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Sample records for simplex virus-mediated human

  1. Herpes simplex virus-mediated human hypoxanthine-guanine phosphoribosyltransferase gene transfer into neuronal cells

    SciTech Connect

    Palella, T.D.; Silverman, L.J.; Schroll, C.T.; Homa, F.L.; Levine, M.; Kelley, W.N.

    1988-01-01

    The virtually complete deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) results in a devastating neurological disease, Lesch-Nyhan syndrome. Transfer of the HPRT gene into fibroblasts and lymphoblasts in vitro and into hematopoietic cells in vivo has been accomplished by other groups with retroviral-derived vectors. It appears to be necessary, however, to transfer the HPRT gene into neuronal cells to correct the neurological dysfunction of this disorder. The neurotropic virus herpes simplex virus type 1 has features that make it suitable for use as a vector to transfer the HPRT gene into neuronal tissue. This report describes the isolation of an HPRT-deficient rat neuroma cell line, designated B103-4C, and the construction of a recombinant herpes simplex virus type 1 that contained human HPRT cDNA. These recombinant viruses were used to infect B103-4C cells. Infected cells expressed HPRT activity which was human in origin.

  2. Injury-specific promoters enhance herpes simplex virus mediated gene therapy for treating neuropathic pain in rodents

    PubMed Central

    Smith, Sherika N.; Paige, Candler; Velazquez, Kandy T.; Smith, Terika P.; Raja, Srinivasa N.; Wilson, Steven P.; Sweitzer, Sarah M.

    2015-01-01

    Chronic neuropathic pain is often difficult to treat with current pain medications. Gene therapy is currently being explored as a therapeutic approach for the treatment of neuropathic and cancer pain. In this study we sought to use an injury-specific promoter to deliver the mu opioid receptor (MOR) transgene such that expression would only occur during the injured state in response to release of injury-specific galanin. To determine whether an injury specific promoter can produce neuron-specific MOR expression and enhanced antinociception we compared animals infected with a galanin promoter virus (galMOR) or a human cytomegalovirus (CMV) promoter virus. (cmvMOR). In behavioral assays, we found an earlier onset and a larger magnitude of antinociception in animals infected with galMOR compared to cmvMOR. Immunohistochemistry of dorsal root ganglion (DRG) neurons revealed a significant increase in MOR positive staining in cmvMOR and galMOR treated mice. Spinal cord sections from galMOR treated mice showed a greater increase in density but not area of MOR positive staining. These results suggest that using injury-specific promoters to drive gene expression in primary afferent neurons can influence the onset and magnitude of antinociception in a rodent model of neuropathic pain and can be used to upregulate MOR expression in populations of neurons that are potentially injury specific. Perspective An injury specific promoter (galMOR) was used to drive MOR expression in a population- and injury- specific manner. GalMOR increased antinociception and density of MOR staining in spinal cord. This article presents evidence that promoter selection is an important component in successful gene expression in an injury- and population-specific manner. PMID:25576797

  3. Human Herpes Simplex Virus Type 1 in Confiscated Gorilla

    PubMed Central

    Oxford, Kristie L.; Gardner-Roberts, David; Kinani, Jean-Felix; Spelman, Lucy; Barry, Peter A.; Cranfield, Michael R.; Lowenstine, Linda J.

    2014-01-01

    In 2007, we detected human herpes simplex virus type 1, which caused stomatitis, in a juvenile confiscated eastern lowland gorilla (Gorilla beringei graueri) that had a high degree of direct contact with human caretakers. Our findings confirm that pathogens can transfer between nonhuman primate hosts and humans. PMID:25341185

  4. Human herpes simplex virus type 1 in confiscated gorilla.

    PubMed

    Gilardi, Kirsten V K; Oxford, Kristie L; Gardner-Roberts, David; Kinani, Jean-Felix; Spelman, Lucy; Barry, Peter A; Cranfield, Michael R; Lowenstine, Linda J

    2014-11-01

    In 2007, we detected human herpes simplex virus type 1, which caused stomatitis, in a juvenile confiscated eastern lowland gorilla (Gorilla beringei graueri) that had a high degree of direct contact with human caretakers. Our findings confirm that pathogens can transfer between nonhuman primate hosts and humans. PMID:25341185

  5. Evolutionary Origins of Human Herpes Simplex Viruses 1 and 2

    PubMed Central

    Wertheim, Joel O.; Smith, Martin D.; Smith, Davey M.; Scheffler, Konrad; Kosakovsky Pond, Sergei L.

    2014-01-01

    Herpesviruses have been infecting and codiverging with their vertebrate hosts for hundreds of millions of years. The primate simplex viruses exemplify this pattern of virus–host codivergence, at a minimum, as far back as the most recent common ancestor of New World monkeys, Old World monkeys, and apes. Humans are the only primate species known to be infected with two distinct herpes simplex viruses: HSV-1 and HSV-2. Human herpes simplex viruses are ubiquitous, with over two-thirds of the human population infected by at least one virus. Here, we investigated whether the additional human simplex virus is the result of ancient viral lineage duplication or cross-species transmission. We found that standard phylogenetic models of nucleotide substitution are inadequate for distinguishing among these competing hypotheses; the extent of synonymous substitutions causes a substantial underestimation of the lengths of some of the branches in the phylogeny, consistent with observations in other viruses (e.g., avian influenza, Ebola, and coronaviruses). To more accurately estimate ancient viral divergence times, we applied a branch-site random effects likelihood model of molecular evolution that allows the strength of natural selection to vary across both the viral phylogeny and the gene alignment. This selection-informed model favored a scenario in which HSV-1 is the result of ancient codivergence and HSV-2 arose from a cross-species transmission event from the ancestor of modern chimpanzees to an extinct Homo precursor of modern humans, around 1.6 Ma. These results provide a new framework for understanding human herpes simplex virus evolution and demonstrate the importance of using selection-informed models of sequence evolution when investigating viral origin hypotheses. PMID:24916030

  6. Herpes simplex virus latency in isolated human neurons.

    PubMed Central

    Wigdahl, B; Smith, C A; Traglia, H M; Rapp, F

    1984-01-01

    Herpes simplex virus is most probably maintained in the ganglion neurons of the peripheral nervous system of humans in a latent form that can reactivate to produce recurrent disease. As an approximation of this cell-virus interaction, we have constructed a herpes simplex virus latency in vitro model system using human fetus sensory neurons as the host cell. Human fetus neurons were characterized as neuronal in origin by the detection of the neuropeptide substance P and the neuron-specific plasma membrane A2B5 antigen. Virus latency was established by blocking complete expression of the virus genome by treatment of infected human neurons with a combination of human leukocyte interferon and (E)-5-(2-bromovinyl)-2'-deoxyuridine for 7 days. After removal of inhibitors, virus latency was maintained for at least 9 days. This in vitro model will provide a system to analyze, in a primary human neuron, the state of the herpes simplex virus genome during establishment and maintenance of experimental latency. Images PMID:6091142

  7. Expression of varicella-zoster virus and herpes simplex virus in normal human trigeminal ganglia

    SciTech Connect

    Vafai, A.; Wellish, M.; Devlin, M.; Gilden, D.H. ); Murray, R.S. Veterans Administration Medical Center, Denver, CO )

    1988-04-01

    Lysates of radiolabeled explants from four human trigeminal ganglia were immunoprecipitated with antibodies to varicella-zoster virus (VZV) and to herpes simplex virus. Both herpes simplex virus- and VZV-specific proteins were detected in lysates of all four ganglia. Absence of reactivity in ganglion explants with monoclonal antibodies suggested that herpes simplex virus and VZV were not reactivated during the culture period. In situ hybridization studies demonstrated the presence of RNA transcripts from the VZV immediate early gene 63. This approach to the detection of herpes simplex virus and VZV expression in human ganglia should facilitate analysis of viral RNA and proteins in human sensory ganglia.

  8. Human herpes simplex virus: life cycle and development of inhibitors.

    PubMed

    Kukhanova, M K; Korovina, A N; Kochetkov, S N

    2014-12-01

    WHO reports that 90% of human population is infected by different types of herpesviruses, which develop latency or cause oral and genital herpes, conjunctivitis, eczema herpeticum, and other diseases. Herpesvirus almost always accompanies HIV-infection and complicates AIDS treatment. Herpes simplex virus type 1 is one of the most wide spread viruses from the Herpesviridae family. HSV virion, genome structure, replication mechanisms, antiherpes drug development strategies, including design of prodrugs, and mutations causing ACV-resistance in clinical HSV isolates are discussed in this review. PMID:25749169

  9. Reactivation of latent herpes simplex virus infection by ultraviolet light: a human model

    SciTech Connect

    Perna, J.J.; Mannix, M.L.; Rooney, J.F.; Notkins, A.L.; Straus, S.E.

    1987-09-01

    Infection with herpes simplex virus often results in a latent infection of local sensory ganglia and a disease characterized by periodic viral reactivation and mucocutaneous lesions. The factors that trigger reactivation in humans are still poorly defined. In our study, five patients with documented histories of recurrent herpes simplex virus infection on the buttocks or sacrum were exposed to three times their minimal erythema dose of ultraviolet light. Site-specific cutaneous herpes simplex virus infection occurred at 4.4 +/- 0.4 days after exposure to ultraviolet light in 8 of 13 attempts at reactivation. We conclude that ultraviolet light can reactivate herpes simplex virus under experimentally defined conditions. This model in humans should prove useful in evaluating the pathophysiology and prevention of viral reactivation.

  10. Detection of herpes simplex virus-specific DNA sequences in latently infected mice and in humans.

    PubMed Central

    Efstathiou, S; Minson, A C; Field, H J; Anderson, J R; Wildy, P

    1986-01-01

    Herpes simplex virus-specific DNA sequences have been detected by Southern hybridization analysis in both central and peripheral nervous system tissues of latently infected mice. We have detected virus-specific sequences corresponding to the junction fragment but not the genomic termini, an observation first made by Rock and Fraser (Nature [London] 302:523-525, 1983). This "endless" herpes simplex virus DNA is both qualitatively and quantitatively stable in mouse neural tissue analyzed over a 4-month period. In addition, examination of DNA extracted from human trigeminal ganglia has shown herpes simplex virus DNA to be present in an "endless" form similar to that found in the mouse model system. Further restriction enzyme analysis of latently infected mouse brainstem and human trigeminal DNA has shown that this "endless" herpes simplex virus DNA is present in all four isomeric configurations. Images PMID:3003377

  11. [Cytoskeletal disorders in human keratinocytes--epidermolysis bullosa simplex].

    PubMed

    Kitajima, Y; Jokura, Y; Yaoita, H

    1991-06-01

    The cytoskeletons possibly related to pathogenesis in skin disease may be limited to keratin intermediate filaments (KIF) in epidermal keratinocytes. Keratins are divided into two subclasses; 11 acidic (type I) keratins and 8 basic (type II) keratins. Combination of equimolar amounts of type I and type II can form KIF. KIFs in human epidermal basal cells consist of a pair of type I and type II keratins specifically synthesized in the basal cells, and those in spinous cells contain two pairs of keratin; a pair of basal cell keratin and another pair of keratin specific for suprabasal cells. In the first section, molecular biology and differentiation of keratins are reviewed. In the second section, epidermolysis bullosa simplex (EBS) was introduced from the view point of abnormal organization of KIFs. In the epidermis of EBS, clefts are induced in the basal cells by minor trauma or frictions consequently to produce bullae. Electron microscopy reveals small spherical aggregations of tonofilaments (KIFs) in the basal cells. In biopsies, these KIF aggregations might be caused by artifacts during procedures for biopsies, so that, in order to avoid these artifacts, we studied the KIF organization in cultured keratinocytes from a patient by immunofluorescence using anti-keratin antibodies and electron microscopy. Anti-keratin antibodies revealed a formation of small droplet-like aggregations of KIFs in many cultured cells adhering to the culture bottles, which were also suggested by electron microscopy. From these observations, it is suggested that the abnormal organization (droplets) of KIFs might be one of intrinsic factors for the pathogenesis of EBS.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1720328

  12. Cutaneous Co-infected Cytomegalovirus and Herpes Simplex Virus Perigenital Ulcers in Human Immunodeficiency Virus Patients.

    PubMed

    Schoenfeld, Jason; Cannon, Sarah; Cam, Kristin; Keller, Matthew

    2013-10-01

    There is uncertainty regarding the pathogenic nature of cytomegalovirus in cutaneous lesions co-infected with herpes simplex virus. It is widely believed that herpes simplex virus is the main pathogenic factor in such lesions and that cytomegalovirus plays little if any role. There are, however, isolated case reports that describe cytomegalovirus as an important driving pathogen in such lesions. The authors present two human immunodeficiency virus patients who have cytomegalovirus and herpes simplex virus co-infected perigenital ulcers, one of whom improved on valacyclovir, while the other, who was already on valacyclovir for chronic herpes simplex virus suppression, showed no improvement with a single dose of cidofovir. He only showed rapid improvement when treated with valganciclovir. The latter patient underscores the viewpoint that at least in some cases, cytomegalovirus may be an important driving force behind the formation of such lesions. The authors therefore recommend that clinicians be aware of the possible pathogenic role of cytomegalovirus in these ulcers, and, in nonhealing ulcers, use anti-cytomegalovirus agents to prevent the onset of systemic disease. These results warrant further study of the pathogenesis of cytomegalovirus in co-infected herpes simplex virus ulcers. PMID:24155993

  13. Stimulation of human lymphocytes by Herpes simplex virus antigens.

    PubMed Central

    Starr, S E; Karatela, S A; Shore, S L; Duffey, A; Nahmias, A J

    1975-01-01

    Lymphocytes from individuals with laboratory evidence of prior infection with herpes simplex virus (HSV) type 1 or type 2 demonstrated transformation (av antigens. Higher stimulation indexes were obtained when lymphocytes were incubated with the homologous as compared with the heterologous antigen. Higher mean lymphocyte stimulation indexes were also demonstrated in seropositive as compared with seronegative individuals. Lymphocytes from children with HSV-1 stomatitis usually became responsive to HSV-1 antigen within 2 to 6 weeks after the onset of illness. Lymphocytes from infants with neonatal HSV-2 infection were stimulated by HSV-2 antigen. PMID:163788

  14. A DNA Fragment of Herpes Simplex 2 and Its Transcription in Human Cervical Cancer Tissue

    PubMed Central

    Frenkel, Niza; Roizman, Bernard; Cassai, Enzo; Nahmias, Andre

    1972-01-01

    A human cervical tumor, free of detectable infectious herpes simplex 2 virus, contained a fragment comprising 39% of herpes viral DNA. Renaturation kinetics indicate that an average of 1 to 3.5 DNA fragments of herpes simplex virus are present per cell, depending on the ploidy of the cells in this particular tumor. Virus-specific sequences were found linked to highly repetitive sequences of host DNA, which reassociated under conditions designed to preclude reassociation of viral sequences. The tumor also contained RNA transcripts complementary to 5% of the viral DNA. The fraction of viral DNA template transcribed in the cervical tumor is considerably less than that transcribed in productively infected cells (50%). PMID:4345508

  15. Herpes simplex virus 2 modulates apoptosis and stimulates NF-{kappa}B nuclear translocation during infection in human epithelial HEp-2 cells

    SciTech Connect

    Yedowitz, Jamie C.; Blaho, John A. . E-mail: john.blaho@mssm.edu

    2005-11-25

    Virus-mediated apoptosis is well documented in various systems, including herpes simplex virus 1 (HSV-1). HSV-2 is closely related to HSV-1 but its apoptotic potential during infection has not been extensively scrutinized. We report that (i) HEp-2 cells infected with HSV-2(G) triggered apoptosis, assessed by apoptotic cellular morphologies, oligosomal DNA laddering, chromatin condensation, and death factor processing when a translational inhibitor (CHX) was added at 3 hpi. Thus, HSV-2 induced apoptosis but was unable to prevent the process from killing cells. (ii) Results from a time course of CHX addition experiment indicated that infected cell protein produced between 3 and 5 hpi, termed the apoptosis prevention window, are required for blocking virus-induced apoptosis. This corresponds to the same prevention time frame as reported for HSV-1. (iii) Importantly, CHX addition prior to 3 hpi led to less apoptosis than that at 3 hpi. This suggests that proteins produced immediately upon infection are needed for efficient apoptosis induction by HSV-2. This finding is different from that observed previously with HSV-1. (iv) Infected cell factors produced during the HSV-2(G) prevention window inhibited apoptosis induced by external TNF{alpha} plus cycloheximide treatment. (v) NF-{kappa}B translocated to nuclei and its presence in nuclei correlated with apoptosis prevention during HSV-2(G) infection. (vi) Finally, clinical HSV-2 isolates induced and prevented apoptosis in HEp-2 cells in a manner similar to that of laboratory strains. Thus, while laboratory and clinical HSV-2 strains are capable of modulating apoptosis in human HEp-2 cells, the mechanism of HSV-2 induction of apoptosis differs from that of HSV-1.

  16. Herpes simplex virus infection in human arterial cells. Implications in arteriosclerosis.

    PubMed Central

    Hajjar, D P; Pomerantz, K B; Falcone, D J; Weksler, B B; Grant, A J

    1987-01-01

    Herpesviruses have been implicated as etiologic factors in the pathogenesis of human arteriosclerosis. We have examined the pathobiological effects of human herpes simplex virus (HSV-1) infection in influencing lipid accumulation and metabolism in human and bovine arterial smooth muscle cells (SMC). Significantly greater amounts of saturated cholesteryl esters (CE) and triacylglycerols (TG) accumulate in HSV-1-infected human and bovine arterial SMC than uninfected cells. This CE accumulation results, in part, from decreased CE hydrolysis. Furthermore, arachidonate-stimulated, HSV-1-infected arterial SMC have a reduced capacity to produce prostacyclin (an agonist of intracellular CE hydrolytic activity) than uninfected, stimulated SMC. It appears that HSV-1 may induce lipid accumulation in arterial SMC similar, in part, to the lipid accumulation observed in vivo during human atherogenesis. Thus, herpesviruses may contribute to lipid accumulation, which is a characteristic feature of atherosclerosis. PMID:3119662

  17. Latent Herpes Simplex Virus 1 Infection Does Not Induce Apoptosis in Human Trigeminal Ganglia

    PubMed Central

    Lindemann, Anja; Sinicina, Inga; Strupp, Michael; Brandt, Thomas; Hüfner, Katharina

    2015-01-01

    Herpes simplex virus 1 (HSV-1) can establish lifelong latency in human trigeminal ganglia. Latently infected ganglia contain CD8+ T cells, which secrete granzyme B and are thus capable of inducing neuronal apoptosis. Using immunohistochemistry and single-cell reverse transcription-quantitative PCR (RT-qPCR), higher frequency and transcript levels of caspase-3 were found in HSV-1-negative compared to HSV-1-positive ganglia and neurons, respectively. No terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) assay-positive neurons were detected. The infiltrating T cells do not induce apoptosis in latently infected neurons. PMID:25762734

  18. High Efficiency Latency and Activation of Herpes Simplex Virus in Human Cells

    NASA Astrophysics Data System (ADS)

    Wigdahl, Brian L.; Scheck, Adrienne C.; de Clercq, Erik; Rapp, Fred

    1982-09-01

    Herpes simplex virus (HSV) exists in humans in a latent form that can be activated. To characterize the molecular basis of the cell-virus interactions and to analyze the state of the latent HSV genome, an in vitro model system was established. In this system a large fraction of the latently infected cells contain an HSV genome that can be activated. Cell survival was reduced minimally after repression of high multiplicity HSV type 1 (HSV-1) infection of human fibroblast cells with (E)-5-(2-bromovinyl)-2'-deoxyuridine in combination with human leukocyte interferon (IFN-α ). A minimum of 1 to 3 percent of the surviving cells contained an HSV genome that could be activated either by human cytomegalovirus superinfection or reduction in incubation temperature.

  19. Factors Influencing Adeno-Associated Virus-Mediated Gene Transfer to Human Cystic Fibrosis Airway Epithelial Cells: Comparison with Adenovirus Vectors

    PubMed Central

    Teramoto, S.; Bartlett, J. S.; McCarty, D.; Xiao, X.; Samulski, R. J.; Boucher, R. C.

    1998-01-01

    Adeno-associated virus (AAV) vectors appear promising for use in gene therapy in cystic fibrosis (CF) patients, yet many features of AAV-mediated gene transfer to airway epithelial cells are not well understood. We compared the transduction efficiencies of AAV vectors and adenovirus (Ad) vectors in immortalized cell lines from CF patients and in nasal epithelial primary cultures from normal humans and CF patients. Similar dose-dependent relationships between the vector multiplicities of infection and the efficiencies of lacZ gene transfer were observed. However, levels of transduction for both Ad and recombinant AAV (rAAV) were significantly lower in the airway epithelial cell than in the control cell lines HeLa and HEK 293. Transduction efficiencies differed among cultured epithelial cell types, with poorly differentiated cells transducing more efficiently than well-differentiated cells. A time-dependent increase in gene expression was observed after infection for both vectors. For Ad, but not for AAV, this increase was dependent on prolonged incubation of cells with the vector. Furthermore, for rAAV (but not for rAd), the delay in maximal transduction could be abrogated by wild-type Ad helper infection. Thus, although helper virus is not required for maximal transduction, it increases the kinetics by which this is achieved. Expression of Ad E4 open reading frame 6 or addition of either hydroxyurea or camptothecin resulted in increased AAV transduction, as previously demonstrated for nonairway cells (albeit to lower final levels), suggesting that second-strand synthesis may not be the sole cause of inefficient transduction. Finally, the efficiency of AAV-mediated ex vivo gene transfer to lung cells was similar to that previously described for Ad vectors in that transduction was limited to regions of epithelial injury and preferentially targeted basal-like cells. These studies address the primary factors influencing rAAV infection of human airway cells and should

  20. Factors influencing adeno-associated virus-mediated gene transfer to human cystic fibrosis airway epithelial cells: comparison with adenovirus vectors.

    PubMed

    Teramoto, S; Bartlett, J S; McCarty, D; Xiao, X; Samulski, R J; Boucher, R C

    1998-11-01

    Adeno-associated virus (AAV) vectors appear promising for use in gene therapy in cystic fibrosis (CF) patients, yet many features of AAV-mediated gene transfer to airway epithelial cells are not well understood. We compared the transduction efficiencies of AAV vectors and adenovirus (Ad) vectors in immortalized cell lines from CF patients and in nasal epithelial primary cultures from normal humans and CF patients. Similar dose-dependent relationships between the vector multiplicities of infection and the efficiencies of lacZ gene transfer were observed. However, levels of transduction for both Ad and recombinant AAV (rAAV) were significantly lower in the airway epithelial cell than in the control cell lines HeLa and HEK 293. Transduction efficiencies differed among cultured epithelial cell types, with poorly differentiated cells transducing more efficiently than well-differentiated cells. A time-dependent increase in gene expression was observed after infection for both vectors. For Ad, but not for AAV, this increase was dependent on prolonged incubation of cells with the vector. Furthermore, for rAAV (but not for rAd), the delay in maximal transduction could be abrogated by wild-type Ad helper infection. Thus, although helper virus is not required for maximal transduction, it increases the kinetics by which this is achieved. Expression of Ad E4 open reading frame 6 or addition of either hydroxyurea or camptothecin resulted in increased AAV transduction, as previously demonstrated for nonairway cells (albeit to lower final levels), suggesting that second-strand synthesis may not be the sole cause of inefficient transduction. Finally, the efficiency of AAV-mediated ex vivo gene transfer to lung cells was similar to that previously described for Ad vectors in that transduction was limited to regions of epithelial injury and preferentially targeted basal-like cells. These studies address the primary factors influencing rAAV infection of human airway cells and should

  1. Decreased T-cell proliferative response to common environmental antigens could be an indicator of early human immunodeficiency virus-mediated lymphocyte lesions.

    PubMed Central

    Tassinari, P; Deibis, L; Blanca, I; Bianco, N E; Echeverría de Pérez, G

    1995-01-01

    To evaluate CD4+/CD29+ cells and their responses to different antigens in polar stages of human immunodeficiency virus (HIV) infection, we studied 26 HIV-seropositive carriers (SPCs) and 15 patients with AIDS simultaneously with 20 healthy volunteers (HVs) and 10 seronegative homosexual and bisexual men (SNH). CD3, CD4, CD29, and CD45RA phenotypes were analyzed by two-color flow cytometry. Significant depletion of CD4+ T cells and both memory (CD4+/CD29+) and naive (CD4+/CD45RA+) T-cell subsets was found among SPCs and AIDS patients compared with the numbers of such cells in the HV and SNH groups. Responses to optimal doses of Candida albicans, streptokinase, and tetanus toxoid were explored in peripheral blood mononuclear cells and CD4(+)- and CD4+/CD29(+)-enriched cell populations. In SPCs, the response to C. albicans in peripheral blood mononuclear cells showed a statistically significant diminution compared with the response of HVs (15,308 versus 35,951 cpm). In addition, a significantly reduced response to streptokinase was evident only when cell preparations were CD4+/CD29+ enriched (3,048 versus 10,367 cpm). Furthermore, the SPC group comprised seven responders to at least one antigen and seven nonresponders to any of the selected specific antigens. Absence of a response in these latter patients was independent of the absolute counts of memory and naive T-cell populations. The response to tetanus toxoid, although diminished in SPCs, was not significantly different from that in controls. Our results suggest that defective responses to common environmental antigens, unrelated to the absolute number of CD4+/CD29+ cells, is probably an early indicator of an HIV-induced lymphocyte lesion. PMID:7583914

  2. [Use of the nested polymerase chain reaction in the differential diagnosis of human herpes simplex virus].

    PubMed

    Glukhov, A I; Gordeev, S A; Al'tshuler, M L; Severin, S E

    2003-02-01

    Herpes is one of the most widespread human viral pathologies. The article depicts a special modification of polymerized chain reaction--(PCR)--(referred to as "nested"), which has a higher sensitivity, specificity and reliability as compared to the ordinary PCR, and which is designed to detect the herpes viruses. The method was initially tested at purified preparation of viral DNA, and later--at clinical materials obtained from patients and healthy donors. Secretions from the urogenital tract (smears), scrapes from the urogenital tracts and urinal cellular samples were examined in patients. Herpes simplex was detected in all cases. As for the healthy people, the identical examinations produced in them mainly the negative findings. Therefore, the nested PCR is a simple, sensitive and effective instrument in the diagnostics and prevention of herpes; it can be recommended for a comprehensive usage in medical practice. PMID:12688217

  3. Antiviral activity of mycosynthesized silver nanoparticles against herpes simplex virus and human parainfluenza virus type 3

    PubMed Central

    Gaikwad, Swapnil; Ingle, Avinash; Gade, Aniket; Rai, Mahendra; Falanga, Annarita; Incoronato, Novella; Russo, Luigi; Galdiero, Stefania; Galdiero, Massimilano

    2013-01-01

    The interaction between silver nanoparticles and viruses is attracting great interest due to the potential antiviral activity of these particles, and is the subject of much research effort in the treatment of infectious diseases. In this work, we demonstrate that silver nanoparticles undergo a size-dependent interaction with herpes simplex virus types 1 and 2 and with human parainfluenza virus type 3. We show that production of silver nanoparticles from different fungi is feasible, and their antiviral activity is dependent on the production system used. Silver nanoparticles are capable of reducing viral infectivity, probably by blocking interaction of the virus with the cell, which might depend on the size and zeta potential of the silver nanoparticles. Smaller-sized nanoparticles were able to inhibit the infectivity of the viruses analyzed. PMID:24235828

  4. Directed Selection of Recombinant Human Monoclonal Antibodies to Herpes Simplex Virus Glycoproteins from Phage Display Libraries

    NASA Astrophysics Data System (ADS)

    Sanna, Pietro Paolo; Williamson, R. Anthony; de Logu, Alessandro; Bloom, Floyd E.; Burton, Dennis R.

    1995-07-01

    Human monoclonal antibodies have considerable potential in the prophylaxis and treatment of viral disease. However, only a few such antibodies suitable for clinical use have been produced to date. We have previously shown that large panels of human recombinant monoclonal antibodies against a plethora of infectious agents, including herpes simplex virus types 1 and 2, can be established from phage display libraries. Here we demonstrate that facile cloning of recombinant Fab fragments against specific viral proteins in their native conformation can be accomplished by panning phage display libraries against viral glycoproteins "captured" from infected cell extracts by specific monoclonal antibodies immobilized on ELISA plates. We have tested this strategy by isolating six neutralizing recombinant antibodies specific for herpes simplex glycoprotein gD or gB, some of which are against conformationally sensitive epitopes. By using defined monoclonal antibodies for the antigen-capture step, this method can be used for the isolation of antibodies to specific regions and epitopes within the target viral protein. For instance, monoclonal antibodies to a nonneutralizing epitope can be used in the capture step to clone antibodies to neutralizing epitopes, or antibodies to a neutralizing epitope can be used to clone antibodies to a different neutralizing epitope. Furthermore, by using capturing antibodies to more immunodominant epitopes, one can direct the cloning to less immunogenic ones. This method should be of value in generating antibodies to be used both in the prophylaxis and treatment of viral infections and in the characterization of the mechanisms of antibody protective actions at the molecular level.

  5. The interplay between human herpes simplex virus infection and the apoptosis and necroptosis cell death pathways.

    PubMed

    Yu, Xiaoliang; He, Sudan

    2016-01-01

    Human herpes simplex virus (HSV) is a ubiquitous human pathogen that establishes a lifelong latent infection and is associated with mucocutaneous lesions. In multicellular organisms, cell death is a crucial host defense mechanism that eliminates pathogen-infected cells. Apoptosis is a well-defined form of programmed cell death executed by a group of cysteine proteases, called caspases. Studies have shown that HSV has evolved strategies to counteract caspase activation and apoptosis by encoding anti-apoptotic viral proteins such as gD, gJ, Us3, LAT, and the ribonucleotide reductase large subunit (R1). Recently, necroptosis has been identified as a regulated form of necrosis that can be invoked in the absence of caspase activity. Receptor-interacting kinase 3 (RIP3 or RIPK3) has emerged as a central signaling molecule in necroptosis; it is activated via interaction with other RIP homotypic interaction motif (RHIM)-containing proteins such as RIP1 (or RIPK1). There is increasing evidence that HSV R1 manipulates necroptosis via the RHIM-dependent inactivation or activation ofRIP3 in a species-specific manner. This review summarizes the current understanding of the interplay between HSV infection and cell death pathways, with an emphasis on apoptosis and necroptosis. PMID:27154074

  6. Overcoming drug-resistant herpes simplex virus (HSV) infection by a humanized antibody

    PubMed Central

    Krawczyk, Adalbert; Arndt, Michaela A. E.; Grosse-Hovest, Ludger; Weichert, Wilko; Giebel, Bernd; Dittmer, Ulf; Hengel, Hartmut; Jäger, Dirk; Schneweis, Karl E.; Eis-Hübinger, Anna M.; Roggendorf, Michael; Krauss, Jürgen

    2013-01-01

    Despite the availability of antiviral chemotherapy, herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) infections remain a severe global health problem. Of particular concern is the growing incidence of drug resistance in immunocompromised patients, which stresses the urgency to develop new effective treatment alternatives. We have developed a humanized monoclonal antibody (mAb hu2c) that completely abrogates viral cell-to-cell spread, a key mechanism by which HSV-1/2 escapes humoral immune surveillance. Moreover, mAb hu2c neutralized HSV fully independent of complement and/or immune effector cell recruitment in a highly efficient manner. Prophylactic and therapeutic administration of mAb hu2c completely prevented infection-related mortality of severely immunodeficient mice being challenged with a lethal dose of HSV-1. The high neutralization capacity of mAb hu2c was fully maintained toward clinical HSV isolates being multiresistant to standard antiviral drugs, and infection was fully resolved in 7/8 nonobese diabetic/SCID mice being infected with a multidrug resistant HSV-1 patient isolate. Immunohistochemical studies revealed no significant cross-reactivity of the antibody toward human tissues. These features warrant further clinical development of mAb hu2c as an immunotherapeutic compound for the management of severe and particularly drug-resistant HSV infections. PMID:23569258

  7. Human cytomegalovirus renders cells non-permissive for replication of herpes simplex viruses

    SciTech Connect

    Cockley, K.D.

    1988-01-01

    The herpes simplex virus (HSV) genome during production infection in vitro may be subject to negative regulation which results in modification of the cascade of expression of herpes virus macromolecular synthesis leading to establishment of HSV latency. In the present study, human embryonic lung (HEL) cells infected with human cytomegalovirus (HCMV) restricted the replication of HSV type-1 (HSV-1). A delay in HSV replication of 15 hr as well as a consistent, almost 1000-fold inhibition of HSV replication in HCMV-infected cell cultures harvested 24 to 72 hr after superinfection were observed compared with controls infected with HSV alone. HSV type-2 (HSV-2) replication was similarly inhibited in HCMV-infected HEL cells. Prior ultraviolet-irradiation (UV) of HCMV removed the block to HSV replication, demonstrating the requirement for an active HCMV genome. HCMV deoxyribonucleic acid (DNA) negative temperature-sensitive (ts) mutants inhibited HSV replications as efficiently as wild-type (wt) HCMV at the non-permissive temperature. Evidence for penetration and replication of superinfecting HSV into HCMV-infected cells was provided by blot hybridization of HSV DNA synthesized in HSV-superinfected cell cultures and by cesium chloride density gradient analysis of ({sup 3}H)-labeled HSV-1-superinfected cells.

  8. Enhanced replication of herpes simplex virus type 1 in human cells

    SciTech Connect

    Miller, C.S.; Smith, K.O. )

    1991-02-01

    The effects of DNA-damaging agents on the replication of herpes simplex virus type 1 (HSV-1) were assessed in vitro. Monolayers of human lung fibroblast cell lines were exposed to DNA-damaging agents (methyl methanesulfonate (MMS), methyl methanethiosulfonate (MMTS), ultraviolet light (UV), or gamma radiation (GR)) at specific intervals, before or after inoculation with low levels of HSV-1. The ability of cell monolayers to support HSV-1 replication was measured by direct plaque assay and was compared with that of untreated control samples. In this system, monolayers of different cell lines infected with identical HSV-1 strains demonstrated dissimilar levels of recovery of the infectious virus. Exposure of DNA-repair-competent cell cultures to DNA-damaging agents produced time-dependent enhanced virus replication. Treatment with agent before virus inoculation significantly (p less than 0.025) increased the number of plaques by 10 to 68%, compared with untreated control cultures, while treatment with agent after virus adsorption significantly increased (p less than 0.025) the number of plaques by 7 to 15%. In a parallel series of experiments, cells deficient in DNA repair (xeroderma pigmentosum) failed to support enhanced virus replication. These results suggest that after exposure to DNA-damaging agents, fibroblasts competent in DNA repair amplify the replication of HSV-1, and that DNA-repair mechanisms that act on a variety of chromosomal lesions may be involved in the repair and biological activation of HSV-1 genomes.

