from yeast two-hybrid interaction screens using GST pull-down, co-immunoprecipitation and protein co-localisation assays have validated interactions of pUL47 with CC2D1A/1B, CIN85, CHMP6 and ALIX, pUL46 and pUL49 with CC2D1A/1B and CIN85, and pUL16 with CC2D1A/1B. Furthermore, the newly identified ESCRT associated proteins CC2D1A and CC2D1B have been detected in purified virions. The role of the identified ESCRT proteins in HSV-1 replication has been investigated using siRNA depletion. Unfortunately siRNA depletions of the various ESCRT candidates individually or in combinations did not show any significant effect on HSV-1 replication. Overall these data suggest that unlike HIV and other retroviruses, HSV-1 has evolved multiple parallel pathways to hijack the ESCRT machinery to facilitate its replication, particularly, through the interactions that lead directly to the recruitment of CHMP4A/B/C proteins. Disruption of some of these pathways did not prevent HSV-1 replication in tissue culture, suggesting any one potential pathway is sufficient for ESCRT recruitment to sites of HSV-1 assembly.
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Haupt, Borris. "Herpes simplex virus-1 (HSV-1) as a gene delivery vector for neural precursor cells." Thesis, University College London (University of London), 2004. http://discovery.ucl.ac.uk/1446639/.
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The thesis work presented evaluated the potential for use of disabled herpes simplex virus-1 (HSV-1) as gene delivery vectors for neural precursor cells and studied the effects of delivered recombinant factors on the de novo development of dopaminergic neurons from neural precursor cells. Highly and less disabled HSV-1 has been studied with respect to gene delivery efficiency and effects on cellular integrity in primary neural progenitor cells, neural stem cells grown as neurospheres, and in endogenous neural stem cell niches in the adult rat. Data from autografts of virally transduced neurospheres into the striatum of rats were also presented. The characteristics of virally transduced neural precursor cells were compared to other viral vector systems reported in literature. With respect to the study of differentiation factors, work has concentrated on fibroblast growth factor 8b (FGF8b). This has demonstrated that FGF8b is a mitogen for neural precursor cells in vitro. The study showed that neural stem cells isolated from different regions of the developing brain can be expanded in FGF8b alone and retain their stem cell characteristics, e.g. the capacity of self-renewal and multipotentiality. Growth curves and dose responses of neural precursor cells expanded in FGF8b further confirmed these findings. The study also showed survival effects of FGF8b on dopaminergic neurons derived from mesencephalic precursor cells. Further the effects of FGF8b on proliferation and differentiation of endogenous stem cells were also investigated. Finally, the thesis work involved the construction and generation of highly and less disabled viruses expressing FGF8b, sonic hedgehog, basic fibroblast growth factor, and the transcription factor nurr1. Expression and bioactivity of the various constructs was confirmed. The effects of these factors on dopamine neuron development were then studied in vitro using neural progenitors and neural precursor cells for which gene delivery had been optimized in the first part of this thesis.
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Caligiuri, Kyle. "Investigation of the deregulated miRNome identified during acute viral infections in a murine model of HSV-1 encephalitis." Springer Science+Business Media, LLC, 2013. http://hdl.handle.net/1993/23926.
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Herpes simplex virus type 1 (HSV-1) is a double stranded DNA virus that causes epithelial skin infections and persists through the life of the host by infecting neurons, where it can switch to a latent state to evade an immune response. In rare cases during primary infection or after reactivation, instead of undergoing lytic infection at the epithelial surface, it instead travels to the brain and causes herpes simplex virus encephalitis (HSVE) which can have a ≥70% mortality rate if untreated. As the virus takes over its host cell, it gains control of the host cell machinery and manipulates host gene expression in order to evade the immune system and to pool its resources into the replication of the virus. One aspect of the dysregulated gene expression involves microRNAs (miRNAs). MiRNAs are short, non-coding RNAs that bind to the 3' untranslated region (3'UTR) of messenger RNAs (mRNAs), leading to translational repression of the target. Dysregulated miRNAs are often down-regulated during infection as the virus takes over, but many miRNAs have also been found to be up-regulated as well1–5. The aim of this study is to observe the full cellular miRNA changes in the context of an acute viral encephalitic infection using HSV-1, and to further characterize selected up-regulated miRNAs to determine their function in the context of the disease state. Of particular note were miR-141 and miR-200c which showed anti-apoptotic effects on neuronal cell culture and did not impact cell viability during an over-expression of the miRNAs. MiR-141, miR-183 and miR-200a expression was enriched within specific areas of the brain during infection. In addition, the potential for miR-150 to bind to a bioinformatically predicted target site within the shared 3'UTR of the HSV-1 UL18, UL19 and UL20 genes was explored. Examining the changes in expression of this class of regulatory RNAs and investigating their potential functions may yield new insight into the relationship between host and virus during infection.
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Jalouli, Jamshid. "Human Papilloma Virus, Epstein-Barr Virus, and Herpes Simplex Virus Type-1 in Oral Squamous Cell Carcinomas from Three Populations." Doctoral thesis, Uppsala universitet, Käkkirurgi, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-128912.