  9. Entry of Oncolytic Herpes Simplex Virus into Human Squamous Cell Carcinoma Cells by Ultrasound.

    PubMed

    Okunaga, Shusuke; Takasu, Ayako; Meshii, Noritoshi; Imai, Tomoaki; Hamada, Masakagu; Iwai, Soichi; Yura, Yoshiaki

    2015-10-01

    Low-intensity ultrasound is a useful method to introduce materials into cells due to the transient formation of micropores, called sonoporations, on the cell membrane. Whether oncolytic herpes simplex virus type 1 (HSV-1) can be introduced into oral squamous cell carcinoma (SCC) cells through membrane pores remains undetermined. Human SCC cell line SAS and oncolytic HSV-1 RH2, which was deficient in the 134.5 gene and fusogenic, were used. Cells were exposed to ultrasound in the presence or absence of microbubbles. The increase of virus entry was estimated by plaque numbers. Viral infection was hardly established without the adsorption step, but plaque number was increased by the exposure of HSV-1-inoculated cells to ultrasound. Plaque number was also increased even if SAS cells were exposed to ultrasound and inoculated with RH2 without the adsorption step. This effect was abolished when the interval from ultrasound exposure to virus inoculation was prolonged. Scanning electron microscopy revealed depressed spots on the cell surface after exposure to ultrasound. These results suggest that oncolytic HSV-1 RH2 can be introduced into SAS cells through ultrasound-mediated pores of the cell membrane that are resealed after an interval. PMID:26516901

  10. Biophysical Characterization of Nucleophosmin Interactions with Human Immunodeficiency Virus Rev and Herpes Simplex Virus US11

    PubMed Central

    Nouri, Kazem; Moll, Jens M.; Milroy, Lech-Gustav; Hain, Anika; Dvorsky, Radovan; Amin, Ehsan; Lenders, Michael; Nagel-Steger, Luitgard; Howe, Sebastian; Smits, Sander H. J.; Hengel, Hartmut; Schmitt, Lutz; Münk, Carsten; Brunsveld, Luc; Ahmadian, Mohammad R.

    2015-01-01

    Nucleophosmin (NPM1, also known as B23, numatrin or NO38) is a pentameric RNA-binding protein with RNA and protein chaperon functions. NPM1 has increasingly emerged as a potential cellular factor that directly associates with viral proteins; however, the significance of these interactions in each case is still not clear. In this study, we have investigated the physical interaction of NPM1 with both human immunodeficiency virus type 1 (HIV-1) Rev and Herpes Simplex virus type 1 (HSV-1) US11, two functionally homologous proteins. Both viral proteins show, in mechanistically different modes, high affinity for a binding site on the N-terminal oligomerization domain of NPM1. Rev, additionally, exhibits low-affinity for the central histone-binding domain of NPM1. We also showed that the proapoptotic cyclic peptide CIGB-300 specifically binds to NPM1 oligomerization domain and blocks its association with Rev and US11. Moreover, HIV-1 virus production was significantly reduced in the cells treated with CIGB-300. Results of this study suggest that targeting NPM1 may represent a useful approach for antiviral intervention. PMID:26624888

  11. Entry of Oncolytic Herpes Simplex Virus into Human Squamous Cell Carcinoma Cells by Ultrasound

    PubMed Central

    Okunaga, Shusuke; Takasu, Ayako; Meshii, Noritoshi; Imai, Tomoaki; Hamada, Masakagu; Iwai, Soichi; Yura, Yoshiaki

    2015-01-01

    Low-intensity ultrasound is a useful method to introduce materials into cells due to the transient formation of micropores, called sonoporations, on the cell membrane. Whether oncolytic herpes simplex virus type 1 (HSV-1) can be introduced into oral squamous cell carcinoma (SCC) cells through membrane pores remains undetermined. Human SCC cell line SAS and oncolytic HSV-1 RH2, which was deficient in the γ134.5 gene and fusogenic, were used. Cells were exposed to ultrasound in the presence or absence of microbubbles. The increase of virus entry was estimated by plaque numbers. Viral infection was hardly established without the adsorption step, but plaque number was increased by the exposure of HSV-1-inoculated cells to ultrasound. Plaque number was also increased even if SAS cells were exposed to ultrasound and inoculated with RH2 without the adsorption step. This effect was abolished when the interval from ultrasound exposure to virus inoculation was prolonged. Scanning electron microscopy revealed depressed spots on the cell surface after exposure to ultrasound. These results suggest that oncolytic HSV-1 RH2 can be introduced into SAS cells through ultrasound-mediated pores of the cell membrane that are resealed after an interval. PMID:26516901

  12. Effects of dimethyl prostaglandin A1 on herpes simplex virus and human immunodeficiency virus replication

    NASA Technical Reports Server (NTRS)

    Hughes-Fulford, M.; McGrath, M. S.; Hanks, D.; Erickson, S.; Pulliam, L.

    1992-01-01

    We have investigated the direct effect of dimethyl prostaglandin A1 (dmPGA1) on the replication of herpes simplex virus (HSV) and human immunodeficiency virus type 1 (HIV-1). dmPGA1 significantly inhibited viral replication in both HSV and HIV infection systems at concentrations of dmPGA1 that did not adversely alter cellular DNA synthesis. The 50% inhibitory concentration (ID50) for several HSV type 1 (HSV-1) strains ranged from 3.8 to 5.6 micrograms/ml for Vero cells and from 4.6 to 7.3 micrograms/ml for human foreskin fibroblasts. The ID50s for two HSV-2 strains varied from 3.8 to 4.5 micrograms/ml for Vero cells; the ID50 was 5.7 micrograms/ml for human foreskin fibroblasts. We found that closely related prostaglandins did not have the same effect on the replication of HSV; dmPGE2 and dmPGA2 caused up to a 60% increase in HSV replication compared with that in untreated virus-infected cells. HIV-1 replication in acutely infected T cells (VB line) and chronically infected macrophages was assessed by quantitative decreases in p24 concentration. The effective ID50s were 2.5 micrograms/ml for VB cells acutely infected with HIV-1 and 5.2 micrograms/m for chronically infected macrophages. dmPGA1 has an unusual broad-spectrum antiviral activity against both HSV and HIV-1 in vitro and offers a new class of potential therapeutic agents for in vivo use.

  13. Treatment of experimental human mesothelioma using adenovirus transfer of the herpes simplex thymidine kinase gene.

    PubMed Central

    Smythe, W R; Hwang, H C; Elshami, A A; Amin, K M; Eck, S L; Davidson, B L; Wilson, J M; Kaiser, L R; Albelda, S M

    1995-01-01

    OBJECTIVE: The authors demonstrate the ability of an adenovirus vector expressing the herpes simplex thymidine kinase (HSVtk) gene to treat human malignant mesothelioma growing within the peritoneal cavity of severe combined immunodeficient (SCID) mice. BACKGROUND DATA: Introduction of the HSVtk gene into tumor cells renders them sensitive to the antiviral drug ganciclovir (GCV). This approach has been used previously to treat experimental brain tumors. Although malignant mesothelioma is refractory to current therapies, its localized nature and the accessibility of the pleural space make it a potential target for a similar type of in vivo gene therapy using adenovirus. METHODS: An adenovirus containing the HSVtk gene (Ad.RSVtk) was used to transduce mesothelioma cells in vitro. These cells were then injected into the flanks of SCID mice. Ad.RSVtk was also injected directly into the peritoneal cavity of SCID mice with established human mesothelioma tumors. Mice were subsequently treated for 7 days with GCV at a dose of 5 mg/kg. RESULTS: Mesothelioma cells transduced in vitro with Ad.RSVtk formed nodules when injected in the subcutaneous tissue. These tumors could be eliminated by the administration of GCV, even when as few as 10% of cells were transduced to express HSVtk (bystander effect). Administration of Ad.RSVtk into the peritoneal space of animals with established multifocal human mesothelioma followed by GCV therapy resulted in the eradication of macroscopic tumor in 90% of animals and microscopic tumor in 80% of animals when evaluated after 30 days. The median survival of animals treated with Ad.RSVtk/GCV was significantly longer than that of control animals treated with similar protocols. CONCLUSION: These results indicate that an adenoviral vector containing the HSVtk gene is effective in treating established malignant mesothelioma in an in vivo setting and raise the possibility of using adenovirus transfer of HSVtk for clinical trials in mesothelioma and

  14. Global Secretome Characterization of Herpes Simplex Virus 1-Infected Human Primary Macrophages

    PubMed Central

    Miettinen, Juho J.; Matikainen, Sampsa

    2012-01-01

    Herpes simplex virus 1 (HSV-1) is a common pathogen infecting the majority of people worldwide at some stage in their lives. The early host response to viral infection is initiated by the cells of the innate immune response, including macrophages. Here, we have characterized the secretome of HSV-1-infected human primary macrophages using high-throughput quantitative proteomics. We identified and quantified 516 distinct human proteins with high confidence from the macrophage secretome upon HSV-1 infection, and the secretion of 411 proteins was >2-fold increased upon beta interferon (IFN-β) priming and/or HSV-1 infection. Bioinformatics analysis of the secretome data revealed that most of the secreted proteins were intracellular, and almost 80% of the proteins whose secretion increased more than 2-fold were known exosomal proteins. This strongly suggests that nonclassical, vesicle-mediated protein secretion is activated in IFN-β-primed and HSV-1-infected macrophages. Proteins related to immune and inflammatory responses, interferon-induced proteins, and endogenous danger signal proteins were efficiently secreted upon IFN-β priming and HSV-1 infection. The secreted IFN-induced proteins include interferon-induced tetratricopeptide protein 2 (IFIT2), IFIT3, signal transducer and activator of transcription 1 (STAT1), and myxovirus resistance protein A (MxA), implicating that these proteins also have important extracellular antiviral functions. Proinflammatory cytokine interleukin-1β was not released by HSV-1-infected macrophages, demonstrating that HSV-1 can antagonize inflammasome function. In conclusion, our results provide a global view of the secretome of HSV-1-infected macrophages, revealing host factors possibly having a role in antiviral defense. PMID:22973042

  15. Griffithsin and Carrageenan Combination To Target Herpes Simplex Virus 2 and Human Papillomavirus

    PubMed Central

    Levendosky, Keith; Mizenina, Olga; Martinelli, Elena; Jean-Pierre, Ninochka; Kizima, Larisa; Rodriguez, Aixa; Kleinbeck, Kyle; Bonnaire, Thierry; Robbiani, Melissa; Zydowsky, Thomas M.; O'Keefe, Barry R.

    2015-01-01

    Extensive preclinical evaluation of griffithsin (GRFT) has identified this lectin to be a promising broad-spectrum microbicide. We set out to explore the antiviral properties of a GRFT and carrageenan (CG) combination product against herpes simplex virus 2 (HSV-2) and human papillomavirus (HPV) as well as determine the mechanism of action (MOA) of GRFT against both viruses. We performed the experiments in different cell lines, using time-of-addition and temperature dependence experiments to differentiate inhibition of viral attachment from entry and viral receptor internalization. Surface plasmon resonance (SPR) was used to assess GRFT binding to viral glycoproteins, and immunoprecipitation and immunohistochemistry were used to identify the specific glycoprotein involved. We determined the antiviral activity of GRFT against HSV-2 to be a 50% effective concentration (EC50) of 230 nM and provide the first evidence that GRFT has moderate anti-HPV activity (EC50 = 0.429 to 1.39 μM). GRFT blocks the entry of HSV-2 and HPV into target cells but not the adsorption of HSV-2 and HPV onto target cells. The results of the SPR, immunoprecipitation, and immunohistochemistry analyses of HSV-2 combined suggest that GRFT may block viral entry by binding to HSV-2 glycoprotein D. Cell-based assays suggest anti-HPV activity through α6 integrin internalization. The GRFT-CG combination product but not GRFT or CG alone reduced HSV-2 vaginal infection in mice when given an hour before challenge (P = 0.0352). While GRFT significantly protected mice against vaginal HPV infection when dosed during and after HPV16 pseudovirus challenge (P < 0.026), greater CG-mediated protection was afforded by the GRFT-CG combination for up to 8 h (P < 0.0022). These findings support the development of the GRFT-CG combination as a broad-spectrum microbicide. PMID:26369967

  16. Griffithsin and Carrageenan Combination To Target Herpes Simplex Virus 2 and Human Papillomavirus.

    PubMed

    Levendosky, Keith; Mizenina, Olga; Martinelli, Elena; Jean-Pierre, Ninochka; Kizima, Larisa; Rodriguez, Aixa; Kleinbeck, Kyle; Bonnaire, Thierry; Robbiani, Melissa; Zydowsky, Thomas M; O'Keefe, Barry R; Fernández-Romero, José A

    2015-12-01

    Extensive preclinical evaluation of griffithsin (GRFT) has identified this lectin to be a promising broad-spectrum microbicide. We set out to explore the antiviral properties of a GRFT and carrageenan (CG) combination product against herpes simplex virus 2 (HSV-2) and human papillomavirus (HPV) as well as determine the mechanism of action (MOA) of GRFT against both viruses. We performed the experiments in different cell lines, using time-of-addition and temperature dependence experiments to differentiate inhibition of viral attachment from entry and viral receptor internalization. Surface plasmon resonance (SPR) was used to assess GRFT binding to viral glycoproteins, and immunoprecipitation and immunohistochemistry were used to identify the specific glycoprotein involved. We determined the antiviral activity of GRFT against HSV-2 to be a 50% effective concentration (EC50) of 230 nM and provide the first evidence that GRFT has moderate anti-HPV activity (EC50 = 0.429 to 1.39 μM). GRFT blocks the entry of HSV-2 and HPV into target cells but not the adsorption of HSV-2 and HPV onto target cells. The results of the SPR, immunoprecipitation, and immunohistochemistry analyses of HSV-2 combined suggest that GRFT may block viral entry by binding to HSV-2 glycoprotein D. Cell-based assays suggest anti-HPV activity through α6 integrin internalization. The GRFT-CG combination product but not GRFT or CG alone reduced HSV-2 vaginal infection in mice when given an hour before challenge (P = 0.0352). While GRFT significantly protected mice against vaginal HPV infection when dosed during and after HPV16 pseudovirus challenge (P < 0.026), greater CG-mediated protection was afforded by the GRFT-CG combination for up to 8 h (P < 0.0022). These findings support the development of the GRFT-CG combination as a broad-spectrum microbicide. PMID:26369967

  17. Dissection of the Antibody Response against Herpes Simplex Virus Glycoproteins in Naturally Infected Humans

    PubMed Central

    Huang, Zhen-Yu; Whitbeck, J. Charles; Ponce de Leon, Manuel; Lou, Huan; Wald, Anna; Krummenacher, Claude; Eisenberg, Roselyn J.; Cohen, Gary H.

    2014-01-01

    ABSTRACT Relatively little is known about the extent of the polyclonal antibody (PAb) repertoire elicited by herpes simplex virus (HSV) glycoproteins during natural infection and how these antibodies affect virus neutralization. Here, we examined IgGs from 10 HSV-seropositive individuals originally classified as high or low virus shedders. All PAbs neutralized virus to various extents. We determined which HSV entry glycoproteins these PAbs were directed against: glycoproteins gB, gD, and gC were recognized by all sera, but fewer sera reacted against gH/gL. We previously characterized multiple mouse monoclonal antibodies (MAbs) and mapped those with high neutralizing activity to the crystal structures of gD, gB, and gH/gL. We used a biosensor competition assay to determine whether there were corresponding human antibodies to those epitopes. All 10 samples had neutralizing IgGs to gD epitopes, but there were variations in which epitopes were seen in individual samples. Surprisingly, only three samples contained neutralizing IgGs to gB epitopes. To further dissect the nature of these IgGs, we developed a method to select out gD- and gB-specific IgGs from four representative sera via affinity chromatography, allowing us to determine the contribution of antibodies against each glycoprotein to the overall neutralization capacity of the serum. In two cases, gD and gB accounted for all of the neutralizing activity against HSV-2, with a modest amount of HSV-1 neutralization directed against gC. In the other two samples, the dominant response was to gD. IMPORTANCE Antibodies targeting functional epitopes on HSV entry glycoproteins mediate HSV neutralization. Virus-neutralizing epitopes have been defined and characterized using murine monoclonal antibodies. However, it is largely unknown whether these same epitopes are targeted by the humoral response to HSV infection in humans. We have shown that during natural infection, virus-neutralizing antibodies are principally

  18. Lentigo Simplex

    MedlinePlus

    ... body, including areas that are not exposed to sunlight. Multiple lentigos are associated with several inherited syndromes, ... as identical to those caused by exposure to sunlight. Who's At Risk Lentigo simplex may occur in ...

  19. Herpes Simplex

    MedlinePlus

    ... is an infection that is caused by a herpes simplex virus (HSV). Oral herpes causes cold sores around the mouth or face. ... affects the genitals, buttocks or anal area. Other herpes infections can affect the eyes, skin, or other parts of the body. The virus can be dangerous in newborn babies or in ...

  20. A subset of human plasmacytoid dendritic cells expresses CD8α upon exposure to herpes simplex virus type 1

    PubMed Central

    Schuster, Philipp; Thomann, Sabrina; Werner, Maren; Vollmer, Jörg; Schmidt, Barbara

    2015-01-01

    Classical and plasmacytoid dendritic cells (DC) play important roles in the defense against murine and human infections with herpes simplex virus (HSV). So far, CD8α expression has only been reported for murine DC. CD8α+ DC have prominent cross-presenting activities, which are enhanced by murine CD8α+ PDC. The human orthologue of murine CD8α+ DC, the CD141 (BDCA3)+ DC, mainly cross-present after TLR3 ligation. We report here the serendipitous finding that a subset of human PDC upregulates CD8α upon HSV-1 stimulation, as shown by gene array and flow cytometry analyses. CD8α, not CD8ß, was expressed upon exposure. Markers of activation, migration, and costimulation were upregulated on CD8α-expressing human PDC. In these cells, increased cytokine and chemokine levels were detected that enhance development and function of T, B, and NK cells, and recruit immature DC, monocytes, and Th1 cells, respectively. Altogether, human CD8α+ PDC exhibit a highly activated phenotype and appear to recruit other immune cells to the site of inflammation. Further studies will show whether CD8α-expressing PDC contribute to antigen cross-presentation, which may be important for immune defenses against HSV infections in vitro and in vivo. PMID:26082771

  1. Entry Pathways of Herpes Simplex Virus Type 1 into Human Keratinocytes Are Dynamin- and Cholesterol-Dependent

    PubMed Central

    Hsu, Mei-Ju; Rixon, Frazer J.; Knebel-Mörsdorf, Dagmar

    2011-01-01

    Herpes simplex virus type 1 (HSV-1) can enter cells via endocytic pathways or direct fusion at the plasma membrane depending on the cell line and receptor(s). Most studies into virus entry have used cultured fibroblasts but since keratinocytes represent the primary entry site for HSV-1 infection in its human host, we initiated studies to characterize the entry pathway of HSV-1 into human keratinocytes. Electron microscopy studies visualized free capsids in the cytoplasm and enveloped virus particles in vesicles suggesting viral uptake both by direct fusion at the plasma membrane and by endocytic vesicles. The ratio of the two entry modes differed in primary human keratinocytes and in the keratinocyte cell line HaCaT. Inhibitor studies further support a role for endocytosis during HSV-1 entry. Infection was inhibited by the cholesterol-sequestering drug methyl-β-cyclodextrin, which demonstrates the requirement for host cholesterol during virus entry. Since the dynamin-specific inhibitor dynasore and overexpression of a dominant-negative dynamin mutant blocked infection, we conclude that the entry pathways into keratinocytes are dynamin-mediated. Electron microscopy studies confirmed that virus uptake is completely blocked when the GTPase activity of dynamin is inhibited. Ex vivo infection of murine epidermis that was treated with dynasore further supports the essential role of dynamin during entry into the epithelium. Thus, we conclude that HSV-1 can enter human keratinocytes by alternative entry pathways that require dynamin and host cholesterol. PMID:22022400

  2. Activation of human papillomavirus type 18 gene expression by herpes simplex virus type 1 viral transactivators and a phorbol ester

    SciTech Connect

    Gius, D.; Laimins, L.A.

    1989-02-01

    Several viral trans-activators and a tumor promoter were examined for the ability to activate human papillomavirus type 18 (HPV-18) gene expression. A plasmid containing the HPV-18 noncoding region placed upstream of the chloramphenicol acetyltransferase reporter gene was cotransfected with different herpes simplex virus type 1 (HSV-1) genes into several cell lines. Both HSV-1 TIF and ICPO activated HPV-18 expression; however, activation by TIF was observed only in epithelial cells, while ICPO stimulated expression in a wide variety of cells. The element activated by both TIF and ICOP was mapped to a 229-base-pair fragment which also contains an HPV-18 epithelial cell-preferred enhancer. The inclusion of a papillomavirus E2 trans-activator with TIF and ICOP further increased HPV-18 expression. In contrast, the HSV-1 ICP4 and ICP27 genes, as well as the human T-cell lymphotropic virus type I and human immunodeficiency virus type 1 tat genes, were found to have no effect on HPV-18 expression. In transient assays, the addition of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) also activated HPV-18 expression. The region of HPV-18 activated by TPA was localized to a sequence which is homologous to other TPA-responsive elements.

  3. Herpes simplex virus 1 tropism for human sensory ganglion neurons in the severe combined immunodeficiency mouse model of neuropathogenesis.

    PubMed

    Zerboni, Leigh; Che, Xibing; Reichelt, Mike; Qiao, Yanli; Gu, Haidong; Arvin, Ann

    2013-03-01

    The tropism of herpes simplex virus (HSV-1) for human sensory neurons infected in vivo was examined using dorsal root ganglion (DRG) xenografts maintained in mice with severe combined immunodeficiency (SCID). In contrast to the HSV-1 lytic infectious cycle in vitro, replication of the HSV-1 F strain was restricted in human DRG neurons despite the absence of adaptive immune responses in SCID mice, allowing the establishment of neuronal latency. At 12 days after DRG inoculation, 26.2% of human neurons expressed HSV-1 protein and 13.1% expressed latency-associated transcripts (LAT). Some infected neurons showed cytopathic changes, but HSV-1, unlike varicella-zoster virus (VZV), only rarely infected satellite cells and did not induce fusion of neuronal and satellite cell plasma membranes. Cell-free enveloped HSV-1 virions were observed, indicating productive infection. A recombinant HSV-1-expressing luciferase exhibited less virulence than HSV-1 F in the SCID mouse host, enabling analysis of infection in human DRG xenografts for a 61-day interval. At 12 days after inoculation, 4.2% of neurons expressed HSV-1 proteins; frequencies increased to 32.1% at 33 days but declined to 20.8% by 61 days. Frequencies of LAT-positive neurons were 1.2% at 12 days and increased to 40.2% at 33 days. LAT expression remained at 37% at 61 days, in contrast to the decline in neurons expressing viral proteins. These observations show that the progression of HSV-1 infection is highly restricted in human DRG, and HSV-1 genome silencing occurs in human neurons infected in vivo as a consequence of virus-host cell interactions and does not require adaptive immune control. PMID:23269807

  4. Human gamma interferon and tumor necrosis factor exert a synergistic blockade on the replication of herpes simplex virus.

    PubMed Central

    Feduchi, E; Alonso, M A; Carrasco, L

    1989-01-01

    The replication of herpes simplex virus type 1 (HSV-1) is not inhibited in either HeLa or HEp-2 cells treated with human alpha interferon (HuIFN-alpha), particularly when high multiplicities of infection are used. However, HuIFN-gamma partially inhibits HSV-1 translation in HEp-2 cells infected at low multiplicities. Under these conditions, the transcription of genes alpha 22, TK, and gamma 0 is greatly diminished. The combined addition of human tumor necrosis factor (TNF) and HuIFN-gamma to HEp-2 cells exerts a synergistic inhibition of HSV-1 translation. Cells treated with both cytokines continue synthesizing cellular proteins, even 20 h after HSV-1 infection. As little as 10 U of IFN-gamma per ml blocked HSV-1 DNA replication, provided that TNF was also present in the medium. Analyses of HSV-1 gene transcription suggest that the action of both TNF and IFN-gamma blocked a step that comes at or prior to early HSV-1 gene expression. This early step in HSV-1 replication inhibited by TNF and IFN-gamma occurs after virus attachment and entry into cells, since the internalization of radioactive HSV-1 virion particles was not blocked by the presence of the two cytokines. Therefore, we conclude that the synergistic action of TNF plus IFN-gamma affects a step in HSV-1 replication that comes after virus entry but before or at the transcription of immediate-early genes. Images PMID:2536838

  5. Native and recombinant herpes simplex virus type 1 envelope proteins induce human immune T-lymphocyte responses.

    PubMed

    Torseth, J W; Cohen, G H; Eisenberg, R J; Berman, P W; Lasky, L A; Cerini, C P; Heilman, C J; Kerwar, S; Merigan, T C

    1987-05-01

    The abilities of whole herpes simplex virus type 1 (HSV-1) antigen (HSV-ag) and purified HSV-1 native and recombinant envelope proteins to stimulate in vitro T-lymphocyte responses were compared in patients with recurrent herpes labialis. Immunochemically purified preparations of native glycoproteins B, C, and D (ngB, ngC, ngD) from cultured HSV-1 as well as expressed recombinant plasmid preparations of gD (rgD-1t, rgD-45K) elicited lymphocyte proliferation (LT) and production of gamma interferon (IFN-gamma) and interleukin-2 (IL-2) only in seropositive individuals. The IFN-gamma induced by rgD-1t correlated with the time to the next herpetic lesion in 19 volunteers followed to recurrence (r = 0.69, P less than 0.008), although the magnitude and frequency of LT and IFN-gamma responses were lower with either recombinant or native purified antigens than with the whole-virus antigen. Combinations of ngB plus ngD or ngB plus ngC plus ngD stimulated more IFN-gamma, equivalent to whole-virus-antigen responses. Recombinant-derived human IL-2 also specifically increased LT and IFN-gamma responses in antigen-driven cultures. ngD stimulated IL-2 and LT responses similar to those of whole-virus antigen and higher than those of ngC. HSV-ag and ngB induced significantly higher titers of total IFN than could be accounted for by IFN-gamma; this was not seen for the other antigens, which induced only IFN-gamma. HSV-ag-driven Leu 2a-, plastic-nonadherent blood cells, unlike whole peripheral blood mononuclear cells, showed evidence of an increase and then a decline in the frequency of HSV-responsive cells after a lesion recurrence. These studies suggest that HSV-1 envelope proteins are capable of stimulating an immune T-helper-cell response which is associated with the prevention of human herpes simplex lesion recurrence. Although the whole virus probably contains additional important antigens, increasing concentrations or combinations of certain purified glycoproteins or the

  6. Positive associations between infections of Toxoplasma gondii and seropositivity with Anisakis simplex in human patients suffering from chronic urticaria.

    PubMed

    Fernández-Fígares, V; Rodero, M; Valls, A; De Frutos, C; Daschner, A; Cuéllar, C

    2015-11-01

    Toxoplasma gondii is a food-borne and orofecal microorganism which produces chronic infection, and attempts have been made to prove its negative association with atopy in the context of the hygiene hypothesis. Anisakis simplex is a fish parasite associated with chronic urticaria (CU) in endemic regions. We analysed the relationship between both infectious agents in CU. We included 42 patients with chronic urticaria (18 patients with CU associated with A. simplex sensitization and 24 not sensitized CU patients). Patients were assessed for atopy by a skin prick test (SPT) against common aeroallergens and for respiratory symptoms. Anisakis simplex sensitization was assessed by SPT and specific IgE by CAP fluoro-enzyme immunoassay (CAP-FEIA). Anti-T. gondii IgG levels were measured by enzyme-linked immunosorbent assay (ELISA). CU patients were analysed with respect to T. gondii seropositivity, A. simplex sensitization, atopy and immigrant status. The seroprevalence of T. gondii was 40.5% in CU patients and 42.1% in the control group. Immigrants were more frequently infected by T. gondii (41.2% versus 12%; P =0.036). Anti-T. gondii IgG antibodies were associated with past A. simplex parasitism (odds ratio 6.73; P =0.03) and independently with atopic sensitization (odds ratio 5.85; P =0.04). In CU patients, T. gondii has no protective effect on atopic sensitization or A. simplex sensitization. PMID:24991841

  7. Access to Nectin Favors Herpes Simplex Virus Infection at the Apical Surface of Polarized Human Epithelial Cells▿

    PubMed Central

    Galen, Benjamin; Cheshenko, Natalia; Tuyama, Ana; Ramratnam, Bharat; Herold, Betsy C.

    2006-01-01

    Viral entry may preferentially occur at the apical or the basolateral surfaces of polarized cells, and differences may impact pathogenesis, preventative strategies, and successful implementation of viral vectors for gene therapy. The objective of these studies was to examine the polarity of herpes simplex virus (HSV) entry using several different human epithelial cell lines. Human uterine (ECC-1), colonic (CaCo-2), and retinal pigment (ARPE-19) epithelial cells were grown on collagen-coated inserts, and the polarity was monitored by measuring the transepithelial cell resistance. Controls were CaSki cells, a human cervical cell line that does not polarize in vitro. The polarized cells, but not CaSki cells, were 16- to 50-fold more susceptible to HSV infection at the apical surface than at the basolateral surface. Disruption of the tight junctions by treatment with EGTA overcame the restriction on basolateral infection but had no impact on apical infection. No differences in binding at the two surfaces were observed. Confocal microscopy demonstrated that nectin-1, the major coreceptor for HSV entry, sorted preferentially to the apical surface, overlapping with adherens and tight junction proteins. Transfection with small interfering RNA specific for nectin-1 resulted in a significant reduction in susceptibility to HSV at the apical surface but had little impact on basolateral infection. Infection from the apical but not the basolateral surface triggered focal adhesion kinase phosphorylation and led to nuclear transport of viral capsids and viral gene expression. These studies indicate that access to nectin-1 contributes to preferential apical infection of these human epithelial cells by HSV. PMID:17005657

  8. Herpes simplex virus type 2 or human herpesvirus 8 infection and prostate cancer risk: A meta-analysis.

    PubMed

    Ge, Xiaoxiao; Wang, Xiao; Shen, Peng

    2013-05-01

    Prostate cancer is the second most frequently diagnosed type of cancer and the sixth leading cause of cancer mortality among males worldwide. The aim of this study was to investigate the association between the infection by herpes simplex virus type 2 (HSV-2) or human herpesvirus 8 (HHV-8) and the risk of prostate cancer. A systematic literature search was performed using PubMed, Cochrane Library, Web of Science, Scopus, CNKI and CBM. The association of HSV-2 or HHV-8 infection with the risk of prostate cancer was separately assessed. Estimates of the odds ratio (OR) with 95% confidence interval (CI) were pooled by the fixed- or random-effects model. A total of 11 articles with 2,996 cases and 3,875 controls were included in this meta-analysis. HSV-2 infection was associated with increased prostate cancer risk (OR=1.209; 95% CI, 1.003-1.456). Results of the stratified analysis suggested that such an association existed among participants from North and South America (OR=1.226; 95% CI, 1.000-1.503). No significant correlation was observed in the HHV-8 group (OR=1.106; 95% CI, 0.765-1.598). Further investigations and large-sample studies are required to elucidate the possible mechanism underlying viral carcinogenesis and the association between herpes virus infection and the risk of prostate cancer. PMID:24648964

  9. Human antibody-dependent cellular cytotoxicity and natural killer cytotoxicity to herpes simplex virus-infected autologous and allogeneic cells.

    PubMed Central

    Kohl, S; Moore, C M

    1983-01-01

    Using cultured skin shavings, human cellular cytotoxicity to uninfected and herpes simplex virus (HSV)-infected autologous and allogeneic fibroblasts and Chang liver cells was analysed in a 51Cr release assay. The effector cell requirements and characterization, time kinetics and antibody requirements were similar using each HSV-infected target cell in an antibody-dependent cellular cytotoxicity (ADCC) system. There was lower natural killer cytotoxicity (NKC) to uninfected autologous cells than unrelated cells in an 18 hr assay. NKC to infected autologous and unrelated fibroblasts was similar to that mediated against Chang liver cells. Thus NKC to uninfected fibroblasts correlated with the relationship of effector and target cells while NKC to infected cells correlated with the intrinsic lytic potential of the effector cells. The autologous system offers little advantage in the analysis of ADCC or NKC in normal individuals to virus-infected cells, but is probably crucial for the detection of HLA-restricted T-cell cytotoxicity. The demonstration of autologous anti-viral ADCC and NKC lends further credence to the in vivo importance of the mechanisms. PMID:6848451

  10. Complement Opsonization Promotes Herpes Simplex Virus 2 Infection of Human Dendritic Cells

    PubMed Central

    Ellegård, Rada; Nyström, Sofia; Rondahl, Elin; Serrander, Lena; Bergström, Tomas; Sjöwall, Christopher; Eriksson, Kristina

    2016-01-01

    ABSTRACT Herpes simplex virus 2 (HSV-2) is one of the most common sexually transmitted infections globally, with a very high prevalence in many countries. During HSV-2 infection, viral particles become coated with complement proteins and antibodies, both present in genital fluids, which could influence the activation of immune responses. In genital mucosa, the primary target cells for HSV-2 infection are epithelial cells, but resident immune cells, such as dendritic cells (DCs), are also infected. DCs are the activators of the ensuing immune responses directed against HSV-2, and the aim of this study was to examine the effects opsonization of HSV-2, either with complement alone or with complement and antibodies, had on the infection of immature DCs and their ability to mount inflammatory and antiviral responses. Complement opsonization of HSV-2 enhanced both the direct infection of immature DCs and their production of new infectious viral particles. The enhanced infection required activation of the complement cascade and functional complement receptor 3. Furthermore, HSV-2 infection of DCs required endocytosis of viral particles and their delivery into an acid endosomal compartment. The presence of complement in combination with HSV-1- or HSV-2-specific antibodies more or less abolished HSV-2 infection of DCs. Our results clearly demonstrate the importance of studying HSV-2 infection under conditions that ensue in vivo, i.e., conditions under which the virions are covered in complement fragments and complement fragments and antibodies, as these shape the infection and the subsequent immune response and need to be further elucidated. IMPORTANCE During HSV-2 infection, viral particles should become coated with complement proteins and antibodies, both present in genital fluids, which could influence the activation of the immune responses. The dendritic cells are activators of the immune responses directed against HSV-2, and the aim of this study was to examine the

  11. Human and Simian Immunodeficiency Virus-Mediated Upregulation of the Apoptotic Factor TRAIL Occurs in Antigen-Presenting Cells from AIDS-Susceptible but Not from AIDS-Resistant Species▿ †

    PubMed Central

    Kim, Nayoung; Dabrowska, Alicja; Jenner, Richard G.; Aldovini, Anna

    2007-01-01

    Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections lead to AIDS in humans and rhesus macaques (RM), while they are asymptomatic in species naturally infected with SIV, such as chimpanzees, sooty mangabeys (SM), and African green monkeys (AGM). Differential CD4+ T-cell apoptosis may be responsible for these species-specific differences in susceptibility to disease. To identify factors that influence the different apoptotic responses of these species, we analyzed virus-infected human and nonhuman primate peripheral blood mononuclear cells (PBMC). We found that the apoptotic factor TRAIL was present at higher levels in human and RM PBMC cultures and was mediating, at least in part, CD4+ T-cell apoptosis in these cultures. The species-specific increase in TRAIL and death receptor expression observed with cultures also occurred in vivo in SIV-infected RM but not in SIV-infected SM. In human and RM myeloid immature dendritic cells and macrophages, the virus-induced expression of TRAIL and other interferon-inducible genes, which did not occur in the same cells from chimpanzee, SM, and AGM, was Tat dependent. Our results link the differential induction of TRAIL in human and nonhuman primate cells to species-specific differences in disease susceptibility. PMID:17494085

  12. Human and simian immunodeficiency virus-mediated upregulation of the apoptotic factor TRAIL occurs in antigen-presenting cells from AIDS-susceptible but not from AIDS-resistant species.