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Most oral squamous cell carcinoma (OSCC) is believed to develop via a multistep process of cumulative gene damage in epithelial cells. Increasing incidence of OSCC and evidence that traditional risk factors may not be responsible directed us to investigate the prevalence of virus in pre- and malignant samples.The integration of the DNA from human papillomavirus (HPV), Epstein-Barr virus (EBV), and Herpes simplex (HSV) into the human genome is associated with the expression of oncogenes and the down-regulation of tumor-suppressor genes in OSCC carcinogenesis. This thesis compared samples from India and Sudan, two countries on two continents having a documented high incidence of oral cancer, with specimens from Sweden, with its known low incidence of oral cancer. Each region has, in addition to smoking, a unique non-smoked tobacco habits with documented carcinogenic effects. These countries also typify areas of low and high socioeconomic living conditions with their expected impact on disease development. The study populations were selected from tobacco users and nonusers with OSCC, oral sub-mucous fibrosis (India), oral lichen planus (Sweden), oral leukoplakia with and without dysplasia and snuff-induced lesions (Sweden and Sudan). An expedient method was developed for extracting DNA from old formalin-fixed and paraffin-embedded biopsies. The prevalence of HPV, EBV, and HSV was investigated using PCR/DNA sequencing and southern blot hybridization analysis. We found HPV and EBV to be most prevalent in samples of tissue characterized as normal, with decreasing prevalence in dysplastic and malignant lesions. This intriguing finding that prevalence decreases as neoplastic development proceeds warrants further investigation. Our data do not at first sight support the conclusion that viruses and tobacco use jointly interact with cell mechanisms in the development of oral cancer.
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Rozenberg, Flore. "Analyse de determinants de virulence du virus herpes simplex (hsv) dans l'encephalite herpetique humaine ; contribution a l'etude du pouvoir neuropathogene de hsv chez l'homme." Paris 11, 1997. http://www.theses.fr/1997PA114857.
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Van, Buren Lauren Kay. "HSV-1 Infection of C3H Central Nervous System Cell Lines." Wright State University / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=wright1189746668.
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Ye, Shanli. "DNA Sequences Involved in the Regulation of Human c-myc Gene Expression by Herpes Simplex Virus Type 1 (HSV-1)." PDXScholar, 1995. https://pdxscholar.library.pdx.edu/open_access_etds/5221.
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The human c-myc gene is a cellular proto-oncogene composed of three exons and two introns. Transcription of c-myc is controlled by two promoters, Pl and P2. The activity of these promoters is regulated by many factors, such as cellular transcription factors E2F, YYl, and HSV-1 immediate-early proteins, ICPO, ICP4. Many regulatory elements located both upstream of and between P 1 and P2 have been identified, and some of these are required for optimum expression of c-myc. In this thesis research, a region downstream from P2 in the c-myc exon 1 was identified by its response to transactivation by HSV-1 immediate-early proteins, ICPO and ICP4. The purpose of this research was to examine this region for regulatory sites that respond to HSV-1 infection. I hypothesized that after HSV-1 infection, ICPO and ICP4 activate c-myc expression, in part, through regulatory sequences present in exon 1. To test for this hypothesis, reporter plasmids containing (I) the c-myc promoter (from - 101 bp relative to Pl) and exon 1 coupled to the bacterial CAT gene were constructed. (ii) The c-myc exon sequences used were either intact (wild-type) or they were constructed with various deletions. The activities of these plasmids were examined in transient expression assays. To analyze protein binding, electrophoretic mobility shift assay (EMSA) and completion EMSAs were carried out. The results from these experiments lead to the following conclusions: (i) ICP4 and ICPO serve as activators, whereas ICP27 inhibits c-myc gene expression. (ii) The region from +332 to +513 within the c-myc exon 1 contains an important element required for transactivation of the c-myc gene by HSV-1 proteins. (iii) Cellular proteins, including factor YYl, bind to the region from +332 to +513 in the c-myc exon 1. Although the exact mechanism by which HSV-1 immediate-early proteins regulate cmyc gene expression is still not clear, it gives rise to a possibility that this regulation is caused by turning on or activation of the cellular regulatory proteins by ICP4 and ICPO. The cellular proteins in turn activate the c-myc gene expression by interacting with the ciselement downstream from P2.
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Dollery, Stephen. "Identification and characterization of low pH-triggered conformational changes in the herpes simplex virus glycoprotein B." VCU Scholars Compass, 2011. http://scholarscompass.vcu.edu/etd/176.
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Herpesviruses can enter host cells by pH-dependent endocytic pathways in a cell-specific manner. The role of pH in herpesvirus endocytosis is unclear. Herpes simplex virus (HSV) is a paradigm for virus membrane fusion via a complex of glycoproteins. HSV glycoproteins B, D and the heterodimer H-L are necessary and sufficient for membrane fusion. This work analyzes the structure and function of HSV glycoproteins B, D, and H-L at neutral pH, and at the physiological low-pH encountered during endocytic entry. It is demonstrated that mildly acidic low pH triggers specific conformational changes in HSV gB at a pH of 5.7 to 6.0. The antigenic structure of gB functional region I that is critical for fusion is specifically altered by mildly acidic pH both in vitro and during entry into host cells. Point mutations within gB functional region 1 that block membrane fusion still allow conformational changes in region 1. This suggests that specific hydrophobic residues are essential for fusion domain insertion into the host cell membrane but not conformational change. The detected conformational changes were reversible, similar to other class III fusion glycoproteins. Exposure to mildly acidic pH directly triggered the fusion function of HSV glycoproteins and caused gB, but not other glycoproteins, to become more hydrophobic. The oligomeric conformation of gB is altered at a similar pH range. In addition, several approaches were used to monitor gB throughout glycoprotein synthesis and maturation. It is shown that gB may cotranslationally fold and oligomerize as it is synthesized on the ribosome. As gB matures it then alters conformation and/or binding partner to form antigenically distinct populations of gB within the cell and virion. I conclude that intracellular low pH induces changes in gB conformation that, together with additional triggers such as receptor-binding, are essential for virion-cell fusion during herpesviral entry by endocytosis.
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Bain, Sharon Joanne Macnab. "Analysis of protein-protein interactions in the shell of herpes simplex virus type 1 (HSV-1) capsids." Thesis, University of Glasgow, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.301830.
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Kather, Angela. "Pro- and antiapoptotic events in Herpes simplex virus type 1 (HSV-1) infection of immature dendritic cells." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2012. http://dx.doi.org/10.18452/16464.
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Herpes simplex virus Typ 1 (HSV-1) ist ein humanpathogenes Virus der Familie Herpesviridae. Für eine erfolgreiche Virusreplikation besitzt HSV-1 mehrere Gene, die in den meisten infizierten Zelltypen Apoptose verhindern. Im Gegensatz dazu führt die HSV-1 Infektion eines zentralen Zelltyps des Immunsystems, den unreifen dendritischen Zellen (iDCs), zu Apoptose. Dies könnte ein Aspekt der HSV-1 Immunevasion sein. Bisher waren die Ursachen der Apoptose von HSV-1 infizierten iDCs unzureichend aufgeklärt. Es wurde jedoch gezeigt, dass das antiapoptotische zelluläre Protein c-FLIP in HSV-1 infizierten iDCs reduziert ist. In dieser Arbeit wurde die c-FLIP Menge in iDCs erstmalig mit Hilfe von RNA Interferenz erfolgreich reduziert. Dies bestätigte die Bedeutung von c-FLIP für die Lebensfähigkeit von iDCs. Folglich könnte auch die Reduktion der c-FLIP Menge nach HSV-1 Infektion iDCs für Apoptose empfindlich machen. Die HSV-1 induzierte c-FLIP Reduktion erfolgte in späten Stadien der Infektion, abhängig von der ordnungsgemäßen Expression viraler „early“ und „leaky late“ Gene. Sie fand nicht auf RNA Ebene statt und war unabhängig vom Proteasom und der Bindung an den „death inducing signaling complex“. Stattdessen wurde c-FLIP wahrscheinlich von einer viralen oder zellulären Protease abgebaut. In dieser Arbeit wurde erstmals gezeigt, dass zusätzlich zu Veränderungen im zellulären Apoptosesignalnetzwerk der Mangel an einem antiapoptotischen viralen Faktor zur Apoptose von HSV-1 infizierten iDCs beiträgt. Eine Microarray Analyse der HSV-1 Genexpression ergab, dass HSV-1 Latenz-assoziierte Transkripte (LATs) in apoptotischen iDCs signifikant geringer exprimiert waren als in nicht-apoptotischen epithelialen Zellen. LATs besitzen in Neuronen und epithelialen Zellen eine antiapoptotische Aktivität. Diese könnte den Mangel an c-FLIP kompensieren. Übereinstimmend mit dieser Hypothese induzierte eine HSV-1 LAT-Deletionsmutante mehr Apoptose in iDCs im Vergleich zum Wildtyp-Virus.Herpes simplex virus type 1 (HSV-1) is a human pathogen which belongs to the family Herpesviridae. HSV-1 encodes several genes, which serve to efficiently prevent apoptosis in most infected cell types, thereby ensuring successful virus replication. In contrast, HSV-1 infection of one central cell type of the immune system, immature dendritic cells (iDCs), results in apoptosis. This could be one aspect of HSV-1 immunevasion. So far, the mechanisms underlying apoptosis of HSV-1 infected iDCs were poorly defined. However, it has been shown that the antiapoptotic cellular protein c-FLIP is reduced in HSV-1 infected iDCs. In this work, the amount of c-FLIP was for the first time successfully reduced in iDCs by RNA interference. This confirmed the importance of c-FLIP for viability of iDCs. Therefore, it is likely that c-FLIP reduction after HSV-1 infection also sensitizes iDCs to apoptosis. HSV-1 induced c-FLIP reduction occurred at late stages of infection and was dependent on proper expression of early and leaky late virus genes. Furthermore, it was not operative at the RNA level and was independent from the proteasome and binding to the death inducing signaling complex. Rather, c-FLIP was presumably degraded by a viral or cellular protease. In this work it was shown for the first time, that in addition to changes in the cellular apoptosis signaling network, the lack of one antiapoptotic viral factor contributes to apoptosis of HSV-1 infected iDCs. HSV-1 latency-associated transcripts (LATs) were significantly lower expressed in apoptotic iDCs compared to non-apoptotic epithelial cells, determined by microarray analysis of HSV-1 gene expression. It is known that in neurons and epithelial cells, LATs possess a potent antiapoptotic activity. This could compensate the lack of c-FLIP. Consistent with this hypothesis, a LAT deletion mutant of HSV-1 induced more apoptosis in iDCs compared to the respective wild type virus.
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Bonnet, Catherine. "Surinfection cutanée à Herpes simplex virus (HSV) dans un service de brûlés : à propos de 9 observations." Bordeaux 2, 1995. http://www.theses.fr/1995BOR2M034.