    PubMed

    Kim, Nayoung; Dabrowska, Alicja; Jenner, Richard G; Aldovini, Anna

    2007-07-01

    Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections lead to AIDS in humans and rhesus macaques (RM), while they are asymptomatic in species naturally infected with SIV, such as chimpanzees, sooty mangabeys (SM), and African green monkeys (AGM). Differential CD4(+) T-cell apoptosis may be responsible for these species-specific differences in susceptibility to disease. To identify factors that influence the different apoptotic responses of these species, we analyzed virus-infected human and nonhuman primate peripheral blood mononuclear cells (PBMC). We found that the apoptotic factor TRAIL was present at higher levels in human and RM PBMC cultures and was mediating, at least in part, CD4(+) T-cell apoptosis in these cultures. The species-specific increase in TRAIL and death receptor expression observed with cultures also occurred in vivo in SIV-infected RM but not in SIV-infected SM. In human and RM myeloid immature dendritic cells and macrophages, the virus-induced expression of TRAIL and other interferon-inducible genes, which did not occur in the same cells from chimpanzee, SM, and AGM, was Tat dependent. Our results link the differential induction of TRAIL in human and nonhuman primate cells to species-specific differences in disease susceptibility. PMID:17494085

  13. Repertoire of Epitopes Recognized by Serum IgG from Humans Vaccinated with Herpes Simplex Virus 2 Glycoprotein D

    PubMed Central

    Huang, Zhen-Yu; Cairns, Tina M.; Gallagher, John R.; Lou, Huan; Ponce-de-Leon, Manuel; Belshe, Robert B.; Eisenberg, Roselyn J.; Cohen, Gary H.

    2014-01-01

    ABSTRACT The results of a clinical trial of a subunit vaccine against genital herpes were recently reported (R. B. Belshe, P. A. Leone, D. I. Bernstein, A. Wald, M. J. Levin, J. T. Stapleton, I. Gorfinkel, R. L. Morrow, M. G. Ewell, A. Stokes-Riner, G. Dubin, T. C. Heineman, J. M. Schulte, C. D. Deal, N. Engl. J. Med. 366:34–43, 2012, doi:10.1056/NEJMoa1103151). The vaccine consisted of a soluble form of herpes simplex virus 2 (HSV-2) glycoprotein D (gD2) with adjuvant. The goal of the current study was to examine the composition of the humoral response to gD2 within a selected subset of vaccinated individuals. Serum samples from 30 vaccine recipients were selected based upon relative enzyme-linked immunosorbent assay (ELISA) titers against gD2; 10 samples had high titers, 10 had medium titers, and the remaining 10 had low ELISA titers. We employed a novel, biosensor-based monoclonal antibody (MAb)-blocking assay to determine whether gD2 vaccination elicited IgG responses against epitopes overlapping those of well-characterized MAbs. Importantly, IgGs from the majority of gD2-immunized subjects competed for gD binding with four antigenically distinct virus-neutralizing MAbs (MC2, MC5, MC23, and DL11). Screening of patient IgGs against overlapping peptides spanning the gD2 ectodomain revealed that about half of the samples contained antibodies against linear epitopes within the N and C termini of gD2. We found that the virus-neutralizing abilities of the 10 most potent samples correlated with overall gD-binding activity and to an even greater extent with the combined content of IgGs against the epitopes of MAbs MC2, MC5, MC23, and DL11. This suggests that optimal virus-neutralizing activity is achieved by strong and balanced responses to the four major discontinuous neutralizing epitopes of gD2. IMPORTANCE Several herpes simplex virus 2 (HSV-2) subunit vaccine studies have been conducted in human subjects using a recombinant form of HSV-2 glycoprotein D (gD2

  14. Evaluation of Cynanchum otophyllum glucan sulfate against human immunodeficiency virus and herpes simplex virus as a microbicide agent

    PubMed Central

    Tao, Jian; Yang, Jing; Chen, Chaoyin; Cao, Xiaomei; Zhao, Shenglan; Ben, Kunlong

    2011-01-01

    Objective: The root of Cynanchum otophyllum—also known as Qing Yang Sheng—is a traditional ethnical Chinese medicine. The objective of this study was to evaluate in vitro activities and safety of C. otophyllum glucan sulfate (PS20) against Human Immunodeficiency Virus (HIV) and Herpes Simplex Virus (HSV). Materials and Methods: Anti-HIV activity was detected with syncytial formation assay and quantitative P24 Enzyme-Linked Immunosorbent Assay (ELISA). Anti-HSV activity was detected with plaque reduction assay; cytotoxicity was tested with MTT colorimetric assay; and anti-bacterial activity was tested with microdilution method. Anti-HIV mechanism was investigated with fusion inhibition, time of addition, and pretreatment. Results: The 50% Inhibition Concentration (IC50) of PS20 for HIV-1IIIB, HIV-Ada-M, HIV-1Bal, HSV-I, and -II were 0.26 ± 0.02 mM, 0.46 ± 0.02 mM, 0.90 ± 0.04 mM, 3.45 ± 0.85 μM, and 0.70 ± 0.22 mM, respectively. Selectivity Indices (SI) were 653, 50, 39, 85, and 362, respectively. Studies on anti-HIV mechanism of PS20 showed that the target molecule should be the envelope protein. The 50% Cytotoxicity Concentrations (CC50) of PS20 for HeLa and ME-180 cell lines and human foreskin fibroblast cells was more than 70 μM. The Minimum Inhibitory Concentration (MIC) for vaginal lactobacilli was more than 1000 μM. Conclusion: PS20 possesses anti-HIV and HSV effect and low cytotoxicity to epithelium cells and vaginal lactobacilli. It may be considered as a potential microbicide agent for further investigation. PMID:22021996

  15. Lichen simplex chronicus

    MedlinePlus

    Lichen simplex chronicus is a skin condition caused by chronic itching and scratching. ... You can control lichen simplex chronicus by controlling scratching and reducing stress. The condition may return or move to different areas on the ...

  16. Herpes Simplex Virus (HSV)

    MedlinePlus

    ... rashes clinical tools newsletter | contact Share | Herpes Simplex Virus (HSV) A parent's guide to condition and treatment ... skin or mouth sores with the herpes simplex virus (HSV) is called primary herpes. This may be ...

  17. Serum herpes simplex antibodies

    MedlinePlus

    ... gov/ency/article/003352.htm Serum herpes simplex antibodies To use the sharing features on this page, please enable JavaScript. Serum herpes simplex antibodies is a blood test that looks for antibodies ...

  18. Variability of human immunodeficiency virus-1 in the female genital reservoir during genital reactivation of herpes simplex virus type 2.

    PubMed

    LeGoff, J; Roques, P; Jenabian, M-A; Charpentier, C; Brochier, C; Bouhlal, H; Gresenguet, G; Frost, E; Pepin, J; Mayaud, P; Belec, L

    2015-09-01

    Clinical and subclinical genital herpes simplex virus type 2 (HSV-2) reactivations have been associated with increases in human immunodeficiency virus (HIV)-1 genital shedding. Whether HSV-2 shedding contributes to the selection of specific genital HIV-1 variants remains unknown. We evaluated the genetic diversity of genital and blood HIV-1 RNA and DNA in 14 HIV-1/HSV-2-co-infected women, including seven with HSV-2 genital reactivation, and seven without as controls. HIV-1 DNA and HIV-1 RNA env V1-V3 sequences in paired blood and genital samples were compared. The HSV-2 selection pressure on HIV was estimated according to the number of synonymous substitutions (dS), the number of non-synonymous substitutions (dN) and the dS/dN ratio within HIV quasi-species. HIV-1 RNA levels in cervicovaginal secretions were higher in women with HSV-2 replication than in controls (p0.02). Plasma HIV-1 RNA and genital HIV-1 RNA and DNA were genetically compartmentalized. No differences in dS, dN and the dS/dN ratio were observed between the study groups for either genital HIV-1 RNA or plasma HIV-1 RNA. In contrast, dS and dN in genital HIV-1 DNA were significantly higher in patients with HSV-2 genital reactivation (p <0.01 and p <0.05, respectively). The mean of the dS/dN ratio in genital HIV-1 DNA was slightly higher in patients with HSV-2 genital replication, indicating a trend for purifying selection (p 0.056). HSV-2 increased the genetic diversity of genital HIV-1 DNA. These observations confirm molecular interactions between HSV-2 and HIV-1 at the genital tract level. PMID:26003280

  19. Inducible gene expression of the human immunodeficiency virus LTR in a replication-incompetent herpes simplex virus vector.

    PubMed

    Warden, M P; Weir, J P

    1996-12-01

    Although replication-incompetent herpes simplex virus (HSV) vectors have the capability to express foreign genes, successful development of these vectors for gene delivery would require that expression of the foreign gene be regulated. To investigate the feasibility of obtaining inducible expression of a foreign gene in such a vector, a replication-incompetent HSV vector, vd120/LTR beta, was developed that used the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) to express the Escherichia coli lacZ gene. Examination of lacZ expression from the HIV-1 LTR in vd120/LTR beta-infected cells indicated that the LTR was active as a promoter under both replicating and nonreplicating conditions, although expression of lacZ under nonreplicating conditions was approximately 4-fold lower. In addition, the LTR expressed lacZ in a manner distinct from that of well-characterized HSV-1 promoters of each temporal class. The effect of the HIV-1 regulatory protein Tat on expression from the LTR in vd120/LTR beta was examined by infection of two different HeLa-derived cell lines that constitutively expressed Tat, HL2/3, and HLtat. Compared to infection of HeLa cells, lacZ expression from vd120/LTR beta-infected HL2/3 and HLtat cells increased from 4- to 24-fold, depending on the multiplicity of vector infection. Sustained expression of lacZ from the LTR in vd120/LTR beta-infected cells was not observed even in the continuous presence of Tat, although vector could be recovered for up to 5 days after infection. However, the amount of recoverable vector decreased during this time, suggesting that cellular cytotoxicity may account for some of the decrease in Tat-mediated expression from the LTR. PMID:8941330

  20. Assessment of brain metabolite correlates of adeno-associated virus-mediated over-expression of human alpha-synuclein in cortical neurons by in vivo (1) H-MR spectroscopy at 9.4 T.

    PubMed

    Cuellar-Baena, Sandra; Landeck, Natalie; Sonnay, Sarah; Buck, Kerstin; Mlynarik, Vladimir; In 't Zandt, René; Kirik, Deniz

    2016-06-01

    In this study, we used proton-localized spectroscopy ((1) H-MRS) for the acquisition of the neurochemical profile longitudinally in a novel rat model of human wild-type alpha-synuclein (α-syn) over-expression. Our goal was to find out if the increased α-syn load in this model could be linked to changes in metabolites in the frontal cortex. Animals injected with AAV vectors encoding for human α-syn formed the experimental group, whereas green fluorescent protein expressing animals were used as the vector-treated control group and a third group of uninjected animals were used as naïve controls. Data were acquired at 2, 4, and 8 month time points. Nineteen metabolites were quantified in the MR spectra using LCModel software. On the basis of 92 spectra, we evaluated any potential gender effect and found that lactate (Lac) levels were lower in males compared to females, while the opposite was observed for ascorbate (Asc). Next, we assessed the effect of age and found increased levels of GABA, Tau, and GPC+PCho. Finally, we analyzed the effect of treatment and found that Lac levels (p = 0.005) were specifically lower in the α-syn group compared to the green fluorescent protein and control groups. In addition, Asc levels (p = 0.05) were increased in the vector-injected groups, whereas glucose levels remained unchanged. This study indicates that the metabolic switch between glucose-lactate could be detectable in vivo and might be modulated by Asc. No concomitant changes were found in markers of neuronal integrity (e.g., N-acetylaspartate) consistent with the fact that α-syn over-expression in cortical neurons did not result in neurodegeneration in this model. We acquired the neurochemical profile longitudinally in a rat model of human wild-type alpha-synuclein (α-syn) over-expression in cortical neurons. We found that Lactate levels were reduced in the α-syn group compared to the control groups and Ascorbate levels were increased in the vector-injected groups

  1. Recombinant adeno-associated virus-mediated high-efficiency, transient expression of the murine cationic amino acid transporter (ecotropic retroviral receptor) permits stable transduction of human HeLa cells by ecotropic retroviral vectors.

    PubMed Central

    Bertran, J; Miller, J L; Yang, Y; Fenimore-Justman, A; Rueda, F; Vanin, E F; Nienhuis, A W

    1996-01-01

    Adeno-associated virus has a broad host range, is nonpathogenic, and integrates into a preferred location on chromosome 19, features that have fostered development of recombinant adeno-associated viruses (rAAV) as gene transfer vectors for therapeutic applications. We have used an rAAV to transfer and express the murine cationic amino acid transporter which functions as the ecotropic retroviral receptor, thereby rendering human cells conditionally susceptible to infection by an ecotropic retroviral vector. The proportion of human HeLa cells expressing the receptor at 60 h varied as a function of the multiplicity of infection (MOI) with the rAAV. Cells expressing the ecotropic receptor were efficiently transduced with an ecotropic retroviral vector encoding a nucleus-localized form of beta-galactosidase. Cells coexpressing the ecotropic receptor and nucleus-localized beta-galactosidase were isolated by fluorescence-activated cell sorting, and cell lines were recovered by cloning at limiting dilution. After growth in culture, all clones contained the retroviral vector genome, but fewer than 10% (3 of 47) contained the rAAV genome and continued to express the ecotropic receptor. The ecotropic receptor coding sequences in the rAAV genome were under the control of a tetracycline-modulated promoter. In the presence of tetracycline, receptor expression was low and the proportion of cells transduced by the ecotropic retroviral vector was decreased. Modulation of receptor expression was achieved with both an episomal and an integrated form of the rAAV genome. These data establish that functional gene expression from an rAAV genome can occur transiently without genome integration. PMID:8794313

  2. Human CD8+ herpes simplex virus-specific cytotoxic T-lymphocyte clones recognize diverse virion protein antigens.

    PubMed Central

    Tigges, M A; Koelle, D; Hartog, K; Sekulovich, R E; Corey, L; Burke, R L

    1992-01-01

    The role of the HLA class I-restricted, CD8+, herpes simplex virus (HSV)-specific cytotoxic T lymphocytes (CTL) in the control of human HSV infections is controversial because previous reports suggest that a substantial portion of the antigen-specific lytic response is mediated by CD4+ cells. To address this question directly, we isolated HSV-specific CD8+ CTL clones from a patient with recurrent genital herpes. These CTL were cloned by coculturing responder peripheral blood mononuclear cells (PBMC) with phytohemagglutinin-stimulated PBMC that had been infected with live HSV-2 and then irradiated prior to the addition of responder cells. After 1 week, CTL were cloned by limiting dilution using phytohemagglutinin stimulation and allogeneic feeder PBMC. Seven clones were isolated; all seven clones were CD8+ CD4- CD3+ DRbright, six lysed only HSV-2-infected targets, and one lysed both HSV-1- and HSV-2-infected targets. Antigen presentation was restricted by two to three different HLA class I loci. To determine the antigens recognized by these HSV-specific CTL, target cells were infected with HSV in the presence of acyclovir, 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole, or cycloheximide in a series of drug block/release protocols to limit the repertoire of viral gene expression to select transcriptional classes. Five of the clones exhibited a different pattern of cytotoxicity, suggesting that each recognized a distinct HSV antigen. One of the clones appears to be directed against an immediate-early antigen; six of the clones recognize virion proteins. Five of these clones recognized internal virion proteins that could be introduced into target cells by HSV infection in the absence of virus gene expression. Antigen specificity was further tested by using vaccinia virus vectors that express glycoproteins gD2 and gB2 or the tegument protein VP16. One clone lysed vaccinia virus/gD2-infected target cells; the remaining clones did not recognize any of these gene

  3. Human papilloma virus, herpes simplex virus and epstein barr virus in oral squamous cell carcinoma from eight different countries.

    PubMed

    Jalouli, Jamshid; Jalouli, Miranda M; Sapkota, Dipak; Ibrahim, Salah O; Larsson, Per-Anders; Sand, Lars

    2012-02-01

    Oral squamous cell carcinoma (OSCC) is a major health problem in many parts of the world, and the major causative agents are thought to be the use of alcohol and tobacco. Oncogenic viruses have also been suggested to be involved in OSCC development. This study investigated the prevalence of human papillomaviruses (HPV), herpes simplex virus (HSV) and Epstein-Barr virus (EBV) in 155 OSCC from eight different countries from different ethnic groups, continents and with different socioeconomic backgrounds. 41 A total of OSCCs were diagnosed in the tongue (26%) and 23 in the floor of the mouth (15%); the other 91 OSCCs were diagnosed in other locations (59%). The patients were also investigated regarding the use of alcohol and smoking and smokeless tobacco habits. Tissue samples were obtained from formalin-fixed, paraffin-embedded samples of the OSCC. DNA was extracted and the viral genome was examined by single, nested and semi-nested PCR assays. Sequencing of double-stranded DNA from the PCR product was carried out. Following sequencing of the HPV-, HSV- and EBV-positive PCR products, 100% homology between the sampels was found. Of all the 155 OSCCs examined, 85 (55%) were positive for EBV, 54 (35%) for HPV and 24 (15%) for HSV. The highest prevalence of HPV was seen in Sudan (65%), while HSV (55%) and EBV (80%) were most prevalent in the UK. In 34% (52/155) of all the samples examined, co-infection by two (46/155=30%) or three (6/155=4%) virus specimens was detected. The most frequent double infection was HPV with EBV in 21% (32/155) of all OSCCs. There was a statistically significant higher proportion of samples with HSV (p=0.026) and EBV (p=0.015) in industrialized countries (Sweden, Norway, UK and USA) as compared to developing countries (Sudan, India, Sri Lanka and Yemen). Furthermore, there was a statistically significant higher co-infection of HSV and EBV in samples from industrialized countries (p=0.00031). No firm conclusions could be drawn regarding the

  4. Novel Method Based on Real-Time Cell Analysis for Drug Susceptibility Testing of Herpes Simplex Virus and Human Cytomegalovirus.

    PubMed

    Piret, Jocelyne; Goyette, Nathalie; Boivin, Guy

    2016-08-01

    The plaque reduction assay (PRA) is the gold standard phenotypic method to determine herpes simplex virus (HSV) and human cytomegalovirus (HCMV) susceptibilities to antiviral drugs. However, this assay is subjective and labor intensive. Here, we describe a novel antiviral phenotypic method based on real-time cell analysis (RTCA) that measures electronic impedance over time. The effective drug concentrations that reduced by 50% (EC50s) the cytopathic effects induced by HSV-1 and HCMV were evaluated by both methods. The EC50s of acyclovir and foscarnet against a reference wild-type (WT) HSV-1 strain in Vero cells were, respectively, 0.5 μM and 32.6 μM by PRA and 0.8 μM and 93.6 μM by RTCA. The EC50 ratios for acyclovir against several HSV-1 thymidine kinase (TK) mutants were 101.8×, 73.4×, 28.8×, and 35.4× (PRA) and 18.0×, 52.0×, 5.5×, and 87.8× (RTCA) compared to those for the WT. The EC50 ratios for acyclovir and foscarnet against the HSV-1 TK/DNA polymerase mutant were 182.8× and 9.7× (PRA) and >125.0× and 10.8× (RTCA) compared to the WT. The EC50s of ganciclovir and foscarnet against WT HCMV strain AD169 in fibroblasts were, respectively, 1.6 μM and 27.8 μM by PRA and 5.0 μM and 111.4 μM by RTCA. The EC50 ratios of ganciclovir against the HCMV UL97 mutant were 3.8× (PRA) and 8.2× (RTCA) compared to those for the WT. The EC50 ratios of ganciclovir and foscarnet against the HCMV UL97/DNA polymerase mutant were 17.1× and 12.1× (PRA) and 14.7× and 4.6× (RTCA) compared to those for the WT. RTCA allows objective drug susceptibility testing of HSV and HCMV and could permit high-throughput screening of new antivirals. PMID:27252463

  5. Evidence for an involvement of thymidine kinase in the excision repair of ultraviolet-irradiated herpes simplex virus in human cells

    SciTech Connect

    Intine, R.V.; Rainbow, A.J. )

    1990-01-01

    A wild-type strain of herpes simplex virus type 1 (HSV-1:KOS) encoding a functional thymidine kinase (tk+) and a tk- mutant strain (HSV-1:PTK3B) were used to study the role of the viral tk in the repair of UV-irradiated HSV-1 in human cells. UV survival of HSV-1:PTK3B was substantially reduced compared with that of HSV-1:KOS when infecting normal human cells. In contrast, the UV survival of HSV-1:PTK3B was similar to that of HSV-1:KOS when infecting excision repair-deficient cells from a xeroderma pigmentosum patient from complementation group A. These results suggest that the repair of UV-irradiated HSV-1 in human cells depends, in part at least, on expression of the viral tk and that the repair process influenced by tk activity is excision repair or a process dependent on excision repair.

  6. Characterisation of potential novel allergens in the fish parasite Anisakis simplex

    PubMed Central

    Fæste, Christiane Kruse; Jonscher, Karen R.; Dooper, Maaike M.W.B.; Egge-Jacobsen, Wolfgang; Moen, Anders; Daschner, Alvaro; Egaas, Eliann; Christians, Uwe

    2016-01-01

    The parasitic nematode Anisakis simplex occurs in fish stocks in temperate seas. A. simplex contamination of fish products is unsavoury and a health concern considering human infection with live larvae (anisakiasis) and allergic reactions to anisakid proteins in seafood. Protein extracts of A. simplex produce complex band patterns in gel electrophoresis and IgE-immunostaining. In the present study potential allergens have been characterised using sera from A. simplex-sensitised patients and proteome data obtained by mass spectrometry. A. simplex proteins were homologous to allergens in other nematodes, insects, and shellfish indicating cross-reactivity. Characteristic marker peptides for relevant A. simplex proteins were described. PMID:27110489

  7. Herpes B Virus, Macacine Herpesvirus 1, Breaks Simplex Virus Tradition via Major Histocompatibility Complex Class I Expression in Cells from Human and Macaque Hosts

    PubMed Central

    Vasireddi, Mugdha

    2012-01-01

    B virus of the family Herpesviridae is endemic to rhesus macaques but results in 80% fatality in untreated humans who are zoonotically infected. Downregulation of major histocompatibility complex (MHC) class I in order to evade CD8+ T-cell activation is characteristic of most herpesviruses. Here we examined the cell surface presence and total protein expression of MHC class I molecules in B virus-infected human foreskin fibroblast cells and macaque kidney epithelial cells in culture, which are representative of foreign and natural host initial target cells of B virus. Our results show <20% downregulation of surface MHC class I molecules in either type of host cells infected with B virus, which is statistically insignificantly different from that observed in uninfected cells. We also examined the surface expression of MHC class Ib molecules, HLA-E and HLA-G, involved in NK cell inhibition. Our results showed significant upregulation of HLA-E and HLA-G in host cells infected with B virus relative to the amounts observed in other herpesvirus-infected cells. These results suggest that B virus-infected cell surfaces maintain normal levels of MHC class Ia molecules, a finding unique among simplex viruses. This is a unique divergence in immune evasion for B virus, which, unlike human simplex viruses, does not inhibit the transport of peptides for loading onto MHC class Ia molecules because B virus ICP47 lacks a transporter-associated protein binding domain. The fact that MHC class Ib molecules were significantly upregulated has additional implications for host-pathogen interactions. PMID:22973043

  8. Simplex optimization of the variables affecting the micelle-stabilized room temperature phosphorescence of 6-methoxy-2-naphthylacetic acid and its kinetic determination in human urine.

    PubMed

    Pulgarín, J A Murillo; Molina, A Alañón; Pardo, M T Alañón

    2005-04-01

    This article reports the kinetic determination of 6-methoxy-2-naphthylacetic acid (6-MNA), the major metabolite of nabumetone, from micelle-stabilized room temperature phosphorescence (MS-RTP) measurements made by using the stopped-flow mixing technique. This methodology allows one to determine analytes in complex matrices without the need for a tedious separation process. It also shortens analysis times substantially. The proposed method uses simplex methodology to optimize the chemical and instrumental variables affecting the phosphorescence. It was applied to the determination of 6-MNA in human urine. The maximum phosphorescence signal is obtained within only 10 s after the sample is prepared. The maximum slope of the kinetic curve, which corresponds to the maximum rate of the phosphorescence development, is measured at lambda(ex)=273 nm and lambda(em)=516 nm. Least-squares regression was used to fit experimental data, and the detection limit, repeatability, and standard deviation for replicate samples were determined. PMID:15766723

  9. Combination therapy of oncolytic herpes simplex virus HF10 and bevacizumab against experimental model of human breast carcinoma xenograft.

    PubMed

    Tan, Gewen; Kasuya, Hideki; Sahin, Tevfik Tolga; Yamamura, Kazuo; Wu, Zhiwen; Koide, Yusuke; Hotta, Yoshihiro; Shikano, Toshio; Yamada, Suguru; Kanzaki, Akiyuki; Fujii, Tsutomu; Sugimoto, Hiroyuki; Nomoto, Shuji; Nishikawa, Yoko; Tanaka, Maki; Tsurumaru, Naoko; Kuwahara, Toshie; Fukuda, Saori; Ichinose, Toru; Kikumori, Toyone; Takeda, Shin; Nakao, Akimasa; Kodera, Yasuhiro

    2015-04-01

    Breast cancer is one of the most common and feared cancers faced by women. The prognosis of patients with advanced or recurrent breast cancer remains poor despite refinements in multimodality therapies involving chemotherapeutic and hormonal agents. Multimodal therapy with more specific and effective strategy is urgently needed. The oncolytic herpes simplex virus (HSV) has potential to become a new effective treatment option because of its broad host range and tumor selective viral distribution. Bevacizumab is a monoclonal antibody against VEGFA, which inhibits angiogenesis and therefore tumor growth. Our approach to enhance the antitumor effect of the oncolytic HSV is to combine oncolytic HSV HF10 and bevacizumab in the treatment of breast cancer. Our results showed that bevacizumab enhanced viral distribution as well as tumor hypoxia and expanded the population of apoptotic cells and therefore induced a synergistic antitumor effect. HF10 is expected to be a promising agent in combination with bevacizumab in the anticancer treatment. PMID:25156870

  10. Serum herpes simplex antibodies

    MedlinePlus

    ... when it detects harmful substances such as the herpes virus. This test does not detect the virus itself. ... Philadelphia, PA: Elsevier; 2014:chap 308. Whitley RJ. Herpes simplex virus infections In: Goldman L, Schafer AI, eds. Goldman's ...

  11. Inhibition of O-Linked N-Acetylglucosamine Transferase Reduces Replication of Herpes Simplex Virus and Human Cytomegalovirus

    PubMed Central

    Angelova, Magdalena; Ortiz-Meoz, Rodrigo F.; Walker, Suzanne

    2015-01-01

    ABSTRACT O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) is an essential cellular enzyme that posttranslationally modifies nuclear and cytoplasmic proteins via O-linked addition of a single N-acetylglucosamine (GlcNAc) moiety. Among the many targets of OGT is host cell factor 1 (HCF-1), a transcriptional regulator that is required for transactivation of the immediate-early genes of herpes simplex virus (HSV). HCF-1 is synthesized as a large precursor that is proteolytically cleaved by OGT, which may regulate its biological function. In this study, we tested whether inhibition of the enzymatic activity of OGT with a small molecule inhibitor, OSMI-1, affects initiation of HSV immediate-early gene expression and viral replication. We found that inhibiting OGT's enzymatic activity significantly decreased HSV replication. The major effect of the inhibitor occurred late in the viral replication cycle, when it reduced the levels of late proteins and inhibited capsid formation. However, depleting OGT levels with small interfering RNA (siRNA) reduced the expression of HSV immediate-early genes, in addition to reducing viral yields. In this study, we identified OGT as a novel cellular factor involved in HSV replication. Our results obtained using a small molecule inhibitor and siRNA depletion suggest that OGT's glycosylation and scaffolding functions play distinct roles in the replication cycle of HSV. IMPORTANCE Antiviral agents can target viral or host gene products essential for viral replication. O-GlcNAc transferase (OGT) is an important cellular enzyme that catalyzes the posttranslational addition of GlcNAc sugar residues to hundreds of nuclear and cytoplasmic proteins, and this modification regulates their activity and function. Some of the known OGT targets are cellular proteins that are critical for the expression of herpes simplex virus (HSV) genes, suggesting a role for OGT in the replication cycle of HSV. In this study, we found that OGT is required for

  12. Effect of prostaglandins and cyclic adenosine 3',5'-monophosphate modulators on herpes simplex virus growth and interferon response in human cells.

    PubMed Central

    Trofatter, K F; Daniels, C A

    1980-01-01

    Mechanisms whereby prostaglandins and other cyclic adenosine 3',5'-monophosphate (cAMP) modulators might enhance the growth of herpes simplex virus (HSV) in human skin fibroblasts were explored. Prostaglandins A1, B1, E1, E2, and F2 alpha, as well as isoproterenol, imidazole, carbamylcholine, and dibutyryl cAMP had no effect on HSV growth. On the other hand, the phosphodiesterase inhibitors 1-methyl-3-isobutylxanthine and theophylline delayed the growth, suppressed the cell-to-cell spread, but inhibited neither the adsorption nor the penetration of the virus. Although none of the cAMP-elevating reagents directly enhanced HSV growth, they were found to inhibit dose dependently the antiviral action of both type I and HSV antigen-induced human interferon preparations. Furthermore, these reagents suppressed the production of HSV antigen-induced interferon by immune human mononuclear leukocytes. These data support the hypothesis that prostaglandin elaboration in vivo could contribute to exacerbations of HSV infections by compromising the host's interferon defense system. PMID:6244226

  13. An efficient deletion mutant packaging system for defective herpes simplex virus vectors: Potential applications to human gene therapy and neuronal physiology

    SciTech Connect

    Geller, A.I.; Keyomarsi, K.; Bryan, J.; Pardee, A.B. )

    1990-11-01

    The authors have previously described a defective herpes simplex virus (HSV-1) vector system that permits that introduction of virtually any gene into nonmitotic cells. pHSVlac, the prototype vector, stably expresses Escherichia coli {beta}-galactosidase from a constitutive promoter in many human cell lines, in cultured rat neurons from throughout the nervous system, and in cells in the adult rat brain. HSV-1 vectors expressing other genes may prove useful for studying neuronal physiology or performing human gene therapy for neurological diseases, such as Parkinson disease or brain tumors. A HSV-1 temperature-sensitive (ts) mutant, ts K, has been used as helper virus; ts mutants revert to wild type. In contrast, HSV-1 deletion mutants essentially cannot revert to wild type; therefore, use of a deletion mutant as helper virus might permit human gene therapy with HSV-1 vectors. They now report an efficient packaging system for HSV-1 VECTORS USING A DELETION MUTANT, d30EBA, as helper virus; virus is grown on the complementing cell line M64A. pHSVlac virus prepared using the deletion mutant packaging system stably expresses {beta}-galactosidase in cultured rat sympathetic neurons and glia. Both D30EBA and ts K contain a mutation in the IE3 gene of HSV-1 strain 17 and have the same phenotype; therefore, changing the helper virus from ts K to D30EBA does not alter the host range or other properties of the HSV-1 vector system.

  14. Herpes simplex keratitis.

    PubMed

    Kaye, Stephen; Choudhary, Anshoo

    2006-07-01

    Herpes simplex keratitis (HSK) results from an infection with the herpes simplex virus type 1 (HSV-1) also known as human herpesvirus type 1 (HHV-1). Primary infection may involve an ocular or non-ocular site, following which latency might be established principally in the trigeminal ganglion but also in the cornea. During latency, the virus appears as a circular episome associated with histones with active transcription only from the region encoding the latency-associated transcript (LAT). The LAT region is implicated in neuronal survival, anti-apoptosis, virulence, suppression of transcription, establishment of and reactivation from latency. The initial keratitis may develop after infection through the "front door route" (entry into the ocular surface from droplet spread) or "back door route" (spread to the eye from a non-ocular site, principally the mouth). The initial ocular infection may be mild. Visual morbidity results from recurrent keratitis, which leads to corneal scarring, thinning and neovascularisation. Although, recurrent disease may potentially occur through anterograde axonal spread from the trigeminal ganglion to the cornea, recent evidence suggests that HSV-1 in the cornea may be another source of recurrent disease. The pathogenesis and severity of HSK is largely determined by an interaction between viral genes encoded by the strain of HSV-1 and the make up of the host's immune system. Herpetic stromal disease is due to the immune response to virus within the cornea and the ability of the strain to cause corneal stromal disease is correlated with its ability to induce corneal vascularisation. The pathogenesis of corneal scarring and vascularisation is uncertain but appears to be a complex interaction of various cytokines, chemokines and growth factors either brought in by inflammatory cells or produced locally in response to HSV-1 infection. Evidence now suggests that HSV-1 infection disrupts the normal equilibrium between angiogenic and anti

  15. Enhanced antitumor efficacy of an oncolytic herpes simplex virus expressing an endostatin-angiostatin fusion gene in human glioblastoma stem cell xenografts.

    PubMed

    Zhang, Guobin; Jin, Guishan; Nie, Xiutao; Mi, Ruifang; Zhu, Guidong; Jia, William; Liu, Fusheng

    2014-01-01

    Viruses have demonstrated strong potential for the therapeutic targeting of glioblastoma stem cells (GSCs). In this study, the use of a herpes simplex virus carrying endostatin-angiostatin (VAE) as a novel therapeutic targeting strategy for glioblastoma-derived cancer stem cells was investigated. We isolated six stable GSC-enriched cultures from 36 human glioblastoma specimens and selected one of the stable GSCs lines for establishing GSC-carrying orthotopic nude mouse models. The following results were obtained: (a) VAE rapidly proliferated in GSCs and expressed endo-angio in vitro and in vivo 48 h and 10 d after infection, respectively; (b) compared with the control gliomas treated with rHSV or Endostar, the subcutaneous gliomas derived from the GSCs showed a significant reduction in microvessel density after VAE treatment; (c) compared with the control, a significant improvement was observed in the length of the survival of mice with intracranial and subcutaneous gliomas treated with VAE; (d) MRI analysis showed that the tumor volumes of the intracranial gliomas generated by GSCs remarkably decreased after 10 d of VAE treatment compared with the controls. In conclusion, VAE demonstrated oncolytic therapeutic efficacy in animal models of human GSCs and expressed an endostatin-angiostatin fusion gene, which enhanced antitumor efficacy most likely by restricting tumor microvasculature development. PMID:24755877

  16. Enhanced Antitumor Efficacy of an Oncolytic Herpes Simplex Virus Expressing an Endostatin–Angiostatin Fusion Gene in Human Glioblastoma Stem Cell Xenografts

    PubMed Central

    Zhang, Guobin; Jin, Guishan; Nie, Xiutao; Mi, Ruifang; Zhu, Guidong; Jia, William; Liu, Fusheng

    2014-01-01

    Viruses have demonstrated strong potential for the therapeutic targeting of glioblastoma stem cells (GSCs). In this study, the use of a herpes simplex virus carrying endostatin–angiostatin (VAE) as a novel therapeutic targeting strategy for glioblastoma-derived cancer stem cells was investigated. We isolated six stable GSC-enriched cultures from 36 human glioblastoma specimens and selected one of the stable GSCs lines for establishing GSC-carrying orthotopic nude mouse models. The following results were obtained: (a) VAE rapidly proliferated in GSCs and expressed endo–angio in vitro and in vivo 48 h and 10 d after infection, respectively; (b) compared with the control gliomas treated with rHSV or Endostar, the subcutaneous gliomas derived from the GSCs showed a significant reduction in microvessel density after VAE treatment; (c) compared with the control, a significant improvement was observed in the length of the survival of mice with intracranial and subcutaneous gliomas treated with VAE; (d) MRI analysis showed that the tumor volumes of the intracranial gliomas generated by GSCs remarkably decreased after 10 d of VAE treatment compared with the controls. In conclusion, VAE demonstrated oncolytic therapeutic efficacy in animal models of human GSCs and expressed an endostatin–angiostatin fusion gene, which enhanced antitumor efficacy most likely by restricting tumor microvasculature development. PMID:24755877

  17. Vaccinia virus, herpes simplex virus, and carcinogens induce DNA amplification in a human cell line and support replication of a helpervirus dependent parvovirus

    SciTech Connect

    Schlehofer, J.R.; Ehrbar, M.; zur Hausen, H.

    1986-07-15

    The SV40-transformed human kidney cell line, NB-E, amplifies integrated as well as episomal SV40 DNA upon treatment with chemical (DMBA) or physical (uv irradiation) carcinogens (initiators) as well as after infection with herpes simplex virus (HSV) type 1 or with vaccinia virus. In addition it is shown that vaccinia virus induces SV40 DNA amplification also in the SV40-transformed Chinese hamster embryo cell line, CO631. These findings demonstrate that human cells similar to Chinese hamster cells amplify integrated DNA sequences after treatment with carcinogens or infection with specific viruses. Furthermore, a poxvirus--vaccinia virus--similar to herpes group viruses induces DNA amplification. As reported for other systems, the vaccinia virus-induced DNA amplification in NB-E cells is inhibited by coinfection with adeno-associated virus (AAV) type 5. This is in line with previous studies on inhibition of carcinogen- or HSV-induced DNA amplification in CO631 cells. The experiments also demonstrate that vaccinia virus, in addition to herpes and adenoviruses acts as a helper virus for replication and structural antigen synthesis of AAV-5 in NB-E cells.

  18. Herpes Simplex Virus Type 2 Glycoprotein H Interacts with Integrin αvβ3 To Facilitate Viral Entry and Calcium Signaling in Human Genital Tract Epithelial Cells

    PubMed Central

    Cheshenko, Natalia; Trepanier, Janie B.; González, Pablo A.; Eugenin, Eliseo A.; Jacobs, William R.

    2014-01-01

    ABSTRACT Herpes simplex virus (HSV) entry requires multiple interactions at the cell surface and activation of a complex calcium signaling cascade. Previous studies demonstrated that integrins participate in this process, but their precise role has not been determined. These studies were designed to test the hypothesis that integrin αvβ3 signaling promotes the release of intracellular calcium (Ca2+) stores and contributes to viral entry and cell-to-cell spread. Transfection of cells with small interfering RNA (siRNA) targeting integrin αvβ3, but not other integrin subunits, or treatment with cilengitide, an Arg-Gly-Asp (RGD) mimetic, impaired HSV-induced Ca2+ release, viral entry, plaque formation, and cell-to-cell spread of HSV-1 and HSV-2 in human cervical and primary genital tract epithelial cells. Coimmunoprecipitation studies and proximity ligation assays indicated that integrin αvβ3 interacts with glycoprotein H (gH). An HSV-2 gH-null virus was engineered to further assess the role of gH in the virus-induced signaling cascade. The gH-2-null virus bound to cells and activated Akt to induce a small Ca2+ response at the plasma membrane, but it failed to trigger the release of cytoplasmic Ca2+ stores and was impaired for entry and cell-to-cell spread. Silencing of integrin αvβ3 and deletion of gH prevented phosphorylation of focal adhesion kinase (FAK) and the transport of viral capsids to the nuclear pore. Together, these findings demonstrate that integrin signaling is activated downstream of virus-induced Akt signaling and facilitates viral entry through interactions with gH by activating the release of intracellular Ca2+ and FAK phosphorylation. These findings suggest a new target for HSV treatment and suppression. IMPORTANCE Herpes simplex viruses are the leading cause of genital disease worldwide, the most common infection associated with neonatal encephalitis, and a major cofactor for HIV acquisition and transmission. There is no effective vaccine

  19. Different presence of Chlamydia pneumoniae, herpes simplex virus type 1, human herpes virus 6, and Toxoplasma gondii in schizophrenia: meta-analysis and analytical study

    PubMed Central

    Gutiérrez-Fernández, José; Luna del Castillo, Juan de Dios; Mañanes-González, Sara; Carrillo-Ávila, José Antonio; Gutiérrez, Blanca; Cervilla, Jorge A; Sorlózano-Puerto, Antonio

    2015-01-01

    In the present study we have performed both a meta-analysis and an analytical study exploring the presence of Chlamydia pneumoniae, herpes simplex virus type 1, human herpes virus 6, and Toxoplasma gondii antibodies in a sample of 143 schizophrenic patients and 143 control subjects. The meta-analysis was performed on papers published up to April 2014. The presence of serum immunoglobulin G and immunoglobulin A was performed by enzyme-linked immunosorbent assay test. The detection of microbial DNA in total peripheral blood was performed by nested polymerase chain reaction. The meta-analysis showed that: 1) C. pneumoniae DNA in blood and brain are more common in schizophrenic patients; 2) there is association with parasitism by T. gondii, despite the existence of publication bias; and 3) herpes viruses were not more common in schizophrenic patients. In our sample only anti-Toxoplasma immunoglobulin G was more prevalent and may be a risk factor related to schizophrenia, with potential value for prevention. PMID:25848282

  20. Pretreatment of human cervicovaginal mucus with pluronic F127 enhances nanoparticle penetration without compromising mucus barrier properties to herpes simplex virus.

    PubMed

    Ensign, Laura M; Lai, Samuel K; Wang, Ying-Ying; Yang, Ming; Mert, Olcay; Hanes, Justin; Cone, Richard

    2014-12-01

    Mucosal drug delivery nanotechnologies are limited by the mucus barrier that protects nearly all epithelial surfaces not covered with skin. Most polymeric nanoparticles, including polystyrene nanoparticles (PS), strongly adhere to mucus, thereby limiting penetration and facilitating rapid clearance from the body. Here, we demonstrate that PS rapidly penetrate human cervicovaginal mucus (CVM), if the CVM has been pretreated with sufficient concentrations of Pluronic F127. Importantly, the diffusion rate of large polyethylene glycol (PEG)-coated, nonmucoadhesive nanoparticles (PS-PEG) did not change in F127-pretreated CVM, implying that F127 did not significantly alter the native pore structure of CVM. Additionally, herpes simplex virus type 1 (HSV-1) remains adherent in F127-pretreated CVM, indicating that the presence of F127 did not reduce adhesive interactions between CVM and the virions. In contrast to treatment with a surfactant that has been approved for vaginal use as a spermicide (nonoxynol-9 or N9), there was no increase in inflammatory cytokine release in the vaginal tract of mice after daily application of 1% F127 for 1 week. Pluronic F127 pretreatment holds potential as a method to safely improve the distribution, retention, and efficacy of nanoparticle formulations without compromising CVM barrier properties to pathogens. PMID:25347518

  1. Pretreatment of Human Cervicovaginal Mucus with Pluronic F127 Enhances Nanoparticle Penetration without Compromising Mucus Barrier Properties to Herpes Simplex Virus

    PubMed Central

    2015-01-01

    Mucosal drug delivery nanotechnologies are limited by the mucus barrier that protects nearly all epithelial surfaces not covered with skin. Most polymeric nanoparticles, including polystyrene nanoparticles (PS), strongly adhere to mucus, thereby limiting penetration and facilitating rapid clearance from the body. Here, we demonstrate that PS rapidly penetrate human cervicovaginal mucus (CVM), if the CVM has been pretreated with sufficient concentrations of Pluronic F127. Importantly, the diffusion rate of large polyethylene glycol (PEG)-coated, nonmucoadhesive nanoparticles (PS–PEG) did not change in F127-pretreated CVM, implying that F127 did not significantly alter the native pore structure of CVM. Additionally, herpes simplex virus type 1 (HSV-1) remains adherent in F127-pretreated CVM, indicating that the presence of F127 did not reduce adhesive interactions between CVM and the virions. In contrast to treatment with a surfactant that has been approved for vaginal use as a spermicide (nonoxynol-9 or N9), there was no increase in inflammatory cytokine release in the vaginal tract of mice after daily application of 1% F127 for 1 week. Pluronic F127 pretreatment holds potential as a method to safely improve the distribution, retention, and efficacy of nanoparticle formulations without compromising CVM barrier properties to pathogens. PMID:25347518

  2. Tissue-Specific Expression of Herpes Simplex Virus Thymidine Kinase Gene Delivered by Adeno-Associated Virus Inhibits the Growth of Human Hepatocellular Carcinoma in Athymic Mice

    NASA Astrophysics Data System (ADS)

    Su, Hua; Lu, Ronghua; Chang, Judy C.; Kan, Yuet Wai

    1997-12-01

    About 70% of hepatocellular carcinomas are known to express α -fetoprotein, which is normally expressed in fetal but not in adult livers. To induce herpes simplex virus-thymidine kinase expression in these cancer cells, we constructed an adeno-associated viral vector containing the HSV-TK gene under the control of the α -fetoprotein enhancer and albumin promoter. We previously demonstrated in vitro that although this vector can transduce a variety of human cells, only transduced AFP and albumin-expressing hepatocellular carcinoma cell lines were sensitive to killing by ganciclovir (GCV). In the present study, we explored the effect of this vector on hepatocellular carcinoma cells in vivo. Subcutaneous tumors generated in nude mice by implanting hepatocellular carcinoma cells previously transduced with this vector shrank dramatically after treatment with GCV. Bystander effect was also observed on the tumors generated by mixing transduced and untransduced cells. To test whether the tumor cells can be transduced by the virus in vivo, we injected the recombinant adeno-associated virus into tumors generated by untransduced hepatocarcinoma cell line. Tumor growth were retarded after treatment with GCV. These experiments demonstrate the feasibility of in vivo transduction of tumor cell with rAAV.

  3. Short Communication: A Repeated Simian Human Immunodeficiency Virus Reverse Transcriptase/Herpes Simplex Virus Type 2 Cochallenge Macaque Model for the Evaluation of Microbicides

    PubMed Central

    Kenney, Jessica; Derby, Nina; Aravantinou, Meropi; Kleinbeck, Kyle; Frank, Ines; Gettie, Agegnehu; Grasperge, Brooke; Blanchard, James; Piatak, Michael; Lifson, Jeffrey D.; Zydowsky, Thomas M.

    2014-01-01

    Abstract Epidemiological studies suggest that prevalent herpes simplex virus type 2 (HSV-2) infection increases the risk of HIV acquisition, underscoring the need to develop coinfection models to evaluate promising prevention strategies. We previously established a single high-dose vaginal coinfection model of simian human immunodeficiency virus (SHIV)/HSV-2 in Depo-Provera (DP)-treated macaques. However, this model does not appropriately mimic women's exposure. Repeated limiting dose SHIV challenge models are now used routinely to test prevention strategies, yet, at present, there are no reports of a repeated limiting dose cochallenge model in which to evaluate products targeting HIV and HSV-2. Herein, we show that 20 weekly cochallenges with 2–50 TCID50 simian human immunodeficiency virus reverse transcriptase (SHIV-RT) and 107 pfu HSV-2 results in infection with both viruses (4/6 SHIV-RT, 6/6 HSV-2). The frequency and level of vaginal HSV-2 shedding were significantly greater in the repeated exposure model compared to the single high-dose model (p<0.0001). We used this new model to test the Council's on-demand microbicide gel, MZC, which is active against SHIV-RT in DP-treated macaques and HSV-2 and human papillomavirus (HPV) in mice. While MZC reduced SHIV and HSV-2 infections in our repeated limiting dose model when cochallenging 8 h after each gel application, a barrier effect of carrageenan (CG) that was not seen in DP-treated animals precluded evaluation of the significance of the antiviral activity of MZC. Both MZC and CG significantly (p<0.0001) reduced the frequency and level of vaginal HSV-2 shedding compared to no gel treatment. This validates the use of this repeated limiting dose cochallenge model for testing products targeting HIV and HSV-2. PMID:25354024

  4. Nongenital herpes simplex virus.

    PubMed

    Usatine, Richard P; Tinitigan, Rochelle

    2010-11-01

    Nongenital herpes simplex virus type 1 is a common infection usually transmitted during childhood via nonsexual contact. Most of these infections involve the oral mucosa or lips (herpes labialis). The diagnosis of an infection with herpes simplex virus type 1 is usually made by the appearance of the lesions (grouped vesicles or ulcers on an erythematous base) and patient history. However, if uncertain, the diagnosis of herpes labialis can be made by viral culture, polymerase chain reaction, serology, direct fluorescent antibody testing, or Tzanck test. Other nonoral herpes simplex virus type 1 infections include herpetic keratitis, herpetic whitlow, herpes gladiatorum, and herpetic sycosis of the beard area. The differential diagnosis of nongenital herpes simplex virus infection includes aphthous ulcers, acute paronychia, varicella-zoster virus infection, herpangina, herpes gestationis (pemphigoid gestationis), pemphigus vulgaris, and Behçet syndrome. Oral acyclovir suspension is an effective treatment for children with primary herpetic gingivostomatitis. Oral acyclovir, valacyclovir, and famciclovir are effective in treating acute recurrence of herpes labialis (cold sores). Recurrences of herpes labialis may be diminished with daily oral acyclovir or valacyclovir. Topical acyclovir, penciclovir, and docosanol are optional treatments for recurrent herpes labialis, but they are less effective than oral treatment. PMID:21121552

  5. Herpes Simplex Virus Type 1/Adeno-Associated Virus rep+ Hybrid Amplicon Vector Improves the Stability of Transgene Expression in Human Cells by Site-Specific Integration

    PubMed Central

    Wang, Y.; Camp, S. M.; Niwano, M.; Shen, X.; Bakowska, J. C.; Breakefield, X. O.; Allen, P. D.

    2002-01-01

    Herpes simplex virus type 1 (HSV-1) amplicon vectors are promising gene delivery tools, but their utility in gene therapy has been impeded to some extent by their inability to achieve stable transgene expression. In this study, we examined the possibility of improving transduction stability in cultured human cells via site-specific genomic integration mediated by adeno-associated virus (AAV) Rep and inverted terminal repeats (ITRs). A rep− HSV/AAV hybrid amplicon vector was made by inserting a transgene cassette flanked with AAV ITRs into an HSV-1 amplicon backbone, and a rep+ HSV/AAV hybrid amplicon was made by inserting rep68/78 outside the rep− vector 3′ AAV ITR sequence. Both vectors also had a pair of loxP sites flanking the ITRs. The resulting hybrid amplicon vectors were successfully packaged and compared to a standard amplicon vector for stable transduction frequency (STF) in human 293 and Gli36 cell lines and primary myoblasts. The rep+, but not the rep−, hybrid vector improved STF in all three types of cells; 84% of Gli36 and 40% of 293 stable clones transduced by the rep+ hybrid vector integrated the transgene into the AAVS1 site. Due to the difficulty in expanding primary myoblasts, we did not assess site-specific integration in these cells. A strategy to attempt further improvement of STF by “deconcatenating” the hybrid amplicon DNA via Cre-loxP recombination was tested, but it did not increase STF. These data demonstrate that introducing the integrating elements of AAV into HSV-1 amplicon vectors can significantly improve their ability to achieve stable gene transduction by conferring the AAV-like capability of site-specific genomic integration in dividing cells. PMID:12072515

  6. Ultrastructural Visualization of Individual Tegument Protein Dissociation during Entry of Herpes Simplex Virus 1 into Human and Rat Dorsal Root Ganglion Neurons

    PubMed Central

    Aggarwal, Anupriya; Boadle, Ross A.; Kelly, Barbara J.; Diefenbach, Russell J.; Alam, Waafiqa; Cunningham, Anthony L.

    2012-01-01

    Herpes simplex virus 1 (HSV-1) enters neurons primarily by fusion of the viral envelope with the host cell plasma membrane, leading to the release of the capsid into the cytosol. The capsid travels via microtubule-mediated retrograde transport to the nuclear membrane, where the viral DNA is released for replication in the nucleus. In the present study, the composition and kinetics of incoming HSV-1 capsids during entry and retrograde transport in axons of human fetal and dissociated rat dorsal root ganglia (DRG) neurons were examined by wide-field deconvolution microscopy and transmission immunoelectron microscopy (TIEM). We show that HSV-1 tegument proteins, including VP16, VP22, most pUL37, and some pUL36, dissociated from the incoming virions. The inner tegument proteins, including pUL36 and some pUL37, remained associated with the capsid during virus entry and transit to the nucleus in the neuronal cell body. By TIEM, a progressive loss of tegument proteins, including VP16, VP22, most pUL37, and some pUL36, was observed, with most of the tegument dissociating at the plasma membrane of the axons and the neuronal cell body. Further dissociation occurred within the axons and the cytosol as the capsids moved to the nucleus, resulting in the release of free tegument proteins, especially VP16, VP22, pUL37, and some pUL36, into the cytosol. This study elucidates ultrastructurally the composition of HSV-1 capsids that encounter the microtubules in the core of human axons and the complement of free tegument proteins released into the cytosol during virus entry. PMID:22457528

  7. Herpes simplex virus (HSV)-specific proliferative and cytotoxic T-cell responses in humans immunized with an HSV type 2 glycoprotein subunit vaccine.

    PubMed Central

    Zarling, J M; Moran, P A; Brewer, L; Ashley, R; Corey, L

    1988-01-01

    Studies were undertaken to determine whether immunization of humans with a herpes simplex virus type 2 (HSV-2) glycoprotein-subunit vaccine would result in the priming of both HSV-specific proliferating cells and cytotoxic T cells. Peripheral blood lymphocytes (PBL) from all eight vaccines studied responded by proliferating after stimulation with HSV-2, HSV-1, and glycoprotein gB-1. The PBL of five of these eight vaccines proliferated following stimulation with gD-2, whereas stimulation with gD-1 resulted in relatively low or no proliferative responses. T-cell clones were generated from HSV-2-stimulated PBL of three vaccinees who demonstrated strong proliferative responses to HSV-1 and HSV-2. Of 12 clones studied in lymphoproliferative assays, 9 were found to be cross-reactive for HSV-1 and HSV-2. Of the approximately 90 T-cell clones isolated, 14 demonstrated HSV-specific cytotoxic activity. Radioimmunoprecipitation-polyacrylamide gel electrophoresis analyses confirmed that the vaccinees had antibodies only to HSV glycoproteins, not to proteins which are absent in the subunit vaccine, indicating that these vaccinees had not become infected with HSV. Immunization of humans with an HSV-2 glycoprotein-subunit vaccine thus results in the priming of T cells that proliferate in response to stimulation with HSV and its glycoproteins and T cells that have cytotoxic activity against HSV-infected cells. Such HSV-specific memory T cells were detected as late as 2 years following the last boost with the subunit vaccine. Images PMID:2846864

  8. Real-Time PCR Quantification of Genital Shedding of Herpes Simplex Virus (HSV) and Human Immunodeficiency Virus (HIV) in Women Coinfected with HSV and HIV

    PubMed Central

    Legoff, Jérôme; Bouhlal, Hicham; Grésenguet, Gérard; Weiss, Helen; Khonde, Nzambi; Hocini, Hakim; Désiré, Nathalie; Si-Mohamed, Ali; de Dieu Longo, Jean; Chemin, Cécile; Frost, Eric; Pépin, Jacques; Malkin, Jean-Elie; Mayaud, Philippe; Bélec, Laurent

    2006-01-01

    The accuracy and usefulness of laboratory-developed real-time PCR procedures using a Light Cycler instrument (Roche Diagnostics) for detecting and quantifying human immunodeficiency virus type 1 (HIV-1) RNA and DNA as well as herpes simplex virus type 1 (HSV-1)/HSV-2 DNA in cervicovaginal secretions from women coinfected with HIV and HSV were evaluated. For HIV-1, the use of the NEC152 and NEC131 primer set and the NEC-LTR probe in the long terminal repeat gene allowed us to detect accurately the majority of HIV-1 subtypes of group M circulating in sub-Saharan Africa, including subtypes A, B, C, D, and G as well as circulating recombinant forms 02 and 11. The detection threshold of real-time PCR for HIV in cervicovaginal lavage samples was 5 copies per assay for both RNA and DNA; the intra- and interassay coefficients of variation of CT values were 1.30% and 0.69% (HIV-1 RNA) and 1.84% and 0.67% (HIV-1 DNA), respectively. Real-time PCR for HSV using primers and probe targeting the HSV DNA polymerase gene allowed both detection and quantification of HSV DNA and also differentiation between HSV-1 and HSV-2 genotypes. The detection threshold of real-time PCR for HSV was 5 copies per assay; the intra- and interassay coefficients of variation of CT values were 0.96% and 1.49%, respectively. Both manual and automated silica-based procedures were appropriate for combined extraction of HIV and HSV genomes from female genital secretions. Taken together, these findings indicate that real-time PCR may be used as a unique nucleic acid amplification procedure to detect and quantify HIV and HSV genomes in cervicovaginal secretions and thus to assess at reduced costs the genital shedding of both viruses in women included in intervention studies. PMID:16455895

  9. Association of Chlamydia trachomatis infection and herpes simplex virus type 2 serostatus with genital human papillomavirus infection in men: the HIM Study

    PubMed Central

    Alberts, Catharina Johanna; Schim van der Loeff, Maarten F.; Papenfuss, Mary R.; da Silva, Roberto José Carvalho; Villa, Luisa Lina; Lazcano-Ponce, Eduardo; Nyitray, Alan G.; Giuliano, Anna R.

    2013-01-01

    Background Studies in women indicate that some sexually transmitted infections promote human papillomavirus (HPV) persistence and carcinogenesis. Little is known about this association in men, therefore we assessed whether Chlamydia trachomatis (CT) infection and herpes simplex virus type 2 (HSV-2) serostatus are associated with genital HPV prevalence, an early event in HPV related pathogenesis. Methods Genital exfoliated cells, first-void urine and blood from 3,971 men recruited in the USA, Mexico, and Brazil, were tested for HPV, CT, and HSV-2 antibodies, respectively. Multivariable logistic regression was used to assess the association of CT infection and HSV-2 serostatus with four HPV outcomes (any, oncogenic, non-oncogenic only, and multiple infections). Results A total of 64 (1.6%) men were CT positive and 811 (20.4%) men were HSV-2 seropositive. After adjustment for potential confounders, CT was associated with any HPV (aOR 2.19, 95%CI: 1.13–4.24), oncogenic HPV (aOR 3.10, 95%CI: 1.53–6.28), and multiple HPV (aOR 3.43, 95%CI: 1.69-6.95) prevalence. HSV-2 serostatus was associated with any HPV (aOR 1.25, 95%CI: 1.02-1.52), non-oncogenic HPV only (aOR 1.38, 95%CI: 1.08-1.75), and multiple HPV (aOR 1.33, 95%CI: 1.06-1.68) prevalence. In analyses stratified by sexual behaviour, CT infection was significantly associated with HPV detection among men reporting ≥2 recent sexual partners, while HSV-2 serostatus was significantly associated with HPV detection in men reporting 0-5 lifetime sexual partners. Conclusion In this population, CT infection and HSV-2 serostatus were associated with prevalent genital HPV infection. Future prospective studies should investigate whether these infections influence HPV acquisition and/or persistence. PMID:23680908

  10. Deciphering the epidemic synergy of herpes simplex virus type 2 (HSV-2) on human immunodeficiency virus type 1 (HIV-1) infection among women in sub-Saharan Africa

    PubMed Central

    2012-01-01

    Background Herpes Simplex Virus Type 2 (HSV-2) is highly prevalent in regions disproportionately affected by the human immunodeficiency virus (HIV-1) epidemic. The objective of our study was to identify the risk factors of HSV-2 and HIV-1 infections and to examine the association between the two infections. Methods The study participants were recruited through a community based cross-sectional study that was conducted from November 2002 to March 2003 in the Moshi urban district of Northern Tanzania. A two-stage sampling design was used in recruiting the study participants. Information on socio-demographics, alcohol use, sexual behaviors, and STIs symptoms were obtained. Blood and urine samples were drawn for testing of HIV-1, HSV-2 and other STIs. Results The prevalence of HSV-2 infection among all study participants was 43%. The prevalence rate of HSV-2 among the HIV-negative and HIV-positive women was 40% and 65%, respectively. We found 2.72 times odds of having HIV-1 in an HSV-2 positive woman than in an HSV-2 negative woman. Furthermore, HIV-1 and HSV-2 shared common high-risk sexual behavior factors such as early onset of sexual debut, and testing positive for other STIs. Conclusions Our findings suggest that HSV-2 may be both a biological and risk-associated cofactor for HIV-1 acquisition. In resource-limited countries, where both infections are prevalent efforts at symptomatic and diagnostic screening and treatment of HSV-2 should be part of HIV-1 prevention programs. PMID:22909236

  11. Association between the p170 form of human topoisomerase II and progeny viral DNA in cells infected with herpes simplex virus type 1.

    PubMed Central

    Ebert, S N; Subramanian, D; Shtrom, S S; Chung, I K; Parris, D S; Muller, M T

    1994-01-01

    Endogenous host topoisomerase II acts upon herpes simplex virus type 1 (HSV-1) DNA in infected cells (S.N. Ebert, S.S. Shtrom, and M.T. Muller, J. Virol. 56:4059-4066, 1990), and cleavage is directed exclusively at progeny viral DNA while parental DNA is resistant. To evaluate the possibility that HSV-1 induces topoisomerase II activity which could account for the preferential cleavage of progeny viral DNA, we assessed topoisomerase II cleavage activity on cellular and viral DNA substrates before and after the initiation of viral DNA replication. We show that cleavage of a host gene in mock-infected cells was similar to that observed in HSV-1-infected cells, regardless of whether viral DNA replication had occurred. In addition, quantitative measurements revealed comparable amounts of topoisomerase II activity in infected and mock-infected cells; thus, HSV-1 neither induces nor encodes its own type II topoisomerase and cleavages in vivo are due to a preexisting host topoisomerase. Human cells contain two isozymes of topoisomerase II (p170 and p180), encoded by separate genes. Through the use of isozyme-specific antibodies, we demonstrate that only p170 was found to be cross-linked to HSV-1 DNA even though both forms were present at nearly constant levels in HSV-1-infected cells. Immunofluorescence revealed that by 6 h postinfection, p170 becomes redistributed and localized to sites of active viral DNA synthesis. The data suggest that p170 gains preferential access to replicated viral DNA molecules, which explains why topoisomerase II activity is concentrated on progeny DNA. Images PMID:8289331

  12. In Vitro and In Vivo Evaluations of Sodium Lauryl Sulfate and Dextran Sulfate as Microbicides against Herpes Simplex and Human Immunodeficiency Viruses

    PubMed Central

    Piret, Jocelyne; Lamontagne, Julie; Bestman-Smith, Julie; Roy, Sylvie; Gourde, Pierrette; Désormeaux, André; Omar, Rabeea F.; Juhász, Julianna; Bergeron, Michel G.

    2000-01-01

    The efficacy of sodium lauryl sulfate (SLS), a sulfated anionic chaotropic surfactant, and dextran sulfate (DS), a polysulfated carbohydrate, against herpes simplex virus (HSV) and human immunodeficiency virus (HIV) infections was evaluated in cultured cells and in different murine models of HSV infection. Results showed that both SLS and DS were potent inhibitors of the infectivities of various HSV-1 and HSV-2 strains. Pretreatment of HIV-1 (strain NL4-3) with SLS also reduced its infectivity to 1G5 cells. DS prevented the binding of HSV to cell surface receptors and therefore its entry into cells. Pretreatment of HSV-1 (strain F) with 50 μM SLS resulted in a complete loss of virus infectivity to Vero cells. However, viruses were able to enter into cells and to produce in the nuclei capsid shells devoid of a DNA core. The amount of the glycoprotein D gene produced in these cells remained unchanged compared to controls, suggesting that SLS could interfere with the maturation of the virus. At a higher SLS concentration (100 μM), HSV was highly damaged by SLS pretreatment and only a few viral particles could enter into cells to produce abnormal capsids. Although DS was a more potent inhibitor of HSV infectivity in vitro, it was unable to provide any protection in murine models of HSV infection. However, SLS conferred a complete protection of animals infected cutaneously with pretreated viruses. In addition, skin pretreatment of mice with a polymer formulation containing SLS completely prevented the development of cutaneous lesions. More interestingly, intravaginal pretreatment of mice with SLS in a buffered solution also completely protected against lethal HSV-2 infection. Taken together, our results suggest that SLS could thus represent a candidate of choice as a microbicide to prevent the sexual transmission of HIV, HSV, and possibly other pathogens that cause sexually transmitted diseases. PMID:10618073

  13. Virus-specific HLA-restricted lysis of herpes simplex virus-infected human monocytes and macrophages mediated by cytotoxic T lymphocytes

    SciTech Connect

    Torpey, D.J. III

    1987-01-01

    Freshly-isolated peripheral blood human monocytes and 5 day in vitro cultured macrophages were infected with herpes simplex virus type 1 (HSV-1), labeled with /sup 51/Cr, and used as target cells in a 12-14 hour cell-mediated cytotoxicity assay. Mononuclear leukocytes (MNL) from HSV-1 non-immune individuals, whether unstimulated or stimulated with HSV-1 antigen, did not mediate significant lysis of either target cell. HSV-immune MNL, both freshly-isolated and cultured for 5 days without antigen, demonstrated only low levels of natural killer (NK) cell-mediate lysis. MNL from HSV-immune individuals incubated for 5 days in vitro with HSV-1 antigen mediated significant virus-specific lysis of both target cells. Mean virus-specific lysis of autologous monocytes was 8.5(/+-/2.0)% compared to a three-fold greater virus-specific lysis of autologous macrophages. Greater than 70% of this lytic activity was mediated by Leu-11-negative, T3-positive cytotoxic T lymphocytes (CTL). Allogeneic target cells lacking a common HLA determinant were not significantly lysed while T8-positive CTL mediated infrequent lysis of target cells sharing a common HLA-A and/or HLA-B determinant. T4-positive lymphocytes were demonstrated to be the predominant cell mediating lysis of autologous target cells and allogeneic target cells sharing both HLA-A and/or HLA-B plus HLA-DR determinants with the CTL; the T4-positive cell was the sole CTL mediator of lysis of allogeneic target cells having a common HLA-DR determinant.

  14. A Modified Zinc Acetate Gel, a Potential Nonantiretroviral Microbicide, Is Safe and Effective against Simian-Human Immunodeficiency Virus and Herpes Simplex Virus 2 Infection In Vivo

    PubMed Central

    Kenney, Jessica; Rodríguez, Aixa; Kizima, Larisa; Seidor, Samantha; Menon, Radhika; Jean-Pierre, Ninochka; Pugach, Pavel; Levendosky, Keith; Derby, Nina; Gettie, Agegnehu; Blanchard, James; Piatak, Michael; Lifson, Jeffrey D.; Paglini, Gabriela; Zydowsky, Thomas M.; Robbiani, Melissa

    2013-01-01

    We previously showed that a prototype gel comprising zinc acetate (ZA) in carrageenan (CG) protected mice against vaginal and rectal herpes simplex virus 2 (HSV-2) challenge as well as macaques against vaginal simian-human immunodeficiency virus reverse transcriptase (SHIV-RT) challenge. In this work, we modified buffers and cosolvents to obtain a stable, nearly iso-osmolal formulation and evaluated its safety and efficacy against SHIV-RT and HSV-2. In vitro toxicity to lactobacilli and Candida albicans was determined. Macaques were given daily doses of ZA and CG (ZA/CG) or CG alone vaginally for 14 days and challenged with SHIV-RT 24 h later. Mice were challenged vaginally or rectally with HSV-2 immediately after a single gel treatment to measure efficacy or vaginally 12 h after daily gel treatment for 7 days to evaluate the gel's impact on susceptibility to HSV-2 infection. The modified ZA/CG neither affected the viability of lactobacilli or C. albicans nor enhanced vaginal HSV-2 infection after daily ZA/CG treatment. Vaginal SHIV-RT infection of macaques was reduced by 66% (P = 0.006) when macaques were challenged 24 h after the last dose of gel. We observed 60% to 80% uninfected mice after vaginal (P < 0.0001) and rectal (P = 0.008) high-dose HSV-2 challenge. The modified ZA/CG gel is safe and effective in animal models and represents a potential candidate to limit the transmission of HIV and HSV-2. PMID:23752515

  15. Comparison of herpes simplex (HSV) proteins synthesized in Vero, HEP-2 and human megakaryocyte-like cell lines

    SciTech Connect

    Soslau, G.; Pastorino, M.B.; Morgan, D.A.; Brodsky, I.; Howett, M.K.

    1986-05-01

    The natural human host blood cell capable of supporting herpes virus replication has yet to be defined. They found that a recently cultured human megakaryocyte-like (Meg) cell line can support HSV 1 and 2 replication as demonstrated by growth inhibition, CPE, virus production and HSV DNA synthesis. The HSV proteins synthesized and post-translationally modified in Vero and HEp-2 infected cells were compared to the protein species produced in the infected Meg cell since differences may influence antigenic properties and host range. Host cell protein synthesis was greatly reduced in all three cell lines within hours post infection (pi). However, maximum viral protein synthesis occurs between 4 and 24 hrs pi with the Meg cells as compared to 24-48 hrs pi with the other cell lines. The immunoprecipitated /sup 35/S-methionine labeled HSV protein gel patterns for each infected cell line are qualitatively and quantitatively very different from each other. Dramatic differences were also observed when infected cells were labeled with /sup 32/P-ATP (in vitro method) or /sup 32/Pi (in vivo method). Finally, analysis of /sup 3/H-mannose labeled HSV glycoproteins demonstrates that the post-translational modifications of these proteins are significantly altered in the Meg cell as compared to the Vero and HEp-2 cells.

  16. Neonatal herpes simplex virus.

    PubMed

    Berardi, Alberto; Lugli, Licia; Rossi, Cecilia; Maria, Chiara Laguardia; Guidotti, Isotta; Gallo, Claudio; Ferrari, Fabrizio

    2011-10-01

    Herpes simplex virus is an important cause of neonatal infection, which can lead to death or long-term disabilities. Rarely in utero, the transmission frequently occurs during delivery. The disease may be disseminated, localized to the central nervous system, or involving skin, eye and/or mouth. Mortality rates markedly decreased with high-dose antiviral treatment. Diagnosis of neonatal infection is based on viral isolation from ulcerated vesicles or by scarifying mucocutaneous lesions. Recently polymerase chain reaction plays a central role for both viral detection (skin, mucosal, cerebrospinal fluid samples) and response to therapy. Vertical transmission may be decreased by prophylactic antiviral treatment. PMID:21942600

  17. Simplex turbopump design

    NASA Technical Reports Server (NTRS)

    Marsh, Matt; Cowan, Penny

    1994-01-01

    Turbomachinery used in liquid rocket engines typically are composed of complex geometries made from high strength-to-weight super alloys and have long design and fabrication cycle times (3 to 5 years). A simple, low-cost turbopump is being designed in-house to demonstrate the ability to reduce the overall cost to $500K and compress life cycle time to 18 months. The simplex turbopump was designed to provide a discharge pressure of 1500 psia of liquid oxygen at 90 lbm/s. The turbine will be powered by gaseous oxygen. This eliminates the need for an inter-propellant seal typically required to separate the fuel-rich turbine gases from the liquid oxygen pump components. Materials used in the turbine flow paths will utilize existing characterized metals at 800 deg R that are compatible with a warm oxygen environment. This turbopump design would be suitable for integration with a 40 K pound thrust hybrid motor that provides warm oxygen from a tapped-off location to power the turbine. The preliminary and detailed analysis was completed in a year by a multiple discipline, concurrent engineering team. Manpower, schedule, and cost data were tracked during the process for a comparison to the initial goal. The Simplex hardware is the procurement cycle with the expectation of the first test to occur approximately 1.5 months behind the original schedule goal.

  18. [Neonatal herpes simplex infection].

    PubMed

    van Ham-Borawitz, V E J; Stam, E D; Welborn, K M; Sas, T C J

    2016-01-01

    Neonatal encephalitis caused by herpes simplex virus (HSV) is a familiar disease with a high mortality and morbidity rate. Isolated skin-eye-mouth infection is less familiar among professionals. In this article we present two neonates with an isolated skin lesion caused by an HSV infection. Of the neonates infected with HSV, 40-45% show isolated skin-eye-mouth disease. With correct treatment, the risk of spread to the central nervous system will decrease from 50-60% to 5-10%. Typical HSV skin lesions may present at a late stage of the disease or may be masked by a secondary bacterial infection. When a neonate presents with atypical skin lesions starting 7-12 days after the birth, immediate testing for HSV and immediate treatment are required, to decrease the risk of further progression of the disease. PMID:27122069

  19. Herpes Simplex Virus (Cold Sores)

    MedlinePlus

    ... the skin, eyes, and mouth. This is a life-threatening infection that can lead to permanent brain damage or even death. Herpes simplex viruses also cause encephalitis, an infection of the brain. ...

  20. 21 CFR 866.3305 - Herpes simplex virus serological assays.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Herpes simplex virus serological assays. 866.3305 Section 866.3305 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Serological Reagents § 866.3305...

  1. 21 CFR 866.3305 - Herpes simplex virus serological assays.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Herpes simplex virus serological assays. 866.3305 Section 866.3305 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Serological Reagents § 866.3305...

  2. 21 CFR 866.3305 - Herpes simplex virus serological assays.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Herpes simplex virus serological assays. 866.3305 Section 866.3305 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Serological Reagents § 866.3305...

  3. 21 CFR 866.3305 - Herpes simplex virus serological assays.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Herpes simplex virus serological assays. 866.3305 Section 866.3305 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Serological Reagents § 866.3305...

  4. 21 CFR 866.3305 - Herpes simplex virus serological assays.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Herpes simplex virus serological assays. 866.3305 Section 866.3305 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Serological Reagents § 866.3305...

  5. Lichen simplex chronicus on the ankle (image)

    MedlinePlus

    Lichen simplex chronicus on the ankle: Lichen simplex chronicus is also known as neurodermatitis. A minor itch may encourage scratching which increases the irritation, leading to more scratching. This ...

  6. Anisakis simplex: current knowledge.

    PubMed

    Pravettoni, V; Primavesi, L; Piantanida, M

    2012-08-01

    Anisakiasis, firstly described in 1960s in the Netherlands, is a fish-borne parasitic disease caused by the consumption of raw or undercooked fish or cephalopods contaminated by third stage (13) larvae of the Anisakidae family, in particular Anisakis simplex (As), A. pegreffii and Pseudoterranova decipiens. Every year, approximately 20,000 cases of anisakiasis were reported worldwide, over 90% are from Japan and most others in Spain, the Netherlands and Germany, depending on the habits of fish consuming. Live As larvae can elicit i) a parasitic infection of the digestive tract or, occasionally, other organs, causing erosive and/or haemorrhagic lesions, ascites, perforations until granulomas and masses, if larva is not removed, and ii) allergic reactions, as anaphylaxis, acute/chronic urticaria and angioedema. Like other parasite infestations, As larva induces an immune adaptive response characterised by T-lymphocyte proliferation with polyclonal and monoclonal (responsible for As allergic symptoms) IgE production, eosinophilia and mastocytosis. Several As allergens, many of which thermostable, were described In particular the major allergen Ani s 1 and Ani s 7 could characterized a past or a recent infection. There is a general agreement that an active infection is required to initiate allergic sensitivity to Anisakis. Until now, the only effective treatment for anisakiasis is the endoscopic removal of live larvae and the best protection against anisakiasis is to educate consumers about the dangers of eating raw fish and to recommend avoiding the consumption of raw or inadequately thermally treated marine fish or cephalopods. PMID:23092000

  7. MicroRNA-145 regulates oncolytic herpes simplex virus-1 for selective killing of human non-small cell lung cancer cells

    PubMed Central

    2013-01-01

    Background Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide, and novel treatment modalities to improve the prognosis of patients with advanced disease are highly desirable. Oncolytic virotherapy is a promising approach for the treatment of advanced NSCLC. MicroRNAs (miRNAs) may be a factor in the regulation of tumor-specific viral replication. The purpose of this study was to investigate whether miRNA-145 regulated oncolytic herpes simplex virus-1 (HSV-1) can selectively kill NSCLC cells with reduced collateral damage to normal cells. Methods We incorporated 4 copies of miRNA-145 target sequences into the 3′-untranslated region of an HSV-1 essential viral gene, ICP27, to create AP27i145 amplicon viruses and tested their target specificity and toxicity on normal cells and lung cancer cells in vitro. Results miRNA-145 expression in normal cells was higher than that in NSCLC cells. AP27i145 replication was inversely correlated with the expression of miRNA-145 in infected cells. This oncolytic HSV-1 selectively reduced cell proliferation and prevented the colony formation of NSCLC cells. The combination of radiotherapy and AP27i145 infection was significantly more potent in killing cancer cells than each therapy alone. Conclusions miRNA-145-regulated oncolytic HSV-1 is a promising agent for the treatment of NSCLC. PMID:23876001

  8. Development of a high-throughput β-Gal-based neutralization assay for quantitation of herpes simplex virus-neutralizing antibodies in human samples.

    PubMed

    Baccari, Amy; Cooney, Michael; Blevins, Tamara P; Morrison, Lynda A; Larson, Shane; Skoberne, Mojca; Belshe, Robert B; Flechtner, Jessica B; Long, Deborah

    2016-07-19

    Measurement of neutralizing antibodies against herpes simplex virus (HSV) is important for evaluation of candidate vaccines. The established plaque-reduction neutralization assay is time consuming, labor intensive, and difficult to validate and transfer. Here, we describe the characterization of a HSV-neutralization assay based on the expression of a reporter gene, β-galactosidase (β-Gal). Using previously constructed HSV-β-Gal recombinant viruses, HSV-2/Gal and HSV-1/tk12, we developed a colorimetric β-Gal-based neutralization assay that is sensitive and highly reproducible, and performed in less than 48h. HSV-1 and HSV-2 neutralizing titers measured by the β-Gal-based neutralization assay were equivalent to those obtained by a plaque reduction neutralization assay. Intra- and inter-assay precision studies demonstrated that the β-Gal-based assay was repeatable and yielded low and acceptable variation. In addition, comparison of HSV-2 neutralizing antibody (NAb) titers measured in two independent laboratories by two unique β-Gal-based assays showed a highly significant correlation (r=0.9499, p<0.0001) between the two assays. The new assay will serve as an important tool both for preclinical and clinical trials of new HSV vaccines. PMID:27265458

  9. Volatile Organic Compound Gamma-Butyrolactone Released upon Herpes Simplex Virus Type -1 Acute Infection Modulated Membrane Potential and Repressed Viral Infection in Human Neuron-Like Cells

    PubMed Central

    Waguespack, Yan; Figliozzi, Robert W.; Kharel, Madan K.; Zhang, Qiaojuan; Martin-Caraballo, Miguel

    2016-01-01

    Herpes Simplex Virus Type -1 (HSV-1) infections can cause serious complications such as keratitis and encephalitis. The goal of this study was to identify any changes in the concentrations of volatile organic compounds (VOCs) produced during HSV-1 infection of epithelial cells that could potentially be used as an indicator of a response to stress. An additional objective was to study if any VOCs released from acute epithelial infection may influence subsequent neuronal infection to facilitate latency. To investigate these hypotheses, Vero cells were infected with HSV-1 and the emission of VOCs was analyzed using two-dimensional gas chromatograph/mass spectrometry (2D GC/MS). It was observed that the concentrations of gamma-butyrolactone (GBL) in particular changed significantly after a 24-hour infection. Since HSV-1 may establish latency in neurons after the acute infection, GBL was tested to determine if it exerts neuronal regulation of infection. The results indicated that GBL altered the resting membrane potential of differentiated LNCaP cells and promoted a non-permissive state of HSV-1 infection by repressing viral replication. These observations may provide useful clues towards understanding the complex signaling pathways that occur during the HSV-1 primary infection and establishment of viral latency. PMID:27537375

  10. Volatile Organic Compound Gamma-Butyrolactone Released upon Herpes Simplex Virus Type -1 Acute Infection Modulated Membrane Potential and Repressed Viral Infection in Human Neuron-Like Cells.

    PubMed

    Rochford, Kevin; Chen, Feng; Waguespack, Yan; Figliozzi, Robert W; Kharel, Madan K; Zhang, Qiaojuan; Martin-Caraballo, Miguel; Hsia, S Victor

    2016-01-01

    Herpes Simplex Virus Type -1 (HSV-1) infections can cause serious complications such as keratitis and encephalitis. The goal of this study was to identify any changes in the concentrations of volatile organic compounds (VOCs) produced during HSV-1 infection of epithelial cells that could potentially be used as an indicator of a response to stress. An additional objective was to study if any VOCs released from acute epithelial infection may influence subsequent neuronal infection to facilitate latency. To investigate these hypotheses, Vero cells were infected with HSV-1 and the emission of VOCs was analyzed using two-dimensional gas chromatograph/mass spectrometry (2D GC/MS). It was observed that the concentrations of gamma-butyrolactone (GBL) in particular changed significantly after a 24-hour infection. Since HSV-1 may establish latency in neurons after the acute infection, GBL was tested to determine if it exerts neuronal regulation of infection. The results indicated that GBL altered the resting membrane potential of differentiated LNCaP cells and promoted a non-permissive state of HSV-1 infection by repressing viral replication. These observations may provide useful clues towards understanding the complex signaling pathways that occur during the HSV-1 primary infection and establishment of viral latency. PMID:27537375

  11. Expression of Cutaneous Lymphocyte–Associated Antigen and E-selectin Ligand by Circulating Human Memory CD4+ T Lymphocytes Specific for Herpes Simplex Virus Type 2

    PubMed Central

    González, Julio C.; Kwok, William W.; Wald, Anna; McClurkan, Christopher L.; Huang, Jay; Koelle, David M.

    2005-01-01

    Virus-specific memory T lymphocytes traffic to sites of viral infection. Herpes simplex virus (HSV) type 2–specific CD4+ and CD8+ T lymphocytes differ with regard to their homing kinetics to infected tissues. We studied the expression of cutaneous lymphocyte–associated antigen (CLA) and E-selectin ligand (ESL) by HSV-2–specific CD4+ T lymphocytes. Virus-reactive T lymphocytes were identified ex vivo by CD154 or interferon-γ up-regulation. We detected selective expression of CLA by HSV-2–reactive CD4+ T lymphocytes, but at levels lower than those we previously observed for CD8+ T lymphocytes. Short-term HSV-2–reactive CD4+ lines generated from peripheral-blood mononuclear cells preferentially express CLA, compared with cytomegalovirus- or influenza-specific cells. CLA is expressed by HSV-2–reactive cells that are initially CLA negative before restimulation. Short-term culture-expanded HSV-2–specific CD4+ T lymphocytes also selectively express ESL. These findings have implications for the optimization of vaccines for HSV and other cutaneous pathogens. PMID:15609235

  12. Seroprevalence of human herpes simplex, hepatitis B and epstein-barr viruses in children with acute lymphoblastic leukemia in southern iran.

    PubMed

    Mahjour, Seyed Babak; Ghaffarpasand, Fariborz; Fattahi, Mohammad Javad; Ghaderi, Abbas; Fotouhi Ghiam, Alireza; Karimi, Mehran

    2010-12-01

    To investigate the seroprevalence of Herpes Simplex Viruses (HSV1 and HSV2), Ebstein-Barr Virus (EBV) and Hepatitis B Virus (HBV) in children with acute lymphoblastic leukemia (ALL) in southern Iran. 90 patients with ALL and 90 age-sex matched healthy participants were enrolled in this study. Antibodies (IgG) against HBsAg, HSV1, HSV2, EBV different antigens including Epstein-Barr nuclear antigen-1 (EBNA-1), viral capsid antigen (VCA) and early antigen (EA) were measured by enzyme-linked immunosorbent assay (ELISA). There were 54 (60%) male and 36 (40%) female in both study groups with mean age of 8.47 ± 3.61 and 8.61 ± 2.84 years in case and control group respectively (P = 0.812). The prevalence of antibodies against HBsAg (P = 0.002), HSV1 (P < 0.0001), VCA (P = 0.021) and EA (P < 0.0001) antigens of EBV were significantly higher in ALL patients. With the results of this study, we could not exclude a connection between these viral infections and later leukemogenesis in childhood ALL, although nor latent infection nor congenital infection cannot be excluded by this method. PMID:20309661

  13. The Significance of Herpes Simplex for School Nurses

    ERIC Educational Resources Information Center

    Ensor, Deirdre

    2005-01-01

    Herpes simplex is a common recurrent viral infection caused by the herpes simplex virus. The two closely related but distinct viruses that cause herpes simplex infections are herpes simplex 1 (HSV-1) and herpes simplex 2 (HSV-2). HSV-1 is commonly associated with infections around the oral mucosa and is the cause of herpes labialis, often referred…

  14. Virus-mediated EpoR76E Therapy Slows Optic Nerve Axonopathy in Experimental Glaucoma.

    PubMed

    Bond, Wesley S; Hines-Beard, Jessica; GoldenMerry, Y Paul L; Davis, Mara; Farooque, Alma; Sappington, Rebecca M; Calkins, David J; Rex, Tonia S

    2016-02-01

    Glaucoma, a common cause of blindness, is currently treated by intraocular pressure (IOP)-lowering interventions. However, this approach is insufficient to completely prevent vision loss. Here, we evaluate an IOP-independent gene therapy strategy using a modified erythropoietin, EPO-R76E, which has reduced erythropoietic function. We used two models of glaucoma, the murine microbead occlusion model and the DBA/2J mouse. Systemic recombinant adeno-associated virus-mediated gene delivery of EpoR76E (rAAV.EpoR76E) was performed concurrent with elevation of IOP. Axon structure and active anterograde transport were preserved in both models. Vision, as determined by the flash visual evoked potential, was preserved in the DBA/2J. These results show that systemic EpoR76E gene therapy protects retinal ganglion cells from glaucomatous degeneration in two different models. This suggests that EPO targets a component of the neurodegenerative pathway that is common to both models. The efficacy of rAAV.EpoR76E delivered at onset of IOP elevation supports clinical relevance of this treatment. PMID:26502777

  15. Herpes Simplex Virus (HSV) in Infants and Babies

    MedlinePlus

    ... rashes clinical tools newsletter | contact Share | Herpes Simplex Virus (HSV) A parent's guide for infants and babies ... Herpes infections are caused by both herpes simplex virus type 1 (HSV-1) and herpes simplex virus ...

  16. Sendai virus-mediated expression of reprogramming factors promotes plasticity of human neuroblastoma cells.

    PubMed

    Islam, S M Rafiqul; Suenaga, Yusuke; Takatori, Atsushi; Ueda, Yasuji; Kaneko, Yoshiki; Kawana, Hidetada; Itami, Makiko; Ohira, Miki; Yokoi, Sana; Nakagawara, Akira

    2015-10-01

    Neuroblastoma (NB) is the most common extracranial solid tumor that originates from multipotent neural crest cells. NB cell populations that express embryonic stem cell-associated genes have been identified and shown to retain a multipotent phenotype. However, whether somatic reprogramming of NB cells can produce similar stem-cell like populations is unknown. Here, we sought to reprogram NB cell lines using an integration-free Sendai virus vector system. Of four NB cell lines examined, only SH-IN cells formed induced pluripotent stem cell-like colonies (SH-IN 4F colonies) at approximately 6 weeks following transduction. These SH-IN 4F colonies were alkaline phosphatase-positive. Array comparative genomic hybridization analysis indicated identical genomic aberrations in the SH-IN 4F cells as in the parental cells. SH-IN 4F cells had the ability to differentiate into the three embryonic germ layers in vitro, but rather formed NBs in vivo. Furthermore, SH-IN 4F cells exhibited resistance to cisplatin treatment and differentiated into endothelial-like cells expressing CD31 in the presence of vascular endothelial growth factor. These results suggest that SH-IN 4F cells are partially reprogrammed NB cells, and could be a suitable model for investigating the plasticity of aggressive tumors. PMID:26190440

  17. Advancing Paternal Age and Simplex Autism

    ERIC Educational Resources Information Center

    Puleo, Connor Morrow; Schmeidler, James; Reichenberg, Abraham; Kolevzon, Alexander; Soorya, Latha V.; Buxbaum, Joseph D.; Silverman, Jeremy M.

    2012-01-01

    De novo events appear more common in female and simplex autism spectrum disorder (ASD) cases and may underlie greater ASD risk in older fathers' offspring. This study examined whether advancing paternal age predicts an increase in simplex (n = 90) versus multiplex ASD cases (n = 587) in 677 participants (340 families). Whether or not controlling…

  18. Coxeter decompositions of hyperbolic simplexes

    SciTech Connect

    Felikson, A A

    2002-12-31

    A Coxeter decomposition of a polyhedron in a hyperbolic space H{sup n} is a decomposition of it into finitely many Coxeter polyhedra such that any two tiles having a common facet are symmetric with respect to it. The classification of Coxeter decompositions is closely related to the problem of the classification of finite-index subgroups generated by reflections in discrete hyperbolic groups generated by reflections. All Coxeter decompositions of simplexes in the hyperbolic spaces H{sup n} with n>3 are described in this paper.

  19. A Herpes Simplex Virus Type 1 Human Asymptomatic CD8+ T-Cell Epitopes-Based Vaccine Protects Against Ocular Herpes in a “Humanized” HLA Transgenic Rabbit Model

    PubMed Central

    Srivastava, Ruchi; Khan, Arif A.; Huang, Jiawei; Nesburn, Anthony B.; Wechsler, Steven L.; BenMohamed, Lbachir

    2015-01-01

    Purpose. A clinical vaccine that protects from ocular herpes simplex virus type 1 (HSV-1) infection and disease still is lacking. In the present study, preclinical vaccine trials of nine asymptomatic (ASYMP) peptides, selected from HSV-1 glycoproteins B (gB), and tegument proteins VP11/12 and VP13/14, were performed in the “humanized” HLA–transgenic rabbit (HLA-Tg rabbit) model of ocular herpes. We recently reported that these peptides are highly recognized by CD8+ T cells from “naturally” protected HSV-1–seropositive healthy ASYMP individuals (who have never had clinical herpes disease). Methods. Mixtures of three ASYMP CD8+ T-cell peptides derived from either HSV-1 gB, VP11/12, or VP13/14 were delivered subcutaneously to different groups of HLA-Tg rabbits (n = 10) in incomplete Freund's adjuvant, twice at 15-day intervals. The frequency and function of HSV-1 epitope-specific CD8+ T cells induced by these peptides and their protective efficacy, in terms of survival, virus replication in the eye, and ocular herpetic disease were assessed after an ocular challenge with HSV-1 (strain McKrae). Results. All mixtures elicited strong and polyfunctional IFN-γ– and TNF-α–producing CD107+CD8+ cytotoxic T cells, associated with a significant reduction in death, ocular herpes infection, and disease (P < 0.015). Conclusions. The results of this preclinical trial support the screening strategy used to select the HSV-1 ASYMP CD8+ T-cell epitopes, emphasize their valuable immunogenic and protective efficacy against ocular herpes, and provide a prototype vaccine formulation that may be highly efficacious for preventing ocular herpes in humans. PMID:26098469

  20. Treatment of human papillomavirus (HPV) type 16-infected cells using herpes simplex virus type 1 thymidine kinase-mediated gene therapy transcriptionally regulated by the HPV E2 protein.

    PubMed

    Sethi, Neerja; Palefsky, Joel

    2003-01-01

    Human papillomavirus type 16 (HPV-16) is associated with development of anogenital squamous cell cancers (SCCs) and their precursor, intraepithelial neoplasia (IN). Few approaches to the treatment of IN to prevent SCC are targeted specifically to HPV. We have designed an HPV-specific therapy using the herpes simplex virus type 1 thymidine kinase (HSV-1 TK) gene driven by an HPV-specific promoter in the HPV-16 long control region (LCR) (nucleotide 7450-nucleotide 104), which is regulated by the HPV E2 protein. Expression of the HSV-1 TK gene is designed to render HPV-infected cells sensitive to the prodrugs ganciclovir (GCV) and acyclovir (ACV). To assess the E2 specificity of gene expression driven by the HPV-16 LCR, we measured luciferase expression in HPV-positive and HPV-negative cell lines. Significant induction of luciferase activity was observed in HPV-positive cells when compared with four different HPV-negative epithelial cell lines. Cotransfection of an HPV-negative cell line, MDCK, with an HPV-16 E2-expressing plasmid resulted in 15- to 20-fold induction of luciferase activity, suggesting specific activation by E2 protein. A plasmid expressing the HSV-1 TK gene driven by the LCR was transfected into CaSki and SiHa cells. Treatment of transfected cells with either GCV or ACV (20-30 microg/ml) for 6-10 days resulted in 80-95% cell death. Cell death was progressive, dose dependent, and mediated by apoptosis. These results suggest that direct gene transfer of the HSV-1 TK gene into HPV-16-infected cells expressing E2 protein, accompanied by treatment with either GCV or ACV, may be a clinically feasible therapeutic strategy. PMID:12573058

  1. [Update on Herpes Simplex Encephalitis].

    PubMed

    Kuroda, Hiroshi

    2015-07-01

    Herpes simplex encephalitis (HSE), which is caused by the herpes simplex virus (HSV), is a severe neuro-infectious disease characterized by high mortality and morbidity. We reviewed the pathomechanism, diagnosis, and treatment of HSE based on recent progress in the field. The highlighted mechanism of HSE in this review is immune-mediated tissue damage caused by host immunity. Major symptoms of HSE include psychiatric alteration, Klüver-Bucy syndrome, and amnesia, caused by frequent involvement of the limbic system. An important differential diagnosis of HSE is autoimmune limbic encephalitis, including anti-N-methyl-D-aspartate receptor encephalitis, and anti-voltage-gated K+ channel encephalitis. HSE is definitely diagnosed based on the detection of HSV-DNA by polymerase chain reaction and/or the detection of HSV-IgG antibody in the cerebrospinal fluid (CSF). Repeated CSF examinations are required for the accurate diagnosis of HSE. Acyclovir (ACV) plays a central role in the treatment of HSE, and its early initiation is essential for good outcome in patients with HSE. Acute administration of corticosteroids for HSE is controversial; a randomized, double-blind, placebo-controlled trial to investigate the efficacy of add-on corticosteroids to ACV is ongoing. PMID:26160820

  2. Herpes Simplex (Cold Sores and Genital Herpes)

    MedlinePlus

    ... Select a Language: Fact Sheet 508 Herpes Simplex (Cold Sores and Genital Herpes) WHAT IS HERPES? HSV ... virus 1 (HSV1) is the common cause of cold sores (oral herpes) around the mouth. HSV2 normally ...

  3. The AGMA1 poly(amidoamine) inhibits the infectivity of herpes simplex virus in cell lines, in human cervicovaginal histocultures, and in vaginally infected mice.

    PubMed

    Donalisio, Manuela; Quaranta, Paola; Chiuppesi, Flavia; Pistello, Mauro; Cagno, Valeria; Cavalli, Roberta; Volante, Marco; Bugatti, Antonella; Rusnati, Marco; Ranucci, Elisabetta; Ferruti, Paolo; Lembo, David

    2016-04-01

    The development of topical microbicides is a valid approach to protect the genital mucosa from sexually transmitted infections that cannot be contained with effective vaccination, like HSV and HIV infections. A suitable target of microbicides is the interaction between viral proteins and cell surface heparan sulfate proteoglycans (HSPGs). AGMA1 is a prevailingly cationic agmatine-containing polyamidoamine polymer previously shown to inhibit HSPGs dependent viruses, including HSV-1, HSV-2, and HPV-16. The aim of this study was to elucidate the mechanism of action of AGMA1 against HSV infection and assess its antiviral efficacy and biocompatibility in preclinical models. The results show AGMA1 to be a non-toxic inhibitor of HSV infectivity in cell cultures and human cervicovaginal histocultures. Moreover, it significantly reduced the burden of infection of HSV-2 genital infection in mice. The investigation of the mechanism of action revealed that AGMA1 reduces cells susceptibility to virus infection by binding to cell surface HSPGs thereby preventing HSV attachment. This study indicates that AGMA1 is a promising candidate for the development of a topical microbicide to prevent sexually transmitted HSV infections. PMID:26854390

  4. Development and application of a rapid detection system for human papillomavirus and Herpes simplex virus-2 by loop-mediated isothermal amplification assay.

    PubMed

    Yang, Jin-Fang; Zhao, Chang-Zhen; Lu, Ke-Xin

    2016-08-01

    Human papillomavirus (HPV) infection is an important factor that causes cervical cancer and non-melanoma skin cancer (NMSC), while HSV-2 plays an important role when HR-HPV triggers the cancer. Thus, a quick and convenient assay in the detection of HPV and HSV-2in the screening of HPV and HSV-2 infection is required. Two respective HPV and HSV-2 detection methods were established based on loop-mediated isothermal amplification (LAMP) assay. Specific outer primers, inner primers, and loop primers were designed according to the conserved domains of HPV and HSV-2 genomes, respectively, while degenerate primers were used for HPV assay. After optimizing the reaction conditions, the results were observed by LAMP Tubidimeter real-time LA-320. Standard plasmids HPV-L-P and HSV-2-L-P were cloned and used in sensitivity tests of HPV LAMP and HSV-2 LAMP, respectively. Fifty samples of actinic keratosis (AK), 20 samples of squamous cell carcinoma (SCC), 50 samples of basal cell carcinoma (BCC) and 20 samples of seborrheic keratosis (SK) were detected by HPV assay. Seventy three clinical samples of vaginitis, chronic cervicitis, cervical intraepithelial neoplasias and cervical cancer level positive were detected with HPV and HSV-2 assays. The reaction conditions of two assays were the same with a reaction temperature of 63 °C and a reaction time of 45 min. The sensitivity of HPV LAMP assay was 10 copies/μL, while that of the HSV-2 LAMP assay was 100 copies/μL. No cross-reactivity was observed. The HPV positive rates of AK, SCC, BCC and SK samples were 80% (40/50), 75% (15/20), 44% (22/50) and 21% (15/72), respectively. As an economic and quick diagnostic tool, LAMP assay is conducive to the extensive screening of HPV and HSV-2 and has huge potential to be promoted in resource-limited hospitals. PMID:27287497

  5. Antiviral agents for herpes simplex virus.

    PubMed

    Vere Hodge, R Anthony; Field, Hugh J

    2013-01-01

    This review starts with a brief description of herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), the clinical diseases they cause, and the continuing clinical need for antiviral chemotherapy. A historical overview describes the progress from the early, rather toxic antivirals to acyclovir (ACV) which led the way for its prodrug, valacyclovir, to penciclovir and its prodrug, famciclovir (FCV). These compounds have been the mainstay of HSV therapy for two decades and have established a remarkable safety record. This review focuses on these compounds, the preclinical studies which reveal potentially important differences, the clinical trials, and the clinical experience through two decades. Some possible areas for further investigation are suggested. The focus shifts to new approaches and novel compounds, in particular, the combination of ACV with hydrocortisone, known as ME609 or zovirax duo, an HSV helicase-primase inhibitor, pritelivir (AIC316), and CMX001, the cidofovir prodrug for treating resistant HSV infection in immunocompromised patients. Letermovir has established that the human cytomegalovirus terminase enzyme is a valid target and that similar compounds could be sought for HSV. We discuss the difficulties facing the progression of new compounds. In our concluding remarks, we summarize the present situation including a discussion on the reclassification of FCV from prescription-only to pharmacist-controlled for herpes labialis in New Zealand in 2010; should this be repeated more widely? We conclude that HSV research is emerging from a quiescent phase. PMID:23885997

  6. A Drosophila Model of Epidermolysis Bullosa Simplex.

    PubMed

    Bohnekamp, Jens; Cryderman, Diane E; Paululat, Achim; Baccam, Gabriel C; Wallrath, Lori L; Magin, Thomas M

    2015-08-01

    The blistering skin disorder epidermolysis bullosa simplex (EBS) results from dominant mutations in keratin 5 (K5) or keratin 14 (K14) genes, encoding the intermediate filament (IF) network of basal epidermal keratinocytes. The mechanisms governing keratin network formation and collapse due to EBS mutations remain incompletely understood. Drosophila lacks cytoplasmic IFs, providing a 'null' environment to examine the formation of keratin networks and determine mechanisms by which mutant keratins cause pathology. Here, we report that ubiquitous co-expression of transgenes encoding wild-type human K14 and K5 resulted in the formation of extensive keratin networks in Drosophila epithelial and non-epithelial tissues, causing no overt phenotype. Similar to mammalian cells, treatment of transgenic fly tissues with phosphatase inhibitors caused keratin network collapse, validating Drosophila as a genetic model system to investigate keratin dynamics. Co-expression of K5 and a K14(R125C) mutant that causes the most severe form of EBS resulted in widespread formation of EBS-like cytoplasmic keratin aggregates in epithelial and non-epithelial fly tissues. Expression of K14(R125C)/K5 caused semi-lethality; adult survivors developed wing blisters and were flightless due to a lack of intercellular adhesion during wing heart development. This Drosophila model of EBS is valuable for the identification of pathways altered by mutant keratins and for the development of EBS therapies. PMID:25830653

  7. Herpes simplex-like infection in a bottlenose dolphin stranded in the Canary Islands.

    PubMed

    Esperón, F; Fernández, A; Sánchez-Vizcaíno, J M

    2008-08-19

    A bottlenose dolphin, stranded in the Canary Islands in 2001 exhibited non-suppurative encephalitis. No molecular detection of cetacean morbillivirus (CeMV) was found, but a herpesviral-specific band of 250 bp was detected in the lung and brain. The sequenced herpesviral PCR product was compared with GenBank sequences, obtaining 98% homology (p-distance of 0.02) with Human herpesvirus 1 (herpes simplex virus 1 or HSV-1). This is the first report of a herpes simplex-like infection in a stranded dolphin. PMID:18828564

  8. Antihelmintic effects of nutmeg (Myristica fragans) on Anisakis simplex L3 larvae obtained from Micromesistius potassou.

    PubMed

    López, Víctor; Gerique, Javier; Langa, Elisa; Berzosa, César; Valero, Marta Sofía; Gómez-Rincón, Carlota

    2015-06-01

    Anisakis simplex is a foodborne pathogen that can produce human infections and allergic reactions due to the high consumption of raw fish. The seeds of Myristica fragans (Myristicaceae), popularly known as nutmeg, are worldwide used as a culinary spice due to its flavour and properties in food preservation. A nutmeg extract was prepared, analyzed, screened for cytotoxicity and tested against Anisakis simplex L3 larvae. In order to detect the biologically active constituents of the extract, myristicin was tested on the larvae. An acetylcholinesterase inhibition bioassay was also carried out to investigate the antihelmintic mechanism of action. Our results demonstrate that nutmeg exerts antihelmintic effects on Anisakis simplex, being myristicin one of the active compounds. The extract induced a high rate of dead anisakis at concentrations between 0.5 and 0.7 mg/ml without being considered cytotoxic; however, an inhibition of acetylcholinesterase was discarded as the molecular mechanism involved in the activity. PMID:25890576

  9. Influence of herpes simplex virus infection on benzo(a)pyrene metabolism in monkey kidney cells

    SciTech Connect

    Degenhardt, J.H.; Whitcomb, B.; Hall, M.R.

    1984-01-01

    Current research in our laboratory is designed to investigate the intracellular interactions of BP with oncogenic DNA viruses of animals and humans. In this study, our purpose was to determine whether BP is metabolized in herpes simplex virus type 2 (HSV-2) infected cells and whether HSV-2 infection affects intracellular levels of the aryl hydrocarbon hydroxylase system necessary for BP metabolism.

  10. Topical Herpes Simplex Virus 2 (HSV-2) Vaccination with Human Papillomavirus Vectors Expressing gB/gD Ectodomains Induces Genital-Tissue-Resident Memory CD8+ T Cells and Reduces Genital Disease and Viral Shedding after HSV-2 Challenge

    PubMed Central

    Çuburu, Nicolas; Wang, Kening; Goodman, Kyle N.; Pang, Yuk Ying; Thompson, Cynthia D.; Lowy, Douglas R.; Cohen, Jeffrey I.

    2014-01-01

    ABSTRACT No herpes simplex virus 2 (HSV-2) vaccine has been licensed for use in humans. HSV-2 glycoproteins B (gB) and D (gD) are targets of neutralizing antibodies and T cells, but clinical trials involving intramuscular (i.m.) injection of HSV-2 gB and gD in adjuvants have not been effective. Here we evaluated intravaginal (ivag) genetic immunization of C57BL/6 mice with a replication-defective human papillomavirus pseudovirus (HPV PsV) expressing HSV-2 gB (HPV-gB) or gD (HPV-gD) constructs to target different subcellular compartments. HPV PsV expressing a secreted ectodomain of gB (gBsec) or gD (gDsec), but not PsV expressing a cytoplasmic or membrane-bound form, induced circulating and intravaginal-tissue-resident memory CD8+ T cells that were able to secrete gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) as well as moderate levels of serum HSV neutralizing antibodies. Combined immunization with HPV-gBsec and HPV-gDsec (HPV-gBsec/gDsec) vaccines conferred longer survival after vaginal challenge with HSV-2 than immunization with HPV-gBsec or HPV-gDsec alone. HPV-gBsec/gDsec ivag vaccination was associated with a reduced severity of genital lesions and lower levels of viral shedding in the genital tract after HSV-2 challenge. In contrast, intramuscular vaccination with a soluble truncated gD protein (gD2t) in alum and monophosphoryl lipid A (MPL) elicited high neutralizing antibody titers and improved survival but did not reduce genital lesions and viral shedding. Vaccination combining ivag HPV-gBsec/gDsec and i.m. gD2t-alum-MPL improved survival and reduced genital lesions and viral shedding. Finally, high levels of circulating HSV-2-specific CD8+ T cells, but not serum antibodies, correlated with reduced viral shedding. Taken together, our data underscore the potential of HPV PsV as a platform for a topical mucosal vaccine to control local manifestations of primary HSV-2 infection. IMPORTANCE Genital herpes is a highly prevalent chronic

  11. Genomic identification of Anisakis simplex isolates.

    PubMed

    Siles, M; Cuéllar, C; Perteguer, M J

    1997-03-01

    RAPD technique was used to differentiate individuals of Anisakis simplex obtained from Merluccius merluccius, Phycis blennoides, Conger conger and Lepidorhombus boscii, from the North Atlantic Ocean. The amplification patterns of the host DNA controls were markedly different from those obtained for the parasitic material. No variation within the same host was detected. The amplification patterns for larvae obtained from fish of the same genus were somewhat different. The amplification patterns of A. simplex isolates from M. merluccius, P. blennoides, C. conger and L. boscii, were different. These results suggest the possible existence of two populations with a considerable high genetic variability and a different adaptation to different host species. PMID:9166445

  12. Identification of autoclave-resistant Anisakis simplex allergens.

    PubMed

    Carballeda-Sangiao, Noelia; Olivares, Fabiola; Rodriguez-Mahillo, Ana I; Careche, Mercedes; Tejada, Margarita; Moneo, Ignacio; González-Muñoz, Miguel

    2014-04-01

    Anisakis simplex is a fish parasite able to induce allergic reactions in humans infected when eating raw or undercooked fish parasitized with viable third-stage larvae. Some authors claim that exposure to nonviable Anisakis material can result in allergic symptoms in previously sensitized patients, indicating that parasite allergens are resistant to the thermal treatments of usual cooking procedures. Furthermore, some patients report symptoms after eating canned fish. The aim of this work was the analysis of parasite allergen stability in heating to 121 °C in an autoclave to simulate the thermal process applied to canned fish. Third-stage larvae were subjected to autoclaving for 20, 40, and 80 min, and parasite crude extracts were analyzed by electrophoresis, immunoblotting, and a flow-cytometric basophil activation test. Allergens resistant to autoclaving were separated by reversed-phase high-performance liquid chromatography and identified by ion trap mass spectrometry. Protein analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed that autoclaving considerably reduced the number and intensity of identifiable protein bands in a time-dependent manner. Several allergens were detected by immunoblotting with a pool of A. simplex allergic patients' sera after autoclaving. Allergens of 9 and 14 kDa resistant to autoclaving were identified as Ani s 4 and Ani s 1 allergens, respectively. Functional analysis showed that allergens retain their capacity to activate basophils even after autoclaving for 80 min. In conclusion, some relevant A. simplex allergens retain their capacity to bind immunoglobulin E and activate basophils after being subjected to autoclaving, which is a method equivalent to that used in industrial canning processes. PMID:24680072

  13. Herpes simplex virus 2 infection: molecular association with HIV and novel microbicides to prevent disease.

    PubMed

    Suazo, Paula A; Tognarelli, Eduardo I; Kalergis, Alexis M; González, Pablo A

    2015-04-01

    Infection with herpes simplex viruses is one of the most ancient diseases described to affect humans. Infection with these viruses produces vexing effects to the host, which frequently recur. Infection with herpes simplex viruses is lifelong, and currently there is no vaccine or drug to prevent or cure infection. Prevalence of herpes simplex virus 2 (HSV-2) infection varies significantly depending on the geographical region and nears 20% worldwide. Importantly, HSV-2 is the first cause of genital ulcers in the planet. HSV-2 affects approximately 500 million people around the globe and significantly increases the likelihood of acquiring the human immunodeficiency virus (HIV), as well as its shedding. Thus, controlling HSV-2 infection and spread is of public health concern. Here, we review the diseases produced by herpes simplex viruses, the factors that modulate HSV-2 infection, the relationship between HSV-2 and HIV and novel therapeutic and prophylactic microbicides/antivirals under development to prevent infection and pathological outcomes produced by this virus. We also review mutations associated with HSV-2 resistance to common antivirals. PMID:25209142

  14. Herpes Simplex Encephalitis: An Uncommon Presentation

    PubMed Central

    Bansal, Sunil; Bhatia, Rohan; Ahmad, Sohaib

    2016-01-01

    Herpes Simplex Virus (HSV) encephalitis is an uncommon illness, with about 2 cases per 250,000 per year. Most are caused by HSV-1, with 10% having HSV-2 as the aetiologic factor. We present a case of Herpes simplex type1encephalitis in a 70 year old male with an uncommon presentation. The patient was a known case of endogenous depression with no medical records and on no treatment for the same, reported with acute changes in mental state for the past five days. He was talking irrelevantly, had hallucinations and was unduly aggressive and violent. He was subjected to a thorough clinical and diagnostic work-up which included cerebrospinal fluid analysis, CT head and MRI brain. MRI brain was suggestive of mild subdural effusion which hinted towards infectious cause of encephalitis. The cerebrospinal fluid viral serology panel detected herpes simplex type 1 virus (HSV1) that was later confirmed by CSF Polymerase Chain Reaction (PCR) technique. Hence, acyclovir was initiated by intravenous route at a dosage of 10mg/kg body weight and continued for two weeks. This case holds significance in view of the fact that organic causes must be excluded in suspected cases of psychiatric illness especially in the absence of fever. Also, CSF-PCR testing plays a pivotal role in diagnosing herpes simplex encephalitis. PMID:27437286

  15. Herpes Simplex Encephalitis: An Uncommon Presentation.

    PubMed

    Kaeley, Nidhi; Bansal, Sunil; Bhatia, Rohan; Ahmad, Sohaib

    2016-05-01

    Herpes Simplex Virus (HSV) encephalitis is an uncommon illness, with about 2 cases per 250,000 per year. Most are caused by HSV-1, with 10% having HSV-2 as the aetiologic factor. We present a case of Herpes simplex type1encephalitis in a 70 year old male with an uncommon presentation. The patient was a known case of endogenous depression with no medical records and on no treatment for the same, reported with acute changes in mental state for the past five days. He was talking irrelevantly, had hallucinations and was unduly aggressive and violent. He was subjected to a thorough clinical and diagnostic work-up which included cerebrospinal fluid analysis, CT head and MRI brain. MRI brain was suggestive of mild subdural effusion which hinted towards infectious cause of encephalitis. The cerebrospinal fluid viral serology panel detected herpes simplex type 1 virus (HSV1) that was later confirmed by CSF Polymerase Chain Reaction (PCR) technique. Hence, acyclovir was initiated by intravenous route at a dosage of 10mg/kg body weight and continued for two weeks. This case holds significance in view of the fact that organic causes must be excluded in suspected cases of psychiatric illness especially in the absence of fever. Also, CSF-PCR testing plays a pivotal role in diagnosing herpes simplex encephalitis. PMID:27437286

  16. Can Herpes Simplex Virus Encephalitis Cause Aphasia?

    ERIC Educational Resources Information Center

    Naude, H.; Pretorius, E.

    2003-01-01

    Aphasia implies the loss or impairment of language caused by brain damage. The key to understanding the nature of aphasic symptoms is the neuro-anatomical site of brain damage, and not the causative agent. However, because "Herpes simplex" virus (HSV) encephalitis infection usually affects the frontal and temporal lobes, subcortical structures and…

  17. Recurrent lumbosacral herpes simplex virus infection

    PubMed Central

    Vassantachart, Janna M.

    2016-01-01

    We present the case of a 54-year-old white woman with episodic lumbosacral lesions that she had been treating as psoriasis. Evaluation revealed classic herpes simplex virus (HSV) infection. The discussion reviews the significance and potential complications of recurrent lumbosacral HSV infection. PMID:26722168

  18. Chromatin assembly on herpes simplex virus genomes during lytic infection

    PubMed Central

    Lu, Xu; Triezenberg, Steven J

    2009-01-01

    The human herpes simplex viruses HSV-1 and HSV-2 infect a significant portion of the human population. Both viruses can undergo lytic infection in epithelial cells and establish lifelong latency in neuronal cells. The large HSV-1 DNA genomes have long been considered to be devoid of histones both inside the virion particle and inside the cell during lytic infection, but to be packaged in repressive chromatin during latency. However, recent reports indicate that many histone and non-histone chromosomal proteins can associate with viral DNA during lytic infection and may influence important events during the HSV-1 lytic cycle. In this article, we summarize recent developments in this field and their implications. PMID:19682614

  19. Pediatric cancer gone viral. Part II: potential clinical application of oncolytic herpes simplex virus-1 in children

    PubMed Central

    Friedman, Gregory K; Beierle, Elizabeth A; Gillespie, George Yancey; Markert, James M; Waters, Alicia M; Chen, Chun-Yu; Denton, Nicholas L; Haworth, Kellie B; Hutzen, Brian; Leddon, Jennifer L; Streby, Keri A; Wang, Pin-Yi; Cripe, Timothy P

    2015-01-01

    Oncolytic engineered herpes simplex viruses (HSVs) possess many biologic and functional attributes that support their use in clinical trials in children with solid tumors. Tumor cells, in an effort to escape regulatory mechanisms that would impair their growth and progression, have removed many mechanisms that would have protected them from virus infection and eventual virus-mediated destruction. Viruses engineered to exploit this weakness, like mutant HSV, can be safely employed as tumor cell killers, since normal cells retain these antiviral strategies. Many preclinical studies and early phase trials in adults demonstrated that oncolytic HSV can be safely used and are highly effective in killing tumor cells that comprise pediatric malignancies, without generating the toxic side effects of nondiscriminatory chemotherapy or radiation therapy. A variety of engineered viruses have been developed and tested in numerous preclinical models of pediatric cancers and initial trials in patients are underway. In Part II of this review series, we examine the preclinical evidence to support the further advancement of oncolytic HSV in the pediatric population. We discuss clinical advances made to date in this emerging era of oncolytic virotherapy. PMID:26436134

  20. Anisakis simplex: from Obscure Infectious Worm to Inducer of Immune Hypersensitivity

    PubMed Central

    Audicana, M. Teresa; Kennedy, Malcolm W.

    2008-01-01

    Summary: Infection of humans with the nematode worm parasite Anisakis simplex was first described in the 1960s in association with the consumption of raw or undercooked fish. During the 1990s it was realized that even the ingestion of dead worms in food fish can cause severe hypersensitivity reactions, that these may be more prevalent than infection itself, and that this outcome could be associated with food preparations previously considered safe. Not only may allergic symptoms arise from infection by the parasites (“gastroallergic anisakiasis”), but true anaphylactic reactions can also occur following exposure to allergens from dead worms by food-borne, airborne, or skin contact routes. This review discusses A. simplex pathogenesis in humans, covering immune hypersensitivity reactions both in the context of a living infection and in terms of exposure to its allergens by other routes. Over the last 20 years, several studies have concentrated on A. simplex antigen characterization and innate as well as adaptive immune response to this parasite. Molecular characterization of Anisakis allergens and isolation of their encoding cDNAs is now an active field of research that should provide improved diagnostic tools in addition to tools with which to enhance our understanding of pathogenesis and controversial aspects of A. simplex allergy. We also discuss the potential relevance of parasite products such as allergens, proteinases, and proteinase inhibitors and the activation of basophils, eosinophils, and mast cells in the induction of A. simplex-related immune hypersensitivity states induced by exposure to the parasite, dead or alive. PMID:18400801

  1. Translational data from adeno-associated virus-mediated gene therapy of hemophilia B in dogs.

    PubMed

    Nichols, Timothy C; Whitford, Margaret H; Arruda, Valder R; Stedman, Hansell H; Kay, Mark A; High, Katherine A

    2015-03-01

    Preclinical testing of new therapeutic strategies in relevant animal models is an essential part of drug development. The choice of animal models of disease that are used in these studies is driven by the strength of the translational data for informing about safety, efficacy, and success or failure of human clinical trials. Hemophilia B is a monogenic, X-linked, inherited bleeding disorder that results from absent or dysfunctional coagulation factor IX (FIX). Regarding preclinical studies of adeno-associated virus (AAV)-mediated gene therapy for hemophilia B, dogs with severe hemophilia B (<1% FIX) provide well-characterized phenotypes and genotypes in which a species-specific transgene can be expressed in a mixed genetic background. Correction of the hemophilic coagulopathy by sustained expression of FIX, reduction of bleeding events, and a comprehensive assessment of the humoral and cell-mediated immune responses to the expressed transgene and recombinant AAV vector are all feasible end points in these dogs. This review compares the preclinical studies of AAV vectors used to treat dogs with hemophilia B with the results obtained in subsequent human clinical trials using muscle- and liver-based approaches. PMID:25675273

  2. Ebola virus mediated infectivity is restricted in canine and feline cells.

    PubMed

    Han, Ziying; Bart, Stephen M; Ruthel, Gordon; Vande Burgt, Nathan H; Haines, Kathleen M; Volk, Susan W; Vite, Charles H; Freedman, Bruce D; Bates, Paul; Harty, Ronald N

    2016-01-15

    Ebolaviruses and marburgviruses belong to the Filoviridae family and often cause severe, fatal hemorrhagic fever in humans and non-human primates. The magnitude of the 2014 outbreak in West Africa and the unprecedented emergence of Ebola virus disease (EVD) in the United States underscore the urgency to better understand the dynamics of Ebola virus infection, transmission and spread. To date, the susceptibility and possible role of domestic animals and pets in the transmission cycle and spread of EVD remains unclear. We utilized infectious VSV recombinants and lentivirus pseudotypes expressing the EBOV surface glycoprotein (GP) to assess the permissiveness of canine and feline cells to EBOV GP-mediated entry. We observed a general restriction in EBOV-mediated infection of primary canine and feline cells. To address the entry mechanism, we used cells deficient in NPC1, a host protein implicated in EBOV entry, and a pharmacological blockade of cholesterol transport, to show that an NPC1-dependent mechanism of EBOV entry is conserved in canine and feline cells. These data demonstrate that cells of canine and feline origin are susceptible to EBOV GP mediated infection; however, infectivity of these cells is reduced significantly compared to controls. Moreover, these data provide new insights into the mechanism of EBOV GP mediated entry into cells of canine and feline origin. PMID:26711035

  3. Von Willebrand Factor Gene Variants Associate with Herpes simplex Encephalitis.

    PubMed

    Abdelmagid, Nada; Bereczky-Veress, Biborka; Atanur, Santosh; Musilová, Alena; Zídek, Václav; Saba, Laura; Warnecke, Andreas; Khademi, Mohsen; Studahl, Marie; Aurelius, Elisabeth; Hjalmarsson, Anders; Garcia-Diaz, Ana; Denis, Cécile V; Bergström, Tomas; Sköldenberg, Birgit; Kockum, Ingrid; Aitman, Timothy; Hübner, Norbert; Olsson, Tomas; Pravenec, Michal; Diez, Margarita

    2016-01-01

    Herpes simplex encephalitis (HSE) is a rare complication of Herpes simplex virus type-1 infection. It results in severe parenchymal damage in the brain. Although viral latency in neurons is very common in the population, it remains unclear why certain individuals develop HSE. Here we explore potential host genetic variants predisposing to HSE. In order to investigate this we used a rat HSE model comparing the HSE susceptible SHR (Spontaneously Hypertensive Rats) with the asymptomatic infection of BN (Brown Norway). Notably, both strains have HSV-1 spread to the CNS at four days after infection. A genome wide linkage analysis of 29 infected HXB/BXH RILs (recombinant inbred lines-generated from the prior two strains), displayed variable susceptibility to HSE enabling the definition of a significant QTL (quantitative trait locus) named Hse6 towards the end of chromosome 4 (160.89-174Mb) containing the Vwf (von Willebrand factor) gene. This was the only gene in the QTL with both cis-regulation in the brain and included several non-synonymous SNPs (single nucleotide polymorphism). Intriguingly, in human chromosome 12 several SNPs within the intronic region between exon 43 and 44 of the VWF gene were associated with human HSE pathogenesis. In particular, rs917859 is nominally associated with an odds ratio of 1.5 (95% CI 1.11-2.02; p-value = 0.008) after genotyping in 115 HSE cases and 428 controls. Although there are possibly several genetic and environmental factors involved in development of HSE, our study identifies variants of the VWF gene as candidates for susceptibility in experimental and human HSE. PMID:27224245

  4. Von Willebrand Factor Gene Variants Associate with Herpes simplex Encephalitis

    PubMed Central

    Atanur, Santosh; Musilová, Alena; Zídek, Václav; Saba, Laura; Warnecke, Andreas; Khademi, Mohsen; Studahl, Marie; Aurelius, Elisabeth; Hjalmarsson, Anders; Garcia-Diaz, Ana; Denis, Cécile V.; Bergström, Tomas; Sköldenberg, Birgit; Kockum, Ingrid; Aitman, Timothy; Hübner, Norbert; Olsson, Tomas; Pravenec, Michal; Diez, Margarita

    2016-01-01

    Herpes simplex encephalitis (HSE) is a rare complication of Herpes simplex virus type-1 infection. It results in severe parenchymal damage in the brain. Although viral latency in neurons is very common in the population, it remains unclear why certain individuals develop HSE. Here we explore potential host genetic variants predisposing to HSE. In order to investigate this we used a rat HSE model comparing the HSE susceptible SHR (Spontaneously Hypertensive Rats) with the asymptomatic infection of BN (Brown Norway). Notably, both strains have HSV-1 spread to the CNS at four days after infection. A genome wide linkage analysis of 29 infected HXB/BXH RILs (recombinant inbred lines—generated from the prior two strains), displayed variable susceptibility to HSE enabling the definition of a significant QTL (quantitative trait locus) named Hse6 towards the end of chromosome 4 (160.89–174Mb) containing the Vwf (von Willebrand factor) gene. This was the only gene in the QTL with both cis-regulation in the brain and included several non-synonymous SNPs (single nucleotide polymorphism). Intriguingly, in human chromosome 12 several SNPs within the intronic region between exon 43 and 44 of the VWF gene were associated with human HSE pathogenesis. In particular, rs917859 is nominally associated with an odds ratio of 1.5 (95% CI 1.11–2.02; p-value = 0.008) after genotyping in 115 HSE cases and 428 controls. Although there are possibly several genetic and environmental factors involved in development of HSE, our study identifies variants of the VWF gene as candidates for susceptibility in experimental and human HSE. PMID:27224245

  5. Simplex method in problems of light-beam phase control.

    PubMed

    Chesnokov, S S; Davletshina, I V

    1995-12-20

    The possibility of the application of the simplex method to problems of wave-front control for light beams propagating in a nonlinear medium is investigated. A numerical analysis of simplex-method effectiveness in comparison with the gradient procedure of hill climbing is carried out. The regimes of stationary and nonstationary wind refraction are considered. The simplest optimization of the simplex size and the control basis is done. PMID:21068958

  6. Herpes simplex virus colitis in a neonate.

    PubMed

    Daley, Andrew J; Craven, Paul; Holland, Andrew J A; Jones, Cheryl A; Badawi, Nadia; Isaacs, David

    2002-09-01

    Involvement of the gastrointestinal tract in neonates with congenital herpes simplex virus (HSV) infection is rarely described. We report a case of a newborn with disseminated HSV infection associated with profuse hematochezia and late sigmoid colon perforation. Histologic examination showed patchy areas of ulceration with multinucleated giant cells and HSV nucleic acid was detected by polymerase chain reaction in colonic tissue. No clinically apparent episodes of recurrent colitis occurred in the first year of life. PMID:12380594

  7. Macrophage response to oncolytic paramyxoviruses potentiates virus-mediated tumor cell killing.

    PubMed

    Tan, Darren Qiancheng; Zhang, LiFeng; Ohba, Kenji; Ye, Min; Ichiyama, Koji; Yamamoto, Naoki

    2016-04-01

    Tumor-associated macrophages (TAMs) are known to regulate tumor response to many anti-cancer therapies, including oncolytic virotherapy. Oncolytic virotherapy employing oncolytic paramyxoviruses, such as attenuated measles (MeV) and mumps (MuV) viruses, has demonstrated therapeutic potential against various malignancies. However, the response of TAMs to oncolytic paramyxoviruses and the consequent effect on virotherapeutic efficacy remains to be characterized. Here, we demonstrate that the presence of human monocyte-derived macrophages (MDMs), irrespective of initial polarization state, enhances the virotherapeutic effect of MeV and MuV on breast cancer cells. Notably, our finding contrasts those of several studies involving other oncolytic viruses, which suggest that TAMs negatively impact virotherapeutic efficacy by impeding virus replication and dissemination. We found that the enhanced virotherapeutic effect in the presence of MDMs was due to slightly delayed proliferation and significantly elevated cell death that was not a result of increased virus replication. Instead, we found that the enhanced virotherapeutic effect involved several macrophage-associated anti-tumor mediators, and was associated with the modulation of MDMs towards an anti-tumor phenotype. Our findings present an alternative view on the role of TAMs in oncolytic virotherapy, and highlight the immunotherapeutic potential of oncolytic paramyxoviruses; possibly contributing towards the overall efficacy of oncolytic virotherapy. PMID:26763072

  8. Adeno-associated virus-mediated delivery of antiangiogenic factors as an antitumor strategy.

    PubMed

    Nguyen, J T; Wu, P; Clouse, M E; Hlatky, L; Terwilliger, E F

    1998-12-15

    Antiangiogenic tumor therapies have recently attracted intense interest for their broad-spectrum action, low toxicity, and, in the case of direct endothelial targeting, an absence of drug resistance. To promote tumor regression and to maintain dormancy, antiangiogenic agents need to be chronically administered. Gene therapy offers a potential way to achieve sustained therapeutic release of potent antiangiogenic substances. As a step toward this goal, we have generated recombinant adeno-associated virus (rAAV) vectors that carry genes coding for angiostatin, endostatin, and an antisense mRNA species against vascular endothelial growth factor (VEGF). These rAAVs efficiently transduced three human tumor cell lines tested. Transduction with an rAAV-encoding antisense VEGF mRNA inhibited the production of endogenous tumor cell VEGF. Conditioned media from cells transduced with this rAAV or with rAAV-expressing endostatin or angiostatin inhibited capillary endothelial cell proliferation in vitro. Antiangiogenic rAAVs may offer a novel gene therapy approach to undermining tumor neovascularization and cancer progression. PMID:9865720

  9. New strategies against drug resistance to herpes simplex virus.

    PubMed

    Jiang, Yu-Chen; Feng, Hui; Lin, Yu-Chun; Guo, Xiu-Rong

    2016-03-01

    Herpes simplex virus (HSV), a member of the Herpesviridae family, is a significant human pathogen that results in mucocutaneous lesions in the oral cavity or genital infections. Acyclovir (ACV) and related nucleoside analogues can successfully treat HSV infections, but the emergence of drug resistance to ACV has created a barrier for the treatment of HSV infections, especially in immunocompromised patients. There is an urgent need to explore new and effective tactics to circumvent drug resistance to HSV. This review summarises the current strategies in the development of new targets (the DNA helicase/primase (H/P) complex), new types of molecules (nature products) and new antiviral mechanisms (lethal mutagenesis of Janus-type nucleosides) to fight the drug resistance of HSV. PMID:27025259

  10. New strategies against drug resistance to herpes simplex virus

    PubMed Central

    Jiang, Yu-Chen; Feng, Hui; Lin, Yu-Chun; Guo, Xiu-Rong

    2016-01-01

    Herpes simplex virus (HSV), a member of the Herpesviridae family, is a significant human pathogen that results in mucocutaneous lesions in the oral cavity or genital infections. Acyclovir (ACV) and related nucleoside analogues can successfully treat HSV infections, but the emergence of drug resistance to ACV has created a barrier for the treatment of HSV infections, especially in immunocompromised patients. There is an urgent need to explore new and effective tactics to circumvent drug resistance to HSV. This review summarises the current strategies in the development of new targets (the DNA helicase/primase (H/P) complex), new types of molecules (nature products) and new antiviral mechanisms (lethal mutagenesis of Janus-type nucleosides) to fight the drug resistance of HSV. PMID:27025259

  11. Role of CD137 signaling in dengue virus-mediated apoptosis

    SciTech Connect

    Nagila, Amar; Netsawang, Janjuree; Srisawat, Chatchawan; Noisakran, Sansanee; Morchang, Atthapan; Yasamut, Umpa; Puttikhunt, Chunya; Kasinrerk, Watchara; and others

    2011-07-08

    Highlights: {yields} For the first time the role of CD137 in dengue virus (DENV) infection. {yields} Induction of DENV-mediated apoptosis by CD137 signaling. {yields} Sensitization to CD137-mediated apoptosis by dengue virus capsid protein (DENV C). {yields} Nuclear localization of DENV C is required for CD137-mediated apoptosis. -- Abstract: Hepatic dysfunction is a well recognized feature of dengue virus (DENV) infection. However, molecular mechanisms of hepatic injury are still poorly understood. A complex interaction between DENV and the host immune response contributes to DENV-mediated tissue injury. DENV capsid protein (DENV C) physically interacts with the human death domain-associated protein Daxx. A double substitution mutation in DENV C (R85A/K86A) abrogates Daxx interaction, nuclear localization and apoptosis. Therefore we compared the expression of cell death genes between HepG2 cells expressing DENV C and DENV C (R85A/K86A) using a real-time PCR array. Expression of CD137, which is a member of the tumor necrosis factor receptor family, increased significantly in HepG2 cells expressing DENV C compared to HepG2 cells expressing DENV C (R85A/K86A). In addition, CD137-mediated apoptotic activity in HepG2 cells expressing DENV C was significantly increased by anti-CD137 antibody compared to that of HepG2 cells expressing DENV C (R85A/K86A). In DENV-infected HepG2 cells, CD137 mRNA and CD137 positive cells significantly increased and CD137-mediated apoptotic activity was increased by anti-CD137 antibody. This work is the first to demonstrate the contribution of CD137 signaling to DENV-mediated apoptosis.

  12. Herpes Simplex Vaccines: Prospects of Live-attenuated HSV Vaccines to Combat Genital and Ocular infections

    PubMed Central

    Stanfield, Brent; Kousoulas, Konstantin Gus

    2015-01-01

    Herpes simplex virus type-1 (HSV-1) and its closely related type-2 (HSV-2) viruses cause important clinical manifestations in humans including acute ocular disease and genital infections. These viruses establish latency in the trigeminal ganglionic and dorsal root neurons, respectively. Both viruses are widespread among humans and can frequently reactivate from latency causing disease. Currently, there are no vaccines available against herpes simplex viral infections. However, a number of promising vaccine approaches are being explored in pre-clinical investigations with few progressing to early phase clinical trials. Consensus research findings suggest that robust humoral and cellular immune responses may partially control the frequency of reactivation episodes and reduce clinical symptoms. Live-attenuated viral vaccines have long been considered as a viable option for generating robust and protective immune responses against viral pathogens. Varicella zoster virus (VZV) belongs to the same alphaherpesvirus subfamily with herpes simplex viruses. A live-attenuated VZV vaccine has been extensively used in a prophylactic and therapeutic approach to combat primary and recurrent VZV infection indicating that a similar vaccine approach may be feasible for HSVs. In this review, we summarize pre-clinical approaches to HSV vaccine development and current efforts to test certain vaccine approaches in human clinical trials. Also, we discuss the potential advantages of using a safe, live-attenuated HSV-1 vaccine strain to protect against both HSV-1 and HSV-2 infections. PMID:27114893

  13. Therapeutic Immunization with a Mixture of Herpes Simplex Virus 1 Glycoprotein D-Derived “Asymptomatic” Human CD8+ T-Cell Epitopes Decreases Spontaneous Ocular Shedding in Latently Infected HLA Transgenic Rabbits: Association with Low Frequency of Local PD-1+ TIM-3+ CD8+ Exhausted T Cells

    PubMed Central

    Khan, Arif A.; Srivastava, Ruchi; Chentoufi, Aziz A.; Geertsema, Roger; Thai, Nhi Thi Uyen; Dasgupta, Gargi; Osorio, Nelson; Kalantari, Mina; Nesburn, Anthony B.; Wechsler, Steven L.

    2015-01-01

    ABSTRACT Most blinding ocular herpetic disease is due to reactivation of herpes simplex virus 1 (HSV-1) from latency rather than to primary acute infection. No herpes simplex vaccine is currently available for use in humans. In this study, we used the HLA-A*02:01 transgenic (HLA Tg) rabbit model of ocular herpes to assess the efficacy of a therapeutic vaccine based on HSV-1 gD epitopes that are recognized mainly by CD8+ T cells from “naturally” protected HLA-A*02:01-positive, HSV-1-seropositive healthy asymptomatic (ASYMP) individuals (who have never had clinical herpes disease). Three ASYMP CD8+ T-cell epitopes (gD53–61, gD70–78, and gD278–286) were linked with a promiscuous CD4+ T-cell epitope (gD287–317) to create 3 separate pairs of CD4-CD8 peptides, which were then each covalently coupled to an Nε-palmitoyl-lysine moiety, a Toll-like receptor 2 (TLR-2) ligand. This resulted in the construction of 3 CD4-CD8 lipopeptide vaccines. Latently infected HLA Tg rabbits were immunized with a mixture of these 3 ASYMP lipopeptide vaccines, delivered as eye drops in sterile phosphate-buffered saline (PBS). The ASYMP therapeutic vaccination (i) induced HSV-specific CD8+ T cells that prevent HSV-1 reactivation ex vivo from latently infected explanted trigeminal ganglia (TG), (ii) significantly reduced HSV-1 shedding detected in tears, (iii) boosted the number and function of HSV-1 gD epitope-specific CD8+ T cells in draining lymph nodes (DLN), conjunctiva, and TG, and (iv) was associated with fewer exhausted HSV-1 gD-specific PD-1+ TIM-3+ CD8+ T cells. The results underscore the potential of an ASYMP CD8+ T-cell epitope-based therapeutic vaccine strategy against recurrent ocular herpes. IMPORTANCE Seventy percent to 90% of adults harbor herpes simplex virus 1 (HSV-1), which establishes lifelong latency in sensory neurons of the trigeminal ganglia. This latent state sporadically switches to spontaneous reactivation, resulting in viral shedding in tears. Most

  14. Study of Academic Growth Using Simplex Models. Final Report.

    ERIC Educational Resources Information Center

    Werts, Charles E.; Linn, Robert L.

    Forming a sequence covering the various aspects of the simplex model, four articles are presented here under the following titles: "A Simplex Model for Analyzing Academic Growth", "Analyzing Ratings With Correlated Intrajudge Measurement Errors", "The Correlation of States With Gain", and "The Reliability of College Grades from Longitudinal Data".…

  15. Mixing and Simplex Search for Optimal Illumination in Machine Vision

    NASA Astrophysics Data System (ADS)

    Kim, HyungTae; Cho, KyeongYong; Jin, Kyungchan; Yoon, JooSung; Cho, YoungJune

    2014-07-01

    Mixed-color illumination affects the quality of images in industrial vision system and it is important to optimize color and intensity for image acquisition. This study used simplex search to find the optimal illumination in a short amount of time. A typical color mixer synthesized various color of lights by changing the inputs of RGB power LEDs and passing the lights through an optical system. The image quality under mixed-color illumination was calculated according to the sharpness. For the purpose of optimal illumination using simplex search, a probe network was organized with N + 1probing points for N inputs. The shape of the probe network, simplex, was varied through procedures of extension, contraction, and shrinkage. The inputs of the color mixer were changed until the size of the simplex became smaller than a threshold. The simplex search was tested for commercial semiconductor patterns, and was useful for finding the optimal illumination.

  16. Oncolytic virotherapy using herpes simplex virus: how far have we come?

    PubMed Central

    Sokolowski, Nicolas AS; Rizos, Helen; Diefenbach, Russell J

    2015-01-01

    Oncolytic virotherapy exploits the properties of human viruses to naturally cytolysis of cancer cells. The human pathogen herpes simplex virus (HSV) has proven particularly amenable for use in oncolytic virotherapy. The relative safety of HSV coupled with extensive knowledge on how HSV interacts with the host has provided a platform for manipulating HSV to enhance the targeting and killing of human cancer cells. This has culminated in the approval of talimogene laherparepvec for the treatment of melanoma. This review focuses on the development of HSV as an oncolytic virus and where the field is likely to head in the future. PMID:27512683

  17. Early events in herpes simplex virus type 1 infection: photosensitivity of fluorescein isothiocyanate-treated virions.

    PubMed Central

    DeLuca, N; Bzik, D; Person, S; Snipes, W

    1981-01-01

    Herpes simplex virus type 1 is photosensitized by treatment with fluorescein isothiocyante (FITC). The inactivation of FITC-treated virions upon subsequent exposure to light is inhibited by the presence of sodium azide, suggesting the involvement of singlet oxygen in the process. Sodium dodecyl sulfate/polyacrylamide gel electrophoresis revealed that treatment with FITC plus light induces crosslinks in viral envelope glycoproteins. Treatment of virions with high concentrations of FITC (50 micrograms/ml) plus light causes a reduction in the adsorption of the virus to monolayers of human embryonic lung cells. For lower concentrations of FITC (10 micrograms/ml) plus light, treated virions adsorb to the host cells, but remain sensitive to light until entry occurs. The loss of light sensitivity coincides with the development of resistance to antibodies. These results are most consistent with a mechanism of entry for herpes simplex virus involving fusion of the viral membrane with the plasma membrane of the host cell. Images PMID:6262783

  18. Early events in herpes simplex virus type 1 infection: photosensitivity of fluorescein isothiocyanate-treated virions.

    PubMed

    DeLuca, N; Bzik, D; Person, S; Snipes, W

    1981-02-01

    Herpes simplex virus type 1 is photosensitized by treatment with fluorescein isothiocyante (FITC). The inactivation of FITC-treated virions upon subsequent exposure to light is inhibited by the presence of sodium azide, suggesting the involvement of singlet oxygen in the process. Sodium dodecyl sulfate/polyacrylamide gel electrophoresis revealed that treatment with FITC plus light induces crosslinks in viral envelope glycoproteins. Treatment of virions with high concentrations of FITC (50 micrograms/ml) plus light causes a reduction in the adsorption of the virus to monolayers of human embryonic lung cells. For lower concentrations of FITC (10 micrograms/ml) plus light, treated virions adsorb to the host cells, but remain sensitive to light until entry occurs. The loss of light sensitivity coincides with the development of resistance to antibodies. These results are most consistent with a mechanism of entry for herpes simplex virus involving fusion of the viral membrane with the plasma membrane of the host cell. PMID:6262783

  19. Herpes simplex virus latency-associated transcript is a stable intron.

    PubMed Central

    Farrell, M J; Dobson, A T; Feldman, L T

    1991-01-01

    The latency-associated transcript (LAT) is the major viral transcript detected by in situ hybridization of mouse and human sensory ganglia latently infected with herpes simplex virus type 1. The last 750 bases of LAT are complementary to infected-cell polypeptide 0, a herpes simplex virus type 1 immediate-early gene that encodes a transactivating protein that may facilitate re-activation of the virus from the latent state. Several laboratories have shown that LAT accumulates in the nucleus and is not polyadenylylated. Recently, we showed that the promoter for LAT lies 688 bases upstream from its 5' end. We report here that LAT is actually a uniquely stable intron. Furthermore, LAT effectively inhibits transactivation of gene expression by infected-cell polypeptide 0 in transient transfection assays. Images PMID:1846963

  20. Early events in herpes simplex virus type 1 infection: photosensitivity of fluorescein isothiocyanate-treated virions

    SciTech Connect

    DeLuca, N.; Bzik, D.; Person, S.; Snipes, W.

    1981-02-01

    Herpes simplex virus type 1 is photosensitized by treatment with fluorescein isothiocyanate (FITC). The inactivation of FITC-treated virions upon subsequent exposure to light is inhibited by the presence of sodium azide, suggesting the involvement of singlet oxygen in the process. Sodium dodecyl sulfate/polyacrylamide gel electrophoresis revealed that treatment with FITC plus light induces crosslinks in viral envelope glycoproteins. Treatment of virions with high concentrations of FITC (50 ..mu..g/ml) plus light causes a reduction in the adsorption of the virus to monolayers of human embryonic lung cells. For lower concentrations of FITC (10 ..mu..g/ml) plus light, treated virions adsorb to the host cells, but remain sensitive to light until entry occurs. The loss of light sensitivity coincides with the development of resistance to antibodies. These results are most consistent with a mechanism of entry for herpes simplex virus involving fusion of the viral membrane with the plasma membrane of the host cell.

  1. Anisakis simplex larvae: infection status in marine fish and cephalopods purchased from the Cooperative Fish Market in Busan, Korea.

    PubMed

    Choi, Seon Hee; Kim, Jung; Jo, Jin Ok; Cho, Min Kyung; Yu, Hak Sun; Cha, Hee Jae; Ock, Mee Sun

    2011-03-01

    The infection status of marine fish and cephalopods with Anisakis simplex third stage larva (L3) was studied over a period of 1 year. A total of 2,537 specimens, which consisted of 40 species of fish and 3 species of cephalopods, were purchased from the Cooperative Fish Market in Busan, Korea, from August 2006 to July 2007. They were examined for A. simplex L3 from the whole body cavity, viscera, and muscles. A. simplex L3 were confirmed by light microscopy. The overall infection rate reached 34.3%, and average 17.1 larvae were parasitized per infected fish. Fish that recorded the highest infection rate was Lophiomus setigerus (100%), followed by Liparis tessellates (90%), Pleurogrammus azonus (90%), and Scomber japonicus (88.7%). The intensity of infection was the highest in Gadus macrocephalus (117.7 larvae per fish), followed by S. japonicus (103.9 larvae) and L. setigerus (54.2 larvae). Although abundance of A. simplex L3 was not seasonal in most of the fish species, 10 of the 16 selected species showed the highest abundance in February and April. A positive correlation between the intensity of L3 infection and the fish length was obvious in S. japonicus and G. macrocephalus. It was likely that A. simplex L3 are more frequently infected during the spring season in some species of fish. Our study revealed that eating raw or undercooked fish or cephalopods could still be a source of human infection with A. simplex L3 in Korea. PMID:21461267

  2. [Genetic susceptibility to herpes simplex encephalitis].

    PubMed

    Rozenberg, F

    2013-01-01

    Herpes simplex encephalitis (HSE) is a rare but severe complication of frequent and mostly benign infection with herpes simplex virus (HSV). Although rapid and sensitive diagnosis tools and active antiviral drugs are available, HSE morbidity/mortality levels remain unsatisfactory. Molecular and cellular determinants of HSE are incompletely understood. The rarity and severity of the disease have suggested an increased susceptibility of some subjects to HSV infection. Numerous experimental studies have investigated the respective role of host and viral factors in HSE. The results of these studies have illustrated the major role of the innate immune response, in particular interferons (IFNs), in limiting access of the virus into and/or virus replication in the central nervous system (CNS). In a few children with HSE, specific defects of the immune innate response have been identified, which impair the IFN-α/β and IFN-λ production of fibroblasts and/or neurons infected with HSV and render these cells more permissive to infection. The mutations affect proteins involved in the IFN pathway induced by stimulation of the TLR3 receptor. The patients' susceptibility to infection is restricted to HSV CNS invasion, underlining the major role of TLR3 in CNS protection against viral infection. The incomplete clinical penetrance of these molecular defects suggests that other factors (age, infectious dose) are involved in HSE. Whether pathogenesis of adult HSE is similar has not been investigated. PMID:23399415

  3. Herpes simplex encephalitis: adolescents and adults.

    PubMed

    Whitley, Richard J

    2006-09-01

    Herpes simplex encephalitis (HSE) remains one of the most devastating infections of the central nervous system despite available antiviral therapy. Children and adolescents account for approximately one third of all cases of HSE. Clinical diagnosis is suggested in the encephalopathic, febrile patient with focal neurologic signs. However, these clinical findings are not pathognomonic because numerous other diseases in the central nervous system can mimic HSE. Neurodiagnostic evaluation can provide support for the diagnosis by the demonstration of temporal lobe edema/hemorrhage by magnetic resonance image scan and spike and slow-wave activity on electroencephalogram. In the current era, the diagnostic gold standard is the detection of herpes simplex virus (HSV) DNA in the cerebrospinal fluid by polymerase chain reaction (PCR). Although PCR is an excellent test and preferable to brain biopsy, false negatives can occur early after disease onset. Acyclovir is the treatment of choice and is administered at 10 mg/kg every 8 h for 21 days. Even with early administration of therapy after the disease onset, nearly two thirds of survivors have significant residual neurologic deficits. Current investigative efforts are assessing the prognostic value of quantitative PCR detection of viral DNA at the onset of therapy as well as at the completion of therapy and the contribution of prolonged antiviral therapy to improved neurologic outcome. PMID:16675036

  4. Vaccinia Virus Recombinant Expressing Herpes Simplex Virus Type 1 Glycoprotein D Prevents Latent Herpes in Mice

    NASA Astrophysics Data System (ADS)

    Cremer, Kenneth J.; Mackett, Michael; Wohlenberg, Charles; Notkins, Abner Louis; Moss, Bernard

    1985-05-01

    In humans, herpes simplex virus causes a primary infection and then often a latent ganglionic infection that persists for life. Because these latent infections can recur periodically, vaccines are needed that can protect against both primary and latent herpes simplex infections. Infectious vaccinia virus recombinants that contain the herpes simplex virus type 1 (HSV-1) glycoprotein D gene under control of defined early or late vaccinia virus promoters were constructed. Tissue culture cells infected with these recombinant viruses synthesized a glycosylated protein that had the same mass (60,000 daltons) as the glycoprotein D produced by HSV-1. Immunization of mice with one of these recombinant viruses by intradermal, subcutaneous, or intraperitoneal routes resulted in the production of antibodies that neutralized HSV-1 and protected the mice against subsequent lethal challenge with HSV-1 or HSV-2. Immunization with the recombinant virus also protected the majority of the mice against the development of a latent HSV-1 infection of the trigeminal ganglia. This is the first demonstration that a genetically engineered vaccine can prevent the development of latency.

  5. Kernel simplex growing algorithm for hyperspectral endmember extraction

    NASA Astrophysics Data System (ADS)

    Zhao, Liaoying; Zheng, Junpeng; Li, Xiaorun; Wang, Lijiao

    2014-01-01

    In order to effectively extract endmembers for hyperspectral imagery where linear mixing model may not be appropriate due to multiple scattering effects, this paper extends the simplex growing algorithm (SGA) to its kernel version. A new simplex volume formula without dimension reduction is used in SGA to form a new simplex growing algorithm (NSGA). The original data are nonlinearly mapped into a high-dimensional space where the scatters can be ignored. To avoid determining complex nonlinear mapping, a kernel function is used to extend the NSGA to kernel NSGA (KNSGA). Experimental results of simulated and real data prove that the proposed KNSGA approach outperforms SGA and NSGA.

  6. Herpes simplex virus and the alimentary tract.

    PubMed

    Lavery, Eric A; Coyle, Walter J

    2008-08-01

    Herpes simplex virus (HSV) infection is well known as a sexually transmitted disease. However, relatively little has been published concerning the presentations and treatment of HSV infection within the gastrointestinal tract, where HSV most commonly affects the esophagus in both immunocompromised and immunocompetent patients. HSV proctitis is not uncommon and occurs primarily in males having sex with males. In patients with normal immune systems, gastrointestinal HSV infections are generally self-limited and rarely require antiviral therapy. Treatment of infection is suggested for immunocompromised patients, though no large randomized controlled trials have been performed. This article reviews the manifestations of HSV infection within the luminal gastrointestinal tract and options for diagnosis and treatment. PMID:18627656

  7. On the existence of binary simplex codes. [using combinatorial construction

    NASA Technical Reports Server (NTRS)

    Taylor, H.

    1977-01-01

    Using a simple combinatorial construction, the existence of a binary simplex code with m codewords for all m is greater than or equal to 1 is proved. The problem of the shortest possible length is left open.

  8. A Case of Steatocystoma Simplex Involving the Scalp

    PubMed Central

    Hyun, Dong Nyeok; Won, Jong Hoon; Chung, Hyun

    2008-01-01

    Steatocystoma is a benign adnexal tumor originating from the pilosebaceous duct junction which can be classified into two groups (steatocystoma simplex and steatocystoma multiplex). Steatocystoma simplex, which presents as a solitary lesion, is very rare. Steatocystoma simplex occurs most commonly on the face and the case reported herein involving the scalp is extremely rare. A 49-year-old man presented for evaluation and treatment of a solitary papule on the right parietal scalp which had persisted for a period of 1 year. The histopathologic examination revealed a thin-walled cyst consisting of stratified squamous epithelium with hyaline cuticle that lacked a stratum granulosum. Based on clinical and histologic findings, we diagnosed this case as steatocystoma simplex of the scalp and report this rare case. PMID:27303199

  9. Novel agents and strategies to treat herpes simplex virus infections.

    PubMed

    Kleymann, Gerald

    2003-02-01

    The quiet pandemic of herpes simplex virus (HSV) infection has plagued humanity since ancient times, causing mucocutaneous infection, such as herpes labialis and herpes genitalis. Disease symptoms often interfere with everyday activities and occasionally HSV infections are the cause of life-threatening or sight-impairing disease, especially in neonates and the immunocompromised patient population. After primary or initial infection the virus persists for life in a latent form in neurons of the host, periodically reactivating and often resulting in significant psychosocial distress for the patient. Currently, no cure is available. In the mid-1950s the first antiviral, idoxuridine, was developed for topical treatment of herpes disease and, in 1978, vidarabine was licensed for systemic use to treat HSV encephalitis. Acyclovir (Zovirax), a potent, specific and tolerable nucleosidic inhibitor of the herpes DNA polymerase, was a milestone in the development of antiviral drugs in the late 1970s. In the mid-1990s, when acyclovir became a generic drug, valacyclovir (Valtrex) and famciclovir (Famvir), prodrugs of the gold standard and penciclovir (Denavir), Vectavir), a close analogue, were launched. Though numerous approaches and strategies were tested and considerable effort was expended in the search of the next generation of an antiherpetic therapy, it proved difficult to outperform acyclovir. Notable in this regard was the award of a Nobel Prize in 1988 for the elucidation of mechanistic principles which resulted in the development of new drugs such as acyclovir. Vaccines, interleukins, interferons, therapeutic proteins, antibodies, immunomodulators and small-molecule drugs with specific or nonspecific modes of action lacked either efficacy or the required safety profile to replace the nucleosidic drugs acyclovir, valacyclovir, penciclovir and famciclovir as the first choice of treatment. Recently though, new inhibitors of the HSV helicase-primase with potent in vitro

  10. Higher Throughput Quantification of Neutralizing Antibody to Herpes Simplex Viruses

    PubMed Central

    Blevins, Tamara P.; Mitchell, Michelle C.; Korom, Maria; Wang, Hong; Yu, Yinyi; Morrison, Lynda A.; Belshe, Robert B.

    2015-01-01

    We report a rapid, higher throughput method for measuring neutralizing antibody to herpes simplex virus (HSV) in human sera. Clinical isolates and sera from the Herpevac Trial for Women were used in a colorimetric assay in which infection of tissue culture (lack of neutralization) was indicated by substrate metabolism by beta-galactosidase induced in the ELVIS cell line. The neutralization assay was optimized by addition of guinea pig complement, which particularly enhanced neutralizing antibody titers to HSV-2. Higher neutralizing antibody titers were also achieved using virus particles isolated from the supernatant of infected cells rather than lysate of infected cells as the source of virus. The effect of assay incubation time and incubation time with substrate were also optimized. We found that incubating with substrate until a standard optical density of 1.0 was reached permitted a better comparison among virus isolates, and achieved reliable measurement of neutralizing antibody activity. Interestingly, in contrast to results in the absence of complement, addition of complement allowed sera from HSV-2 gD-vaccinated subjects to neutralize HSV-1 and HSV-2 clinical and laboratory isolates with equal potency. PMID:26658766

  11. Cervical cancer: is herpes simplex virus type II a cofactor?

    PubMed Central

    Jones, C

    1995-01-01

    In many ways, cervical cancer behaves as a sexually transmitted disease. The major risk factors are multiple sexual partners and early onset of sexual activity. Although high-risk types of human papillomaviruses (HPV) play an important role in the development of nearly all cases of cervical cancer, other sexually transmitted infectious agents may be cofactors. Herpes simplex virus type 2 (HSV-2) is transmitted primarily by sexual contact and therefore has been implicated as a risk factor. Several independent studies suggest that HSV-2 infections correlate with a higher than normal incidence of cervical cancer. In contrast, other epidemiological studies have concluded that infection with HSV-2 is not a major risk factor. Two separate transforming domains have been identified within the HSV-2 genome, but continued viral gene expression apparently is not necessary for neoplastic transformation. HSV infections lead to unscheduled cellular DNA synthesis, chromosomal amplifications, and mutations. These observations suggest that HSV-2 is not a typical DNA tumor virus. It is hypothesized that persistent or abortive infections induce permanent genetic alterations that interfere with differentiation of cervical epithelium and subsequently induce abnormal proliferation. Thus, HSV-2 may be a cofactor in some but not all cases of cervical cancer. PMID:8665469

  12. Higher Throughput Quantification of Neutralizing Antibody to Herpes Simplex Viruses.

    PubMed

    Blevins, Tamara P; Mitchell, Michelle C; Korom, Maria; Wang, Hong; Yu, Yinyi; Morrison, Lynda A; Belshe, Robert B

    2015-01-01

    We report a rapid, higher throughput method for measuring neutralizing antibody to herpes simplex virus (HSV) in human sera. Clinical isolates and sera from the Herpevac Trial for Women were used in a colorimetric assay in which infection of tissue culture (lack of neutralization) was indicated by substrate metabolism by beta-galactosidase induced in the ELVIS cell line. The neutralization assay was optimized by addition of guinea pig complement, which particularly enhanced neutralizing antibody titers to HSV-2. Higher neutralizing antibody titers were also achieved using virus particles isolated from the supernatant of infected cells rather than lysate of infected cells as the source of virus. The effect of assay incubation time and incubation time with substrate were also optimized. We found that incubating with substrate until a standard optical density of 1.0 was reached permitted a better comparison among virus isolates, and achieved reliable measurement of neutralizing antibody activity. Interestingly, in contrast to results in the absence of complement, addition of complement allowed sera from HSV-2 gD-vaccinated subjects to neutralize HSV-1 and HSV-2 clinical and laboratory isolates with equal potency. PMID:26658766

  13. Recent Progress in Herpes Simplex Virus Immunobiology and Vaccine Research

    PubMed Central

    Koelle, David M.; Corey, Lawrence

    2003-01-01

    Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) cause prevalent, chronic infections that have serious outcomes in some individuals. Neonatal herpes may occur when the infant traverses the cervix during maternal genital herpes. Genital herpes is a major risk factor for human immunodeficiency virus type 1 transmission. Considerable efforts have been made to design and test vaccines for HSV, focusing on genital infection with HSV-2. Several protein subunit vaccines based on HSV-2 envelope glycoproteins have reached advanced-phase clinical trials. These antigens were chosen because they are the targets of neutralizing-antibody responses and because they elicit cellular immunity. Encouraging results have been reported in studies of treatment of HSV-seronegative women with a vaccine consisting of truncated glycoprotein D of HSV-2 and a novel adjuvant. Because most sexual HSV transmission occurs during asymptomatic shedding, it is important to evaluate the impact of vaccination on HSV-2 infection, clinically apparent genital herpes, and HSV shedding among vaccine recipients who acquire infection. There are several other attractive formats, including subunit vaccines that target cellular immune responses, live attenuated virus strains, and mutant strains that undergo incomplete lytic replication. HSV vaccines have also been evaluated for the immunotherapy of established HSV infection. PMID:12525427

  14. Effect of the ionophore monensin on herpes simplex virus type 1-induced cell fusion, glycoprotein synthesis, and virion infectivity.

    PubMed

    Kousoulas, K G; Bzik, D J; Person, S

    1983-01-01

    The ionophore monensin inhibited the formation of mature, fully glycosylated glycoproteins gB, gC, and gD during herpes simplex virus type 1 infection of human embryonic lung cells. Underglycosylated forms, including the apparent high-mannose precursor forms of the major glycoproteins, appeared. Monensin inhibited virus-induced cell fusion. Infectious virions produced in the presence of monensin appeared to contain predominantly underglycosylated glycoproteins. PMID:6307921

  15. Expression of Genes Encoding the Enzymes for Glycogen and Trehalose Metabolism in L3 and L4 Larvae of Anisakis simplex

    PubMed Central

    Łopieńska-Biernat, E.; Zaobidna, E. A.; Dmitryjuk, M.

    2015-01-01

    Trehalose and glycogen metabolism plays an important role in supporting life processes in many nematodes, including Anisakis simplex. Nematodes, cosmopolitan helminths parasitizing sea mammals and humans, cause a disease known as anisakiasis. The aim of this study was to investigate the expression of genes encoding the enzymes involved in the metabolism of trehalose and glycogen—trehalose-6-phosphate synthase (TPS), trehalose-6-phosphate phosphatase (TPP), glycogen synthase (GS), and glycogen phosphorylase (GP)—in stage L3 and stage L4 larvae of A. simplex. The expression of mRNA all four genes, tps, tpp, gs, and gp, was examined by real-time polymerase chain reaction. The A. simplex ribosomal gene (18S) was used as a reference gene. Enzymatic activity was determined. The expression of trehalose enzyme genes was higher in L3 than in L4 larvae, but an inverse relationship was noted for the expression of gs and gp genes. PMID:26783451

  16. Isolation of a nucleocapsid polypeptide of herpes simplex virus types 1 and 2 possessing immunologically type-specific and cross-reactive determinants.

    PubMed

    Heilman, C J; Zweig, M; Stephenson, J R; Hampar, B

    1979-01-01

    A polypeptide (p40) of approximately 40,000 molecular weight was isolated from herpes simplex virus type 1 and 2 nucleocapsids by gel filtration and ion exchange chromatography. This protein appears to be the same as protein 22a described previously (Gibson and Roizman, J. Virol. 10:1044--1052, 1972). Competition immunoassays were developed by using purified p40 and antisera prepared in guinea pigs. The assays indicated that the p40's from herpes simplex virus types 1 and 2 possess both type-specific and cross-reactive antigenic determinants. Antibodies to the p40 cross-reactive determinant reacted with antigens in simian herpes virus SA8-infected cells, but not with antigens induced by pseudorabies virus. Preliminary results indicated that a radioimmunoprecipitation test can be used to detect type-specific herpes simplex virus p40 antibodies in human sera. PMID:85720

  17. Mycosis inhibits cannibalism by Melanoplus sanguinipes, M. differentialis, Schistocerca americana, and Anabrus simplex

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cannibalism is common among the Acrididae and the Mormon cricket, Anabrus simplex, a tettigonid. These behaviors have been proposed as mechanisms for the horizontal transmission of Microsporida and entomopathogenic fungi. After anecdotal observations that Melanoplus sanguinipes and A. simplex did ...

  18. Non-traumatic acquisition of herpes simplex virus infection through the eye.

    PubMed Central

    Kaye, S B; Shimeld, C; Grinfeld, E; Maitland, N J; Hill, T J; Easty, D L

    1992-01-01

    Primary ocular herpes is usually seen as a follicular conjunctivitis and blepharitis, with or without involvement of the cornea. It is unknown, however, to what extent asymptomatic and/or subclinical primary disease occurs, and whether primary ocular herpes follows direct droplet spread to the eye. Previous models of murine ocular herpes have used trauma (scarification) to introduce virus into the cornea, producing disease which results in significant corneal scarring. To mimic a likely route of infection in humans, a droplet containing virus was placed on the mouse eye and clinical disease recorded. At least 1 month after inoculation, serum was assayed for neutralising antibodies and the cornea, iris, and trigeminal ganglion were investigated for evidence of herpes simplex virus type 1, by cocultivation and the polymerase chain reaction. Some animals showed a severe ulcerative blepharitis with little to no involvement of the cornea, while disease was undetectable in others. The development of disease depended on the dose and strain of virus and age of the animal, with older mice appearing more resistant. Virus was isolated from the trigeminal ganglion of younger animals inoculated with higher doses of virus, after 21 days in culture, suggesting that latency had been established. Neutralising antibodies were present in most mice irrespective of the presence of recognisable clinical disease. Using primers for the thymidine kinase and glycoprotein C regions of the viral genome, herpes simplex virus type 1 DNA was found in the cornea, iris, and trigeminal ganglion of most animals and showed a good correlation with the presence of neutralising antibodies. It would thus appear that herpes simplex virus type 1 is able to accede into the cornea, iris, and trigeminal ganglion following nontraumatic application of virus onto the mouse eye. This model mimics primary ocular disease in humans and may be useful for studies on recurrent disease and the spread of ocular herpes

  19. Experimental investigation of herpes simplex virus latency.

    PubMed Central

    Wagner, E K; Bloom, D C

    1997-01-01

    The clinical manifestations of herpes simplex virus infection generally involve a mild and localized primary infection followed by asymptomatic (latent) infection interrupted sporadically by periods of recrudescence (reactivation) where virus replication and associated cytopathologic findings are manifest at the site of initial infection. During the latent phase of infection, viral genomes, but not infectious virus itself, can be detected in sensory and autonomic neurons. The process of latent infection and reactivation has been subject to continuing investigation in animal models and, more recently, in cultured cells. The initiation and maintenance of latent infection in neurons are apparently passive phenomena in that no virus gene products need be expressed or are required. Despite this, a single latency-associated transcript (LAT) encoded by DNA encompassing about 6% of the viral genome is expressed during latent infection in a minority of neurons containing viral DNA. This transcript is spliced, and the intron derived from this splicing is stably maintained in the nucleus of neurons expressing it. Reactivation, which can be induced by stress and assayed in several animal models, is facilitated by the expression of LAT. Although the mechanism of action of LAT-mediated facilitation of reactivation is not clear, all available evidence argues against its involving the expression of a protein. Rather, the most consistent models of action involve LAT expression playing a cis-acting role in a very early stage of the reactivation process. PMID:9227860

  20. Vaccines for herpes simplex virus infections.

    PubMed

    Koelle, David M

    2006-02-01

    Infections with herpes simplex virus (HSV) type 1 (HSV-1) and type 2 (HSV-2) can have serious medical consequences. Although antiviral medications can suppress symptomatic disease, asymptomatic shedding and transmission, they neither cure nor alter the natural history of HSV infections. Manipulation of the immune response is one potential method to decrease disease burden. Current research on prophylactic and therapeutic vaccination approaches is discussed in this review, with a focus on compounds that have entered clinical trials or that display novel compositions or proposed mechanisms of action. One such vaccine is an alum and monophosphoryl lipid A-adjuvanted subunit glycoprotein D2 vaccine that has demonstrated activity in the prevention of HSV-2 infection and disease in HSV-uninfected women in a phase III clinical trial. Further confirmatory clinical trials of this vaccine are currently underway. Other vaccine formats also in development include attenuated live or replication-incompetent HSV-2 strains and technologies that target virus-specific CD8 T-cell responses. PMID:16499283

  1. Herpes simplex virus duodenitis accompanying Crohn's disease.

    PubMed

    Lee, Byung Hoo; Um, Wook Hyun; Jeon, Seong Ran; Kim, Hyun Gun; Lee, Tae Hee; Kim, Wan Jung; Kim, Jin-Oh; Jin, So Young

    2013-11-01

    Herpes simplex virus (HSV) is a recognized cause of gastrointestinal infection in immunodeficient patients. Although a few cases of HSV gastritis and colitis in immunocompromised patients have been reported, there are no reports of HSV duodenitis in patients with Crohn's disease (CD). A 74-year-old female was admitted with general weakness and refractory epigastric pain. She had been diagnosed with CD three years ago. Esophagogastroduodenoscopy (EGD) revealed diffuse edematous and whitish mucosa with multiple erosions in the duodenum. Considering the possibility of viral co-infection, cytomegalovirus (CMV) immunohistochemical staining, PCR, and cultures of duodenal biopsies were performed, all of which were negative with the exception of the isolation of HSV in culture. After administration of intravenous acyclovir for 1 week, follow-up EGD showed almost complete resolution of the lesions and the patient's symptoms improved. In CD patients with refractory gastro-intestinal symptoms, HSV, as well as CMV, should be considered as a possible cause of infection, so that the diagnosis of viral infection is not delayed and the appropriate antiviral treatment can be initiated. PMID:24262595

  2. Uncoating the Herpes Simplex Virus Genome

    PubMed Central

    Newcomb, William W.; Brown, Jay C.

    2007-01-01

    Summary Initiation of infection by herpes simplex virus (HSV-1) involves a step in which the parental virus capsid docks at a nuclear pore and injects its DNA into the nucleus. Once “uncoated” in this way, the virus DNA can be transcribed and replicated. In an effort to clarify the mechanism of DNA injection, we examined DNA release as it occurs in purified capsids incubated in vitro. DNA ejection was observed following two different treatments, trypsin digestion of capsids in solution, and heating of capsids after attachment to a solid surface. In both cases, electron microscopic analysis revealed that DNA was ejected as a single double helix with ejection occurring at one vertex presumed to be the portal. In the case of trypsin-treated capsids, DNA release was found to correlate with cleavage of a small proportion of the portal protein, UL6, suggesting UL6 cleavage may be involved in making the capsid permissive for DNA ejection. In capsids bound to a solid surface, DNA ejection was observed only when capsids were warmed above 4°C. The proportion of capsids releasing their DNA increased as a function of incubation temperature with nearly all capsids ejecting their DNA when incubation was at 37°C. The results demonstrate heterogeneity among HSV-1 capsids with respect to their sensitivity to heat-induced DNA ejection. Such heterogeneity may indicate a similar heterogeneity in the ease with which capsids are able to deliver DNA to the infected cell nucleus. PMID:17540405

  3. Striated muscle involvement in experimental oral infection by herpes simplex virus type 1.

    PubMed

    Gonzalez, María Inés; Sanjuan, Norberto A

    2013-07-01

    Herpes simplex virus type 1 is one of the most frequent causes of oral infection in humans, especially during early childhood. Several experimental models have been developed to study the pathogenesis of this virus but all of them employed adult animals. In this work, we developed an experimental model that uses mice younger than 4 days old, to more closely resemble human infection. Mice were infected subcutaneously with the prototype strain McIntyre of Herpes simplex-1, and the progression of infection was studied by immunoperoxidase. All animals died within 24-72 h post-infection, while viral antigens were found in the oral epithelium, nerves and brain. The most striking result was the finding of viral antigens in the nucleus and cytoplasm of cells belonging to striated muscles. Organotypic cultures of striated muscles were performed, and viral replication was observed in them by immunocytochemistry, electron microscopy and viral isolation. We conclude that the infection of striated muscles is present from the onset of oral infection and, eventually, could explain some clinical observations in humans. PMID:23445118

  4. Dynasore Disrupts Trafficking of Herpes Simplex Virus Proteins

    PubMed Central

    Mues, Mascha B.; Cheshenko, Natalia; Wilson, Duncan W.; Gunther-Cummins, Leslie

    2015-01-01

    ABSTRACT Dynasore, a small-molecule inhibitor of the GTPase activity of dynamin, inhibits the entry of several viruses, including herpes simplex virus (HSV), but its impact on other steps in the viral life cycle has not been delineated. The current study was designed to test the hypothesis that dynamin is required for viral protein trafficking and thus has pleiotropic inhibitory effects on HSV infection. Dynasore inhibited HSV-1 and HSV-2 infection of human epithelial and neuronal cells, including primary genital tract cells and human fetal neurons and astrocytes. Similar results were obtained when cells were transfected with a plasmid expressing dominant negative dynamin. Kinetic studies demonstrated that dynasore reduced the number of viral capsids reaching the nuclear pore if added at the time of viral entry and that, when added as late as 8 h postentry, dynasore blocked the transport of newly synthesized viral proteins from the nucleus to the cytosol. Proximity ligation assays demonstrated that treatment with dynasore prevented the colocalization of VP5 and dynamin. This resulted in a reduction in the number of viral capsids isolated from sucrose gradients. Fewer capsids were observed by electron microscopy in dynasore-treated cells than in control-treated cells. There were also reductions in infectious progeny released into culture supernatants and in cell-to-cell spread. Together, these findings suggest that targeting dynamin-HSV interactions may provide a new strategy for HSV treatment and prevention. IMPORTANCE HSV infections remain a global health problem associated with significant morbidity, particularly in neonates and immunocompromised hosts, highlighting the need for novel approaches to treatment and prevention. The current studies indicate that dynamin plays a role in multiple steps in the viral life cycle and provides a new target for antiviral therapy. Dynasore, a small-molecule inhibitor of dynamin, has pleiotropic effects on HSV-1 and HSV-2

  5. Occurrence of Anisakis simplex sensu stricto in imported Atlantic mackerel (Scomber scombrus) represents a risk for Turkish consumers.

    PubMed

    Pekmezci, Gokmen Zafer

    2014-08-18

    Anisakid larvae are a prevalent food-borne pathogen that has been found in numerous fish species destined for human consumption. The accidental consumption of infected raw or poorly cooked fish may cause gastroenteric diseases and allergies in humans. In spite of the fact that thorough cooking or freezing kills Anisakis worms, this method does not destroy their allergenic capacity. The presence of A. simplex (s.s.) in seafood products may present a health risk for consumers. In Turkey, Atlantic mackerels are marketed as frozen and mainly imported from Norway. The aim of this study was to identify the Anisakis species found in deep-frozen whole Atlantic mackerel (Scomber scombrus) destined for human consumption in fish markets that imported fish from Norway to Turkey. All Anisakis larvae isolated from imported Atlantic mackerel were identified via morphology as third larvae of Anisakis Type I. The ITS region (ITS-1, 5.8S subunit, ITS-2) was amplified and digested with the restriction enzymes Hinf I and Hha I. Larvae of the genus Anisakis were identified via PCR-RFLP as belonging to Anisakis simplex (s.s.), and this was confirmed by sequencing the cox2 gene. The overall prevalence of Anisakis larvae was 25% (95% confidence limits: 13-41%), and the mean intensity was 19.1 (bootstrap 95% confidence limits: 15.3-25.5). Recognized zoonotic A. simplex (s.s.) larvae found in imported Atlantic mackerel could represent a risk. Those who consume them could acquire parasitic allergies. The results will have an important impact on public health risk assessment in that they suggest reviewing critical control points at the Hazard Analysis Critical Control Point (HACCP) programmer to reduce the risk of anisakid-induced allergies among consumers. Consequently, the present study provides the first data regarding the occurrence of A. simplex (s.s.) larvae in imported Atlantic mackerel in Turkish markets. PMID:24935687

  6. Diagnostic imaging of herpes simplex virus encephalitis using a radiolabeled antiviral drug: autoradiographic assessment in an animal model

    SciTech Connect

    Saito, Y.; Rubenstein, R.; Price, R.W.; Fox, J.J.; Watanabe, K.A.

    1984-06-01

    To develop a new approach to the diagnosis of herpes simplex encephalitis, we used a radiolabeled antiviral drug, 2'-fluoro-5-methyl-1-beta-D-arabinosyluracil labeled with carbon 14 ((14C)FMAU), as a probe for selectively imaging brain infection in a rat model by quantitative autoradiography. A high correlation was found between focal infection, as defined by immunoperoxidase viral antigen staining, and increased regional (14C)FMAU uptake in brain sections. Two potential sources of false-positive imaging were defined: high concentrations of drug in the choroid plexus because of its higher permeability compared with brain, and drug sequestration by proliferating uninfected cell populations. Our results support the soundness of the proposed strategy of using a labeled antiviral drug that is selectively phosphorylated by herpes simplex virus type 1 thymidine kinase in conjunction with scanning methods for human diagnosis, and also define some of the factors that must be taken into account when planning clinical application.

  7. Herpes simplex virus virion host shutoff function.

    PubMed Central

    Kwong, A D; Kruper, J A; Frenkel, N

    1988-01-01

    Herpes simplex virus (HSV) virions contain one or more functions which mediate the shutoff of host protein synthesis and the degradation of host mRNA. HSV type 1 (HSV-1) mutants deficient in the virion shutoff of host protein synthesis (vhs mutants) were isolated and were found to be defective in their ability to degrade host mRNA. Furthermore, it was found that viral mRNAs in cells infected with the vhs 1 mutant have a significantly longer functional half-life than viral mRNAs in wild-type virus-infected cells. In the present study we have mapped the vhs1 mutation affecting the virion shutoff of host protein synthesis to a 265-base-pair NruI-XmaIII fragment spanning map coordinates 0.604 to 0.606 of the HSV-1 genome. The mutation(s) affecting the functional half-lives of host mRNA as well as the alpha (immediate-early), beta (early), and gamma (late) viral mRNAs were also mapped within this 265-base-pair fragment. Thus, the shutoff of host protein synthesis is most likely mediated by the same function which decreases the half-life of viral mRNA. The shorter half-life of infected-cell mRNAs may allow a more rapid modulation of viral gene expression in response to changes in the transcription of viral genes. Interestingly, the vhs1 mutation of HSV-1 maps within a region which overlaps the Bg/II-N sequences of HSV-2 DNA shown previously to transform cells in culture. The possible relationship between the transformation and host shutoff functions are discussed. Images PMID:2828686

  8. Retargeting Strategies for Oncolytic Herpes Simplex Viruses

    PubMed Central

    Campadelli-Fiume, Gabriella; Petrovic, Biljana; Leoni, Valerio; Gianni, Tatiana; Avitabile, Elisa; Casiraghi, Costanza; Gatta, Valentina

    2016-01-01

    Most of the oncolytic herpes simplex viruses (HSVs) exhibit a high safety profile achieved through attenuation. They carry defects in virulence proteins that antagonize host cell response to the virus, including innate response, apoptosis, authophagy, and depend on tumor cell proliferation. They grow robustly in cancer cells, provided that these are deficient in host cell responses, which is often the case. To overcome the attenuation limits, a strategy is to render the virus highly cancer-specific, e.g., by retargeting their tropism to cancer-specific receptors, and detargeting from natural receptors. The target we selected is HER-2, overexpressed in breast, ovarian and other cancers. Entry of wt-HSV requires the essential glycoproteins gD, gH/gL and gB. Here, we reviewed that oncolytic HSV retargeting was achieved through modifications in gD: the addition of a single-chain antibody (scFv) to HER-2 coupled with appropriate deletions to remove part of the natural receptors’ binding sites. Recently, we showed that also gH/gL can be a retargeting tool. The insertion of an scFv to HER-2 at the gH N-terminus, coupled with deletions in gD, led to a recombinant capable to use HER-2 as the sole receptor. The retargeted oncolytic HSVs can be administered systemically by means of carrier cells-forcedly-infected mesenchymal stem cells. Altogether, the retargeted oncolytic HSVs are highly cancer-specific and their replication is not dependent on intrinsic defects of the tumor cells. They might be further modified to express immunomodulatory molecules. PMID:26927159

  9. Herpes Simplex Virus: The Interplay Between HSV, Host, and HIV-1.

    PubMed

    Desai, Dipen Vijay; Kulkarni, Smita Shrikant

    2015-12-01

    Herpes simplex virus proteins interact with host (human) proteins and create an environment conducive for its replication. Genital ulceration due to herpes simplex virus type 2 (HSV-2) infections is an important clinical manifestation reported to increase the risk of human immunodeficiency virus type 1 (HIV-1) acquisition and replication in HIV-1/HSV-2 coinfection. Dampening the innate and adaptive immune responses of the skin-resident dendritic cells, HSV-2 not only helps itself, but creates a "yellow brick road" for one of the most dreaded viruses HIV, which is transmitted mainly through the sexual route. Although, data from clinical trials show that HSV-2 suppression reduces HIV-1 viral load, there are hardly any reports presenting conclusive evidence on the impact of HSV-2 coinfection on HIV-1 disease progression. Be that as it may, understanding the interplay between these three characters (HSV, host, and HIV-1) is imperative. This review endeavors to collate studies on the influence of HSV-derived proteins on the host response and HIV-1 replication. Studying such complex interactions may help in designing and developing common strategies for the two viruses to keep these "partners in crime" at bay. PMID:26331265

  10. Simplex-stochastic collocation method with improved scalability

    NASA Astrophysics Data System (ADS)

    Edeling, W. N.; Dwight, R. P.; Cinnella, P.

    2016-04-01

    The Simplex-Stochastic Collocation (SSC) method is a robust tool used to propagate uncertain input distributions through a computer code. However, it becomes prohibitively expensive for problems with dimensions higher than 5. The main purpose of this paper is to identify bottlenecks, and to improve upon this bad scalability. In order to do so, we propose an alternative interpolation stencil technique based upon the Set-Covering problem, and we integrate the SSC method in the High-Dimensional Model-Reduction framework. In addition, we address the issue of ill-conditioned sample matrices, and we present an analytical map to facilitate uniformly-distributed simplex sampling.

  11. SIMPLEX: simulator and postprocessor for free-electron laser experiments

    PubMed Central

    Tanaka, Takashi

    2015-01-01

    SIMPLEX is a computer program developed for simulating the amplification process of free-electron lasers (FELs). It numerically solves the so-called FEL equations describing the evolution of the radiation field and growth of microbunching while the electron beam travels along the undulator. In order to reduce the numerical cost, the FEL equations have been reduced to more convenient forms for numerical implementation by applying reasonable approximations. SIMPLEX is equipped with a postprocessor to facilitate the retrieval of desired information from the simulation results, which is crucial for practical applications such as designing the beamline and analyzing the experimental results. PMID:26289287

  12. A constrained optimization algorithm based on the simplex search method

    NASA Astrophysics Data System (ADS)

    Mehta, Vivek Kumar; Dasgupta, Bhaskar

    2012-05-01

    In this article, a robust method is presented for handling constraints with the Nelder and Mead simplex search method, which is a direct search algorithm for multidimensional unconstrained optimization. The proposed method is free from the limitations of previous attempts that demand the initial simplex to be feasible or a projection of infeasible points to the nonlinear constraint boundaries. The method is tested on several benchmark problems and the results are compared with various evolutionary algorithms available in the literature. The proposed method is found to be competitive with respect to the existing algorithms in terms of effectiveness and efficiency.

  13. SIMPLEX: simulator and postprocessor for free-electron laser experiments.

    PubMed

    Tanaka, Takashi

    2015-09-01

    SIMPLEX is a computer program developed for simulating the amplification process of free-electron lasers (FELs). It numerically solves the so-called FEL equations describing the evolution of the radiation field and growth of microbunching while the electron beam travels along the undulator. In order to reduce the numerical cost, the FEL equations have been reduced to more convenient forms for numerical implementation by applying reasonable approximations. SIMPLEX is equipped with a postprocessor to facilitate the retrieval of desired information from the simulation results, which is crucial for practical applications such as designing the beamline and analyzing the experimental results. PMID:26289287

  14. Modulation of human β-defensin-1 (hBD-1) in plasmacytoid dendritic cells (PDC), monocytes, and epithelial cells by influenza virus, Herpes simplex virus, and Sendai virus and its possible role in innate immunity

    PubMed Central

    Ryan, Lisa K.; Dai, Jihong; Yin, Zhiwei; Megjugorac, Nicholas; Uhlhorn, Victoria; Yim, Sunghan; Schwartz, Kyell D.; Abrahams, Joshua M.; Diamond, Gill; Fitzgerald-Bocarsly, Patricia

    2011-01-01

    hBD comprise a family of antimicrobial peptides that plays a role in bridging the innate and adaptive immune responses to infection. The expression of hBD-2 increases upon stimulation of numerous cell types with LPS and proinflammatory cytokines. In contrast, hBD-1 remains constitutively expressed in most cells in spite of cytokine or LPS stimulation; however, its presence in human PDC suggests it plays a role in viral host defense. To examine this, we characterized the expression of hBD-1 in innate immune cells in response to viral challenge. PDC and monocytes increased production of hBD-1 peptide and mRNA as early as 2 h following infection of purified cells and PBMCs with PR8, HSV-1, and Sendai virus. However, treatment of primary NHBE cells with influenza resulted in a 50% decrease in hBD-1 mRNA levels, as measured by qRT-PCR at 3 h following infection. A similar inhibition occurred with HSV-1 challenge of human gingival epithelial cells. Studies with HSV-1 showed that replication occurred in epithelial cells but not in PDC. Together, these results suggest that hBD-1 may play a role in preventing viral replication in immune cells. To test this, we infected C57BL/6 WT mice and mBD-1(−/−) mice with mouse-adapted HK18 (300 PFU/mouse). mBD-1(−/−) mice lost weight earlier and died sooner than WT mice (P=0.0276), suggesting that BD-1 plays a role in early innate immune responses against influenza in vivo. However, lung virus titers were equal between the two mouse strains. Histopathology showed a greater inflammatory influx in the lungs of mBD-1(−/−) mice at Day 3 postinfection compared with WT C57BL/6 mice. The results suggest that BD-1 protects mice from influenza pathogenesis with a mechanism other than inhibition of viral replication. PMID:21551252

  15. Enhanced viral production and virus-mediated mortality of bacterioplankton in a natural iron-fertilized bloom event above the Kerguelen Plateau

    NASA Astrophysics Data System (ADS)

    Malits, A.; Christaki, U.; Obernosterer, I.; Weinbauer, M. G.

    2014-07-01

    Above the Kerguelen Plateau in the Southern Ocean natural iron fertilization sustains a large phytoplankton bloom over three months during austral summer. During the KEOPS1 project (KErguelen Ocean and Plateau compared Study1) we sampled this phytoplankton bloom during its declining phase along with the surrounding HNLC waters to study the effect of natural iron fertilization on the role of viruses in the microbial food web. Bacterial and viral abundances were 1.7 and 2.1 times, respectively, higher within the bloom than in HNLC waters. Viral production and virus-mediated mortality of bacterioplankton was 4.1 and 4.9 times, respectively, higher in the bloom, while the fraction of infected cells (FIC) and the fraction of lysogenic cells (FLC) showed no significant differences between environments. The present study suggests viruses to be more important for bacterial mortality within the bloom and dominate over protozoan grazing during the late bloom phase. As a consequence, at least at a late bloom stage, viral lysis shunts part of the photosynthetically fixed carbon in iron-fertilized regions into the dissolved organic matter (DOM) pool with potentially less particulate organic carbon transfered to larger members of the food web or exported.

  16. Enhanced viral production and virus-mediated mortality of bacterioplankton in a natural iron-fertilized bloom event above the Kerguelen Plateau

    NASA Astrophysics Data System (ADS)

    Malits, A.; Christaki, U.; Obernosterer, I.; Weinbauer, M. G.

    2014-12-01

    Above the Kerguelen Plateau in the Southern Ocean natural iron fertilization sustains a large phytoplankton bloom over 3 months during austral summer. During the KEOPS1 project (KErguelen Ocean and Plateau compared Study1) we sampled this phytoplankton bloom during its declining phase along with the surrounding high-nutrient-low-chlorophyll (HNLC) waters to study the effect of natural iron fertilization on the role of viruses in the microbial food web. Bacterial and viral abundances were 1.7 and 2.1 times, respectively, higher within the bloom than in HNLC waters. Viral production and virus-mediated mortality of bacterioplankton were 4.1 and 4.9 times, respectively, higher in the bloom, while the fraction of infected cells (FIC) and the fraction of lysogenic cells (FLC) showed no significant differences between environments. The present study suggests viruses to be more important for bacterial mortality within the bloom and dominate over grazing of heterotrophic nanoflagellates (HNFs) during the late bloom phase. As a consequence, at least at a late bloom stage, viral lysis shunts part of the photosynthetically fixed carbon in iron-fertilized regions into the dissolved organic matter (DOM) pool with potentially less particulate organic carbon transferred to larger members of the food web or exported.

  17. Structural basis for the antibody neutralization of Herpes simplex virus

    SciTech Connect

    Lee, Cheng-Chung; Lin, Li-Ling; Chan, Woan-Eng; Ko, Tzu-Ping; Lai, Jiann-Shiun; Wang, Andrew H.-J.

    2013-10-01

    The gD–E317-Fab complex crystal revealed the conformational epitope of human mAb E317 on HSV gD, providing a molecular basis for understanding the viral neutralization mechanism. Glycoprotein D (gD) of Herpes simplex virus (HSV) binds to a host cell surface receptor, which is required to trigger membrane fusion for virion entry into the host cell. gD has become a validated anti-HSV target for therapeutic antibody development. The highly inhibitory human monoclonal antibody E317 (mAb E317) was previously raised against HSV gD for viral neutralization. To understand the structural basis of antibody neutralization, crystals of the gD ectodomain bound to the E317 Fab domain were obtained. The structure of the complex reveals that E317 interacts with gD mainly through the heavy chain, which covers a large area for epitope recognition on gD, with a flexible N-terminal and C-terminal conformation. The epitope core structure maps to the external surface of gD, corresponding to the binding sites of two receptors, herpesvirus entry mediator (HVEM) and nectin-1, which mediate HSV infection. E317 directly recognizes the gD–nectin-1 interface and occludes the HVEM contact site of gD to block its binding to either receptor. The binding of E317 to gD also prohibits the formation of the N-terminal hairpin of gD for HVEM recognition. The major E317-binding site on gD overlaps with either the nectin-1-binding residues or the neutralizing antigenic sites identified thus far (Tyr38, Asp215, Arg222 and Phe223). The epitopes of gD for E317 binding are highly conserved between two types of human herpesvirus (HSV-1 and HSV-2). This study enables the virus-neutralizing epitopes to be correlated with the receptor-binding regions. The results further strengthen the previously demonstrated therapeutic and diagnostic potential of the E317 antibody.

  18. Rescue of skeletal muscles of gamma-sarcoglycan-deficient mice with adeno-associated virus-mediated gene transfer.

    PubMed

    Cordier, L; Hack, A A; Scott, M O; Barton-Davis, E R; Gao, G; Wilson, J M; McNally, E M; Sweeney, H L

    2000-02-01

    In humans, a subset of cases of Limb-girdle muscular dystrophy (LGMD) arise from mutations in the genes encoding one of the sarcoglycan (alpha, beta, gamma, or delta) subunits of the dystrophin-glycoprotein complex. While adeno-associated virus (AAV) is a potential gene therapy vector for these dystrophies, it is unclear if AAV can be used if a diseased muscle is undergoing rapid degeneration and necrosis. The skeletal muscles of mice lacking gamma-sarcoglycan (gsg-/- mice) differ from the animal models that have been evaluated to date in that the severity of the skeletal muscle pathology is much greater and more representative of that of humans with muscular dystrophy. Following direct muscle injection of a recombinant AAV [in which human gamma-sarcoglycan expression is driven by a truncated muscle creatine kinase (MCK) promoter/enhancer], we observed significant numbers of muscle fibers expressing gamma-sarcoglycan and an overall improvement of the histologic pattern of dystrophy. However, these results could be achieved only if injections into the muscle were prior to the development of significant fibrosis in the muscle. The results presented in this report show promise for AAV gene therapy for LGMD, but underscore the need for intervention early in the time course of the disease process. PMID:10933922

  19. Replication-Competent Controlled Herpes Simplex Virus

    PubMed Central

    Bloom, David C.; Feller, Joyce; McAnany, Peterjon; Vilaboa, Nuria

    2015-01-01

    ABSTRACT We present the development and characterization of a replication-competent controlled herpes simplex virus 1 (HSV-1). Replication-essential ICP4 and ICP8 genes of HSV-1 wild-type strain 17syn+ were brought under the control of a dually responsive gene switch. The gene switch comprises (i) a transactivator that is activated by a narrow class of antiprogestins, including mifepristone and ulipristal, and whose expression is mediated by a promoter cassette that comprises an HSP70B promoter and a transactivator-responsive promoter and (ii) transactivator-responsive promoters that drive the ICP4 and ICP8 genes. Single-step growth experiments in different cell lines demonstrated that replication of the recombinant virus, HSV-GS3, is strictly dependent on an activating treatment consisting of administration of a supraphysiological heat dose in the presence of an antiprogestin. The replication-competent controlled virus replicates with an efficiency approaching that of the wild-type virus from which it was derived. Essentially no replication occurs in the absence of activating treatment or if HSV-GS3-infected cells are exposed only to heat or antiprogestin. These findings were corroborated by measurements of amounts of viral DNA and transcripts of the regulated ICP4 gene and the glycoprotein C (gC) late gene, which was not regulated. Similar findings were made in experiments with a mouse footpad infection model. IMPORTANCE The alphaherpesviruses have long been considered vectors for recombinant vaccines and oncolytic therapies. The traditional approach uses vector backbones containing attenuating mutations that restrict replication to ensure safety. The shortcoming of this approach is that the attenuating mutations tend to limit both the immune presentation and oncolytic properties of these vectors. HSV-GS3 represents a novel type of vector that, when activated, replicates with the efficiency of a nonattenuated virus and whose safety is derived from deliberate

  20. [The lysate and recombinant antigens in ELISA-test-systems for diagnostic of herpes simplex].

    PubMed

    Ganova, L A; Kovtoniuk, G V; Korshun, L N; Kiseleva, E K; Tereshchenko, M I; Vudmaska, M I; Moĭsa, L N; Shevchuk, V A; Spivak, N Ia

    2014-08-01

    The lysate and recombinant antigens of various production included informula of ELISA-test-systems were analyzed. The ELISA-test-systems are used for detection of IgG to Herpes simplex virus type I and II. For testing the panel of serums PTH 201 (BBI Inc.) were used. The samples of this panel contain antibodies to Herpes simplex virus type I and II in mixed titers. The 69 serums of donors were used too (17 samples had IgG to Herpes simplex virus type I, 23 samples to Herpes simplex virus type II and 29 samples had no antibodies to Herpes simplex virus). The diagnostic capacity of mixture of recombinant antigens gG1 Herpes simplex virus type I and gG2 Herpes simplex virus type II (The research-and-production complex "DiaprofMed") was comparable with mixture of lysate antigen Herpes simplex virus type I and II (Membrane) EIE Antigen ("Virion Ltd."). In the test-systems for differentiation of IgG to Herpes simplex virus type I the recombinant antigen gG1 Herpes simplex virus type I proved to be comparable with commercial analogue Herpes simplex virus-1 gG1M ("Viral Therapeutics Inc."'). At the same time, capacity to detect IgG to Herpes simplex virus type II in recombinant protein gG2 Herpes simplex virus type II is significantly higher than in its analogue Herpes simplex virus-2 gG2c ("Viral Therapeutics Inc."). PMID:25552056

  1. The Longitudinal Guttman Simplex: Applications to Health Behavior Data.

    ERIC Educational Resources Information Center

    Collins, Linda M.; Dent, Clyde W.

    Because health behavior is often concerned with dynamic constructs, a longitudinal approach to measurement is needed. The Longitudinal Guttman Simplex (LGS) is a measurement model developed especially for dynamic constructs exhibiting cumulative, unitary development measured longitudinally. Data from the Television Smoking Prevention Project, a…

  2. Larvicidal constituents of Zingiber officinale (ginger) against Anisakis simplex.

    PubMed

    Lin, Rong-Jyh; Chen, Chung-Yi; Lee, June-Der; Lu, Chin-Mei; Chung, Li-Yu; Yen, Chuan-Min

    2010-11-01

    In this study, we investigated the anthelmintic activity of [10]-shogaol, [6]-shogaol, [10]-gingerol and [6]-gingerol, compounds isolated from the roots of Zingiber officinale L., Zingiberaceae (ginger), against Anisakis simplex. The above compounds kill or reduce spontaneous movement in A. simplex larvae. The maximum lethal efficacy of [10]-shogaol and [10]-gingerol was approximately 80% and 100%, respectively. We further examined the time course of compound-induced loss of mobility in A. simplex. The results showed that various concentrations of [10]-shogaol, [6]-shogaol, [10]-gingerol and [6]-gingerol have maximum effects on loss of spontaneous movement from 24 to 72 h. In addition, the time course of mortality and the percentage of loss of spontaneous movements were ascertained to determine the minimum effective doses of [10]-gingerol and [10]-shogaol. [10]-Gingerol exhibited a larger maximum larvicidal effect and greater loss of spontaneous movement than [10]-shogaol and albendazole. In addition, these constituents of Zingiber officinale showed effects against 2,2-diphenyl-1-picrylhydrazyl (DPPH) and peroxyl radicals. These constituents of Zingiber officinale are responsible for its larvicidal activity against A. simplex. PMID:20533167

  3. Intrauterine herpes simplex virus infection presenting with hypopigmented lesions.

    PubMed

    Low, Lynette C M; Carton, James; Walker, Marjorie; Tudor-Williams, Gareth; Hardman, Catherine

    2012-01-01

    Genital herpes simplex virus (HSV) is a sexually transmitted infection that can be transmitted from mother to child in utero, perinatally, or postnatally. Cutaneous infection with HSV commonly presents as vesicles affecting the skin, eyes, or mouth. In our case, we report a well child with cutaneous hypopigmented patches at birth that preceded typical blistering. PMID:22010816

  4. Argument Structure of Tsou: Simplex and Complex Predicates

    ERIC Educational Resources Information Center

    Lin, Gujing

    2010-01-01

    This thesis investigates the argument structure of Tsou, a Formosan language within the Austronesian family. The investigation studies both simplex and complex predicates as well as describes the valency groupings and alignment patterns emerging from various clausal configurations. Assuming the stance that language description should respect…

  5. Recurrent Lymphocytic Meningitis Positive for Herpes Simplex Virus Type 2

    PubMed Central

    Seppänen, Mikko; Kautiainen, Hannu; Lokki, Marja-Liisa; Lappalainen, Maija; Valtonen, Ville; Färkkilä, Markus; Kalso, Eija

    2009-01-01

    We found the prevalence of recurrent lymphocytic meningitis associated with herpes simplex virus type 2 (HSV-2) was 2.2/100,000 population in Finland during 1996–2006, higher than previous estimates. PCR was most sensitive in detecting HSV-2 DNA from cerebrospinal fluid if the sample was taken 2–5 days after symptom onset. PMID:19624935

  6. Recurrent lymphocytic meningitis positive for herpes simplex virus type 2.

    PubMed

    Kallio-Laine, Katariina; Seppänen, Mikko; Kautiainen, Hannu; Lokki, Marja Liisa; Lappalainen, Maija; Valtonen, Ville; Färkkilä, Markus; Kalso, Eija

    2009-07-01

    We found the prevalence of recurrent lymphocytic meningitis associated with herpes simplex virus type 2 (HSV-2) was 2.2/100,000 population in Finland during 1996-2006, higher than previous estimates. PCR was most sensitive in detecting HSV-2 DNA from cerebrospinal fluid if the sample was taken 2-5 days after symptom onset. PMID:19624935

  7. Numerical analysis of EPR spectra. 7. The simplex algorithm

    NASA Astrophysics Data System (ADS)

    Beckwith, Athelstan L. J.; Brumby, Steven

    The Simplex algorithm is well suited to the least-squares analysis of highly complex EPR spectra. The application of the algorithm to the analysis of the spectra of benzo[ a]pyrenyl-6-oxy, chloro(methoxycarbonyl)methyl, and cyano(methoxy)methyl free radicals is described.

  8. The N-Simplex and Its Generalizations towards Fractals

    ERIC Educational Resources Information Center

    Kosi-Ulbl, Irena; Pagon, Dusan

    2002-01-01

    Nature is full of different crystals and many of them have shapes of regular geometric objects. Those in which the fractal structure of a geometric object can be recognized are especially unusual. In this paper a generalization of one of these shapes is described: a formation, based on an n-dimensional simplex. The construction of an n-dimensional…

  9. A Streamlined Artificial Variable Free Version of Simplex Method

    PubMed Central

    Inayatullah, Syed; Touheed, Nasir; Imtiaz, Muhammad

    2015-01-01

    This paper proposes a streamlined form of simplex method which provides some great benefits over traditional simplex method. For instance, it does not need any kind of artificial variables or artificial constraints; it could start with any feasible or infeasible basis of an LP. This method follows the same pivoting sequence as of simplex phase 1 without showing any explicit description of artificial variables which also makes it space efficient. Later in this paper, a dual version of the new method has also been presented which provides a way to easily implement the phase 1 of traditional dual simplex method. For a problem having an initial basis which is both primal and dual infeasible, our methods provide full freedom to the user, that whether to start with primal artificial free version or dual artificial free version without making any reformulation to the LP structure. Last but not the least, it provides a teaching aid for the teachers who want to teach feasibility achievement as a separate topic before teaching optimality achievement. PMID:25767883

  10. Nonlinear and Quasi-Simplex Patterns in Latent Growth Models

    ERIC Educational Resources Information Center

    Bianconcini, Silvia

    2012-01-01

    In the SEM literature, simplex and latent growth models have always been considered competing approaches for the analysis of longitudinal data, even if they are strongly connected and both of specific importance. General dynamic models, which simultaneously estimate autoregressive structures and latent curves, have been recently proposed in the…

  11. Predicting a Longitudinal Guttman Simplex of Adolescent Substance Use.

    ERIC Educational Resources Information Center

    McGuigan, Kimberly A.; And Others

    The longitudinal Guttman simplex (LGS), a method of modeling stage sequences or levels over time, allows for individual differences in sequence progression or development. The LGS is particularly appropriate in modeling tobacco, alcohol, and marijuana use stages with adolescent subjects where relationships among drugs and degree of involvement may…

  12. The Law of Cosines for an "n"-Dimensional Simplex

    ERIC Educational Resources Information Center

    Ding, Yiren

    2008-01-01

    Using the divergence theorem technique of L. Eifler and N.H. Rhee, "The n-dimensional Pythagorean Theorem via the Divergence Theorem" (to appear: Amer. Math. Monthly), we extend the law of cosines for a triangle in a plane to an "n"-dimensional simplex in an "n"-dimensional space.

  13. Prevalence of Herpes Simplex Virus Antibodies in Dental Students.

    ERIC Educational Resources Information Center

    Rodu, Brad; And Others

    1992-01-01

    A study of 125 sophomore preclinical dental students found that these young professionals, because of having a low prevalence of herpes simplex virus (HSV) antibodies, are at risk for acquiring a primary HSV infection when treating HSV positive patients and should take precautions to avoid virus transmission. (MSE)

  14. SIMPLEX OPTIMIZATION OF MULTIELEMENT ULTRASONIC EXTRACTION OF ATMOSPHERIC PARTICULATES

    EPA Science Inventory

    A Simplex search was used to locate an optimum for an ultrasonic extraction of trace elements from atmospheric particulates collected on glass fiber high-volume sampler filters. The optimized procedure produced quantitative results for 13 elements with precisions of 10% or less, ...

  15. The "Other" Venereal Diseases: Herpes Simplex, Trichomoniasis and Candidiasis.

    ERIC Educational Resources Information Center

    McNab, Warren L.

    1979-01-01

    Although the term venereal disease has been synonymous with gonorrhea and syphilis, the Center for Disease Control now states that the number of new cases of herpes simplex, trichomoniasis, and candidiasis is rapidly approaching the number of cases of syphilis and gonorrhea. (MM)

  16. Herpes Simplex Virus-1 Encephalitis in Adults: Pathophysiology, Diagnosis, and Management.

    PubMed

    Bradshaw, Michael J; Venkatesan, Arun

    2016-07-01

    Herpetic infections have plagued humanity for thousands of years, but only recently have advances in antiviral medications and supportive treatments equipped physicians to combat the most severe manifestations of disease. Prompt recognition and treatment can be life-saving in the care of patients with herpes simplex-1 virus encephalitis, the most commonly identified cause of sporadic encephalitis worldwide. Clinicians should be able to recognize the clinical signs and symptoms of the infection and familiarize themselves with a rational diagnostic approach and therapeutic modalities, as early recognition and treatment are key to improving outcomes. Clinicians should also be vigilant for the development of acute complications, including cerebral edema and status epilepticus, as well as chronic complications, including the development of autoimmune encephalitis associated with antibodies to the N-methyl-D-aspartate receptor and other neuronal cell surface and synaptic epitopes. Herein, we review the pathophysiology, differential diagnosis, and clinical and radiological features of herpes simplex virus-1 encephalitis in adults, including a discussion of the most common complications and their treatment. While great progress has been made in the treatment of this life-threatening infection, a majority of patients will not return to their previous neurologic baseline, indicating the need for further research efforts aimed at improving the long-term sequelae. PMID:27106239

  17. Update on emerging antivirals for the management of herpes simplex virus infections: a patenting perspective.

    PubMed

    Vadlapudi, Aswani D; Vadlapatla, Ramya K; Mitra, Ashim K

    2013-04-01

    Herpes simplex virus (HSV) infections can be treated efficiently by the application of antiviral drugs. The herpes family of viruses is responsible for causing a wide variety of diseases in humans. The standard therapy for the management of such infections includes acyclovir (ACV) and penciclovir (PCV) with their respective prodrugs valaciclovir and famciclovir. Though effective, long term prophylaxis with the current drugs leads to development of drug-resistant viral isolates, particularly in immunocompromised patients. Moreover, some drugs are associated with dose-limiting toxicities which limit their further utility. Therefore, there is a need to develop new antiherpetic compounds with different mechanisms of action which will be safe and effective against emerging drug resistant viral isolates. Significant advances have been made towards the design and development of novel antiviral therapeutics during the last decade. As evident by their excellent antiviral activities, pharmaceutical companies are moving forward with several new compounds into various phases of clinical trials. This review provides an overview of structure and life cycle of HSV, progress in the development of new therapies, update on the advances in emerging therapeutics under clinical development and related recent patents for the treatment of Herpes simplex virus infections. PMID:23331181

  18. Agents and strategies in development for improved management of herpes simplex virus infection and disease.

    PubMed

    Kleymann, Gerald

    2005-02-01

    The quiet pandemic of herpes simplex virus (HSV) infections has plagued humanity since ancient times, causing mucocutaneous infection such as herpes labialis and herpes genitalis. Disease symptoms often interfere with every-day activities and occasionally HSV infections are the cause of life-threatening or sight-impairing disease, especially in neonates and the immuno-compromised patient population. After infection the virus persists for life in neurons of the host in a latent form, periodically reactivating and often resulting in significant psychosocial distress for the patient. Currently no cure is available. So far, vaccines, ILs, IFNs, therapeutic proteins, antibodies, immunomodulators and small-molecule drugs with specific or non-specific modes of action lacked either efficacy or the required safety profile to replace the nucleosidic drugs acyclovir, valacyclovir, penciclovir and famciclovir as the first choice of treatment. The recently discovered inhibitors of the HSV helicase-primase are the most potent development candidates today. These antiviral agents act by a novel mechanism of action and display low resistance rates in vitro and superior efficacy in animal models. This review summarises the current therapeutic options, discusses the potential of preclinical or investigational drugs and provides an up-to-date interpretation of the challenge to establish novel treatments for herpes simplex disease. PMID:15757392

  19. Update On Emerging Antivirals For The Management Of Herpes Simplex Virus Infections: A Patenting Perspective

    PubMed Central

    Vadlapudi, Aswani D.; Vadlapatla, Ramya K.; Mitra, Ashim K.

    2015-01-01

    Herpes simplex