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Kumaraswamy, Guttalu K. "INNATE AND ADAPTIVE HOST RESPONSE DURING THE INITIAL PHASE OF HERPES SIMPLEX VIRUS ENCEPHALITIS IN THE NEONATAL MOUSE." Kent State University / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=kent1168650862.
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Sowa, Gavin Michael. "ABVIC: A NOVEL FLOW CYTOMETRY-BASED ASSAY FOR THE DETECTION OF HSV-SPECIFIC ANTIBODIES." OpenSIUC, 2016. https://opensiuc.lib.siu.edu/theses/2063.
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Herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) are closely related viruses that establish lifelong infection in their hosts and can periodically reactivate to cause painful lesions. Approximately 50 million Americans are infected with HSV-2, the primary cause of genital ulcerative disease. In addition to the pain of the physical symptoms, genital herpes is highly stigmatized and can cause significant reductions in quality of life. HSV-2 has been demonstrated to have a synergistic relationship with HIV, where it enhances the transmissibility, susceptibility and severity of disease. In addition, potentially life-threatening neonatal herpes occurs in about 1 in 10,000 live births. While there are known means of reducing the risk of transmission, the overwhelming majority of infected persons are unaware of their status, and they remain the driving force behind new infections. Virological tests, such as PCR, are ill suited for asymptomatic infections since the detectable virus is only shed on <10% of days. Currently available type-specific serological tests based on glycoprotein G are prone to false-positive results, lack the sensitivity to detect new infections and may be affected by cross-reactivity between HSV-1 and HSV-2. Due to the known limitations of HSV serological testing, it is not recommended for the general population or pregnant women. In the first half of my thesis, I evaluate a new flow-cytometry-based method that measures serum antibody-binding to virus-infected cells (ABVIC). We obtained a panel of human control sera from Westover Heights Clinic (WHC) and determined if the ABVIC could measure HSV-specific antibody binding to test-cells. We found that the assay was sensitive, semi-quantitative, and could be made type-specific with the addition of a pre-adsorption step. The ABVIC offers an advantage over the standard of care single-antigen tests as the result measuring antibody binding to all viral proteins fixed in their native conformation. In the second half of my thesis, I used the ABVIC assay test n=34 blinded test-sera. Of these, n=17 had previously tested as “indeterminate” by bother Herpeselect ELISA as well as Western Blot. Following unblinding, we found that the ABVIC properly identified all n=17 patient sera of an unambiguous serostatus. Of the indeterminate sera, all were found to be seronegative for HSV-2. Based on these surprising results, we requested an additional n=11 indeterminate samples, which were also found to be HSV-2 seronegative. Most of the "Indeterminate" serum samples exhibited high background, which produced weak reactivity in HerpeSelect and Western blot assays, but did not confound the internally controlled ABVIC test.
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Thapa, Manoj. "Chemokines and chemokine receptors that mediate immune defense to genital herpes simplex virus type 2 (HSV-2) infection." Oklahoma City : [s.n.], 2008.
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Alandijany, Thamir Abdulaziz A. "Distinct temporal regulation of intrinsic and innate intracellular immunity to Herpes Simplex Virus type 1 (HSV-1) infection." Thesis, University of Glasgow, 2018. http://theses.gla.ac.uk/30662/.
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Intrinsic and innate immunity play pivotal roles in limiting the replication of invading viral pathogens. Intrinsic immunity is constitutive and mediated by pre-existing host cell restriction factors (e.g., promyelocytic leukemia-nuclear body (PML-NB) constituent proteins) which directly confer antiviral properties. On the other hand, innate immunity is inducible and upregulated in response to infection. Pattern recognition receptors (PRRs) (e.g., interferon gamma inducible protein 16 (IFI16)) sense pathogen-associated molecular patterns (PAMPs) and induce downstream signaling cascades leading to the induction of Interferon-stimulated gene (ISG) products that confer antiviral properties. These two arms of immunity represent the first line of intracellular defense to HSV-1 infection. Indeed, rapid recruitment of intrinsic and innate immune factors to viral DNA (vDNA) has a significant bearing on the outcome of infection. However, the spatial and temporal regulation of this recruitment remains poorly defined due to the technical challenges associated with vDNA detection at multiplicities of infection (MOI) that do not saturate intrinsic host factors. Utilizing 5-Ethynyl-2’-deoxyuridine (EdU) labeling of HSV-1 DNA in combination with click chemistry, we directly visualized input viral genomes under low MOI conditions (MOI of ≤ 3 PFU/cell) at 30-90 minutes post-addition of virus (mpi). This protocol is sensitive, specific, and compatible with indirect immunofluorescence (IF) staining protocols, providing a valuable assay to investigate the temporal recruitment of immune regulators to infecting vDNA. Upon entry of vDNA into the nucleus, PML-NB associated restriction factors (e.g., PML, SP100, and Daxx) were rapidly recruited to infecting viral genome foci. This process occurred in a PML-dependent manner and led to genome entrapment and silencing within PML-NBs. Interestingly, genome entrapment was observed during both wild-type (WT) and ICP0-null mutant (ΔICP0) HSV-1 infection. During WT HSV-1 infection, ICP0 induced PML degradation and the dispersal of PML-NB restriction factors, highlighting the importance of ICP0 to release viral genomes entrapped within PML-NBs to stimulate the onset of lytic HSV-1 replication. During ΔICP0 HSV-1 infection, vDNA remained stably entrapped within PML-NBs leading to a repression in viral gene expression and a restriction in plaque formation. Importantly, IFI16 was not stably recruited to vDNA entrapped within PML-NBs, and ISG expression was not induced under low MOI conditions that do not saturate PML-NB intrinsic host defenses. These data demonstrate that vDNA entry into the nucleus alone is not sufficient to stimulate the induction of innate immunity. Saturation of intrinsic host defenses under high MOI conditions stimulated the stable recruitment of IFI16 to infecting viral genomes, and induced ISG expression in a PML-, IFI16-, and Janus-associated kinase (JAK)-dependent manner. The induction of this innate immune response was dependent on the onset of vDNA replication, as treatment of the infected cell monolayers with phosphonoacetic acid (PAA), a vDNA polymerase inhibitor, inhibited ISG induction in a dose-dependent manner. Unlike PML depletion, inhibition of JAK signaling failed to relieve the plaque formation defect of ΔICP0 HSV-1, but instead significantly enhanced virus yields. Collectively, these data, for the first time, demonstrate a temporal and sequential induction of intrinsic and innate immunity during HSV-1 infection. Intrinsic immunity is induced within minutes of nuclear infection to restrict the initiation of viral gene transcription and the onset of lytic replication. Escape from this intrinsic repression and initiation of vDNA replication, which takes several hours, triggers the induction of innate immunity. ISG products establish an antiviral state within infected and neighboring uninfected cells to constrict viral propagation and limit the spread of infection. We identify dual roles for PML in the regulation of intrinsic and innate immunity to HSV-1 infection. However, these host defenses are counteracted by the viral ubiquitin ligase ICP0, which targets PML for degradation to promote vDNA release from PML-NBs in order to evade intrinsic viral genome silencing from the onset of nuclear infection.
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Rosa, Danieli Ferrari da. "ESTUDO DOS NÍVEIS SÉRICOS DE ÁCIDO SIÁLICO EM MODELO TUMORAL E VIRAL." Universidade Franciscana, 2018. http://tede.universidadefranciscana.edu.br:8080/handle/UFN-BDTD/274.
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The sialic acid is the generic name of carboxylated monosaccharides family with nine carbon glycoconjugated at terminal portion. These molecule family are involved in several biological processes such cell recognition processes, platelet adhesion, migration, invasion and metastatic potential, it also work as a receptor for bacteria and viruses. High concentrations of total sialic acid in the blood have been reported in different groups of patients with brain tumors, leukemia, melanoma, carcinoma and other kinds of cancers. The cleavage of sialic acid is a crucial step in virus infection influenzae, since this acid is part of the cellular receptor that the virus uses during the process of cellular internalization. The neuraminidase, an enzyme produced by the virus, cleaves the bond between sialic acid and the viral glycoproteins, allowing the entry of viruses into cells.The aim of this study was the analysis of serum sialic acid levels in murine melanoma and Herpes Simplex virus-1 (HSV-1) infection model. In the tumor model were used C57BL/6 and in the viral model BALB/c mice. Mice were injected with 2x105 B16F10 cells subcutaneously in the thigh and the tumor progression was followed each day till it became visible. The HSV-1 infection was conducted by intraperitoneally injection of with 102 PFU of virus. The sialic acid in serum samples was quantified by thiobarbituric method in spectrophotometer at 549 nm. A standard curve with commercial sialic acid was used as parameter for quantification. The results showed that in tumor model the sialic acid was increased compared with control group and have significant difference (p <0.05) in the first day after administration of cells. For the viral infection the concentration of sialic acid showed a significant difference (p <0,05) in the first day after infection when compared infected with control group. The histological analysis in thigh of mice performed 24 hours after administration of B16F10 cells were found compact groups of round or polygonal melanocytes with clear and large cytoplasm, irregular chromatin, hyperchromatic and vacuolated nuclei, eosinophilic nucleoli and atypical mitosis.
O ácido siálico é o nome genérico dado a família de monossacarídeos carboxilados com nove átomos de carbono que aparece na porção terminal de glicoconjugados. Estas moléculas estão envolvidas em vários processos biológicos, tais como, processos de reconhecimento celular, adesão plaquetária, migração, invasão, potencial metastático, sendo também um receptor para bactérias e vírus. O aumento das concentrações séricas de ácido siálico total tem sido descrito em vários grupos de pacientes que sofrem de tumores cerebrais, leucemia, melanoma, carcinoma e outros tipos de cânceres. A clivagem do ácido siálico é um passo crucial para a infecção do vírus Influenza, uma vez que este ácido é parte do receptor celular usado pelo vírus durante o processo de internalização celular. A neuraminidase, enzima produzida pelo vírus, cliva a ligação entre o ácido siálico e as glicoproteínas virais, permitindo a entrada dos vírus nas células. O objetivo desse estudo foi analisar os níveis séricos de ácido siálico em modelo de melanoma murino e modelo de infecção herpética (HSV-1). No modelo tumoral foram utilizados camundongos C57BL/6 e no modelo viral camundongos BALB/c. Os camundongos receberam 2x105 células B16F10 através da administração subcutânea na coxa e a progressão do tumor foi acompanhada todos os dias até o tumor se tornar visível. A infecção com HSV-1 foi realizada através da administração intraperitoneal de 102 PFU de vírus. O ácido siálico das amostras de soro foram quantificadas pelo método tiobarbitúrico em espectrofotômetro à 549 nm. Uma curva padrão com ácido siálico comercial foi usada como parâmetro para a quantificação. Os resultados mostraram que as concentrações de ácido siálico no modelo tumoral foram aumentadas nos animais com tumor quando comparadas ao grupo controle e houve diferença significativa (p< 0,05) no primeiro dia após a administração das células. Para o modelo de infecção viral houve diferença significativa (p< 0,05) no primeiro dia após a infecção quando comparado o grupo infectado com o controle. Na análise histológica da coxa dos camundongos realizada após 24 horas da administração de células B16F10 foram encontrados grupos compactos de melanócitos arredondados ou poligonais, com citoplasma amplo e claro, cromatina irregular, núcleos hipercromáticos e vacuolizados, nucléolos eosinofílicos e mitoses atípicas.
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Hu, Nai-Chung. "Co-occurrence of shedding Herpes Simplex Virus type-2 (HSV-2), Human Papilloma Virus (HPV) and Human Immunodeficiency Virus 1 (HIV-1) in the female genital tract among HIV-infected women." Master's thesis, Faculty of Health Sciences, 2019. http://hdl.handle.net/11427/31250.
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Introduction: Human Immunodeficiency Virus remains as one of the largest pandemics in the world, with the prevalence of more than 70% of HIV-infected individual reside in Sub-Saharan Africa. Moreover, other sexually transmitted viral infection such as Human Papillomavirus and Herpes Simplex Virus also show a high prevalence in Sub-Saharan Africa. Recent studies show the presence of other viral STI in the genital region may have increased HIV shedding in the genital region. However, it not clearly known if the presence of ART or HIV may affect the shedding of other viral STI in the genital region and if the combination of other viral STI treatment and ART is necessary to treat an individual with multiple STI infection. Methods: This is a secondary data analysis study, based on analysing the data collected from a single-site, double-blinded randomized control study (2-IUD study). The research site was the Gugulethu Community Health Centre, Cape Town, South Africa and samples were collected between 2014 and 2018. Analysis was conducted on genital tract specimens of study participants obtained via the Menstrual Cup (MC) and Endocervical Swabs (ECS), collected at baseline, 3 and 6 months’ follow up visit from randomly selected 52 ART-Naïve participants and 56 age-matched women from the ART-Using group of the primary study. Logistic regression models were constructed to measure the associations between possible risk factors and viral STIs. Results are presented as odds ratios (OR) with 95% confidence intervals (CI). Results: ART-Naïve women had higher rates of HIV shedding in the genital tract at each visit. However, more than half of women using ART, most of them virally suppressed, had detectable genital HIV at one or more visits. Most of the participants showed pre-exposure to HSV-2, but shedding of HSV-2 was substantially less common. HPV was detected in 72% of the participants, with no significant difference by ART status. Overall, 70.3% of samples had at least one viral pathogen detected - 60.4% among ART-Using women compared to 82.8% in ART-Naïve women (P<0.001). Compared to ART-Naïve women, ART-Using women were significantly less likely to have co-occurrence of viral shedding overall. However, ART-Using women with higher VL had levels of viral co-occurrence similar to those of ART-Naïve women. Conclusion: Our analysis demonstrated that the ART-Using women were less likely to shed HIV, HSV-2, HPV and viral STI co-infection in the genital tract compared to ART-Naïve women. This may be be driven by plasma VL levels where ART-Using women with lower VL are less likely to shed these viruses compared to women with elevated VL, including those not on ART.
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Brown, Elizabeth L. "Consequences of genital herpes simplex virus infection among vulnerable populations /." Thesis, Connect to this title online; UW restricted, 2006. http://hdl.handle.net/1773/10885.
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Strand, Mårten. "The discovery of antiviral compounds targeting adenovirus and herpes simplex virus : assessment of synthetic compounds and natural products." Doctoral thesis, Umeå universitet, Virologi, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-88186.
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There is a need for new antiviral drugs. Especially for the treatment of adenovirus infections, since no approved anti-adenoviral drugs are available. Adenovirus infections in healthy persons are most often associated with respiratory disease, diarrhea and infections of the eye. These infections can be severe, but are most often self-limiting. However, in immunocompromised patients, adenovirus infections are associated with morbidity and high mortality rates. These patients are mainly stem cell or bone marrow transplantation recipients, however solid organ transplantation recipients or AIDS patients may be at risk as well. In addition, children are at higher risk to develop disseminated disease. Due to the need for effective anti-adenoviral drugs, we have developed a cell based screening assay, using a replication-competent GFP expressing adenovirus vector based on adenovirus type 11 (RCAd11GFP). This assay facilitates the screening of chemical libraries for antiviral activity. Using this assay, we have screened 9800 small molecules for anti-adenoviral activity with low toxicity. One compound, designated Benzavir-1, was identified with activity against representative types of all adenovirus species. In addition, Benzavir-1 was more potent than cidofovir, which is the antiviral drug used for treatment of adenovirus disease. By structure-activity relationships analysis (SAR), the potency of Benzavir-1 was improved. Hence, the improved compound is designated Benzavir-2. To assess the antiviral specificity, the activity of Benzavir-1 and -2 on both types of herpes simplex virus (HSV) was evaluated. Benzavir-2 displayed better efficacy than Benzavir-1 and had an activity comparable to acyclovir, which is the original antiviral drug used for therapy of herpes virus infections. In addition, Benzavir-2 was active against acyclovir-resistant clinical isolates of both HSV types. To expand our search for compounds with antiviral activity, we turned to the natural products. An ethyl acetate extract library was established, with extracts derived from actinobacteria isolated from sediments of the Arctic Sea. Using our screening assay, several extracts with anti-adenoviral activity and low toxicity were identified. By activity-guided fractionation of the extracts, the active compounds could be isolated. However, several compounds had previously been characterized with antiviral activity. Nonetheless, one compound had uncharacterized antiviral activity and this compound was identified as a butenolide. Additional butenolide analogues were found and we proposed a biosynthetic pathway for the production of these compounds. The antiviral activity was characterized and substantial differences in their toxic potential were observed. One of the most potent butenolide analogues had minimal toxicity and is an attractive starting point for further optimization of the anti-adenoviral activity. This thesis describes the discovery of novel antiviral compounds that targets adenovirus and HSV infections, with the emphasis on adenovirus infections. The discoveries in this thesis may lead to the development of new antiviral drugs for clinical use.
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Le, Goff Jérôme. "Interactions entre le VIH-1 et l' herpes simplex de type 2 dans le microenvironnement cellulaire et génital." Paris 7, 2005. http://www.theses.fr/2005PA077105.
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Raker, Verena [Verfasser]. "Herpes simplex virus type 1 (HSV-1) infection alters growth factor signaling in primary cortical brain cells / Verena Raker." Hannover : Bibliothek der Tierärztlichen Hochschule Hannover, 2017. http://d-nb.info/1150340320/34.
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Geltz, Joshua Joseph. "ANALYSIS OF HERPES SIMPLEX VIRUS ICP0 FUNCTION AND THE ANTIBODY RESPONSE TO A LIVE HSV-2 ICP0- MUTANT VACCINE." OpenSIUC, 2015. https://opensiuc.lib.siu.edu/dissertations/1049.
Full textAbstract:
Both herpes simplex virus type-1 (HSV-1) and herpes simplex virus type-2 (HSV-2) are human pathogens that are capable of causing significant disease. More than 600 million people are infected with HSV-2 genital herpes and every day >40,000 new HSV-2 infections are transmitted to naïve recipients. The public health community has long agreed that a preventative vaccine is necessary to reduce the prevalence of HSV-2, but we continue to lack a vaccine to prevent the spread of this sexually transmitted disease. Herpes simplex viruses (HSV) establish a life-long infection in their host where they alternate between a state of latency and productive replication. One of principle determining factors of whether HSV reactivates from a latent state to cause disease is the accumulation of the immediate early viral protein, infected cell protein 0 (ICP0). ICP0 is a potent transactivator of HSV mRNA synthesis. However, in addition to the nuclear transactivating function of ICP0, our lab demonstrated that at later times during infection, ICP0 translocates from the nucleus to the cytoplasm where it reorganizes the host microtubule network (PLoS ONE 5(6): e10975). In the first part of my dissertation, we used the anti-neoplastic drug paclitaxel to determine if ICP0’s microtubule-reorganizing activity is required for efficient replication of HSV- 1. Surprisingly, we observed that paclitaxel prevented ICP0 from dispersing cellular microtubules and inhibited the spread of HSV-1 and HSV-2. Paclitaxel reduced HSV-1 plaque size by up to 100-fold, and inhibition of viral spread was proportional to the efficiency with which doses of paclitaxel stabilized microtubules against ICP0-induced dispersal. Analysis of infected Vero cells confirmed that paclitaxel treatment did not reduce the efficiency of HSV-1 mRNA, protein, DNA, or virion synthesis by more than 3-fold. In contrast, paclitaxel treatment caused an ~20-fold decrease in infectious virus release from HSV-1 infected cells. Comparison of ICP0+ versus ICP0- viruses yielded genetic evidence that ICP0 promotes infectious virus release from HSV-1-infected cells. These results provide the first evidence suggesting that ICP0’s microtubule-reorganizing activity may promote the release of infectious virus from HSVinfected cells. In the second part of my dissertation, I focus less on the basic-science quest to elucidate the function of ICP0 but instead focus on characterizing the antibody response elicited by a highly protective HSV-2 ICP0- vaccine that was developed in our lab. Specifically, despite the belief that virion glycoproteins such as glycoprotein D (gD-2) are the dominant antigens of herpes simplex virus 2 (HSV-2) we have demonstrated mice immunized with a live HSV-2 ICP0- mutant virus, HSV-2 0ΔNLS, are 10 to 100 times better protected against genital herpes than mice immunized with a HSV-2 gD subunit vaccine (PLoS ONE 6:e17748). In light of these results, we sought to determine which viral proteins were the dominant antibody-generators (antigens) of the live HSV-2 0ΔNLS vaccine. Western blot analyses indicated the live HSV-2 0ΔNLS vaccine elicited an IgG antibody response against 9 or more viral proteins. Many antibodies were directed against infected-cell proteins of >100 kDa in size, and only 10 ± 5% of antibodies were directed against gD. Immunoprecipitation (IP) of total HSV-2 antigen with 0ΔNLS antiserum pulled down 19 viral proteins. Mass spectrometry suggested 44% of immunoprecipitated viral peptides were derived from two HSV-2 infected cells proteins, RR-1 and ICP8, whereas only 14% of immunoprecipitated peptides were derived from HSV-2's thirteen glycoproteins. Collectively, the results suggest the immune response to the live HSV-2 0ΔNLS vaccine includes antibodies specific for infected cell proteins, capsid proteins, tegument proteins, and glycoproteins. This increased breadth of antibody-generating proteins may contribute to the live HSV-2 vaccine's capacity to elicit superior protection against genital herpes relative to a gD subunit vaccine. In the final section of my dissertation, I focus on the construction of stable Vero cell lines using a system that relies on Sleeping Beauty transposase to introduce two genetic elements into the chromosomes of target cells: 1. a Tet-regulatable gene-of-interest driven by the VP16- inducible HSV-1 ICP0 promoter and 2. a highly expressed bicistronic gene that expresses the Tet-repressor protein and a puromycin selection marker. The modified bidirectional HSV-1 ICP0 promoter used in this novel expression system 1. drives constitutive expression of a cell surface marker (tNGFR) from the reverse side of the ICP0 promoter, while 2. the Tetregulatable, forward side of the ICP0 promoter allows the expression of a downstream gene-ofinterest to be regulated over an ~100-fold range of gene expression through doxycyclineinduced derepression and induction with VP16. Using this system, stable and regulatable Vero cell lines are reproducibly obtained within one month of initial transfection by using puromycin selection followed by fluorescence-activated cell sorting (FACS) to isolate a pure population of tNGFR+ cells that contain the target gene-of-interest. Vero cell lines that carry a toxic gene, such as HSV-1 ICP0, can be routinely passaged and maintained in cell culture because basal expression of the gene-of-interest can be reduced to low to undetectable levels. However, when the same cell lines are de-repressed, they express adequate levels of HSV-1 ICP0 or HSV-1 origin-binding protein (OBP) to complement an HSV-1 ICP0- mutant . These data suggest this novel gene expression system may have broad uses in biological research because it allows for the efficient generation of stable cell lines that express a gene-of-interest in a highly regulatable manner.
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Gor, Dehila. "Investigation of herpes simplex virus and Cytomegalovirus infection in the immunocompromised host." Thesis, University College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.323037.
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Chatterjee, Koushik. "A study of host genetic determinants of human papillomavirus (HPV) infection, cervical cancer and herpes simplex virus type-2 (HSV-2) infection." Doctoral thesis, University of Cape Town, 2010. http://hdl.handle.net/11427/3160.
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Thakkar, Jay N. "DISCOVERY OF LIGNIN SULFATE AS A POTENT INHIBITOR OF HSV ENTRY INTO CELLS." VCU Scholars Compass, 2006. http://scholarscompass.vcu.edu/etd/711.
Full textAbstract:
The herpes virus family consists of more than hundred members that infect organisms, of which eight, differing markedly in the biology are known to infect humans. HSV- I is the most common one, causing oral lesions and sporadic encephalitis. These infections are highly prevalent affecting at least one in three individuals in the United States.The entry of the herpes virus into the cell is a two-step process. The initial step involves the cell surface heparan sulfate and glycoproteins in the viral envelope which enables the virus to penetrate into the cell. The second step is the fusion step. Depending on the nature of interaction and size of HS chain, a single chain may bind multiple viral ligands on a virion. There is substantial evidence showing that HS plays an important role in viral binding.HS is a heterogeneous, linear sulfated oligosaccharide composed of alternating glucosamine and uronic acid residues, which could specify distinct receptor for various viral ligands. HS, present on most exposed cell surfaces, make an ideal snare for the capture of most herpes viruses and may facilitate subsequent interactions with other co-receptors required for entry. Number of viruses, including HSV- I, HSV- II, HIV- I and dengue virus use sites of HS as receptors for binding to cells. Recently 2000 Liu et.al have characterized a HS based octasaccharide that binds to HSV-I gD. The distinguished feature in the composition of the octasaccharide is the presence of 3-O-sulfate glucosamine residue, which is an uncommon structural modification in HS. Its presence in the HSV-I gD binding sequence may confer specificity of interaction and assist HSV-I entry into the cell.Numerous sulfated molecules have been explored as mimics of HS in the inhibition of HSV-1 entry into cells. To date, most of the sulfated molecules screened for anti-viral activity have been carbohydrates. So, we reasoned that it should be possible to mimic critical interactions of HS with one or more viral glycoprotein using synthetic, non-polysaccharide, sulfated compounds. Further, it may be possible to mimic specific sequence(s) in HS, which play a role in HSV infection, with small synthetic, sulfated, non-carbohydrate molecules. In a search for synthetic mimics of HS as inhibitors of HSV-I infection, we screened a small, synthetic, sulfated flavonoids to discover a potent inhibitory activity arising from sulfation of a macromolecule present as an impurity in a crude natural product.The active principle was identified through an array of biophysical and chemical analyses as lignin sulfate, a heterogeneous; polydisperse network polymer composed of substituted phenylpropanoid monomers. Further, LC-MS with APCI in negative ionization mode, which have been reported in here for the first time for analysis of lignin, has been successfully used to deduce oligomeric structures present in the precursor of the active macromolecule based on the spectrum of the depolymerized lignin. This corroborates well with the structural information obtained using other analytical techniques. We hypothesize that the structural heterogeneity and polydispersity of lignin coupled with optimal combination of sulfate charge and hydrophobicity result in high potency. Given that the native lignin is inactive, lignin sulfate discovered here provides a variety of organic scaffolds that with the critical sulfate groups in space can mimic the HSV-I gD binding sequence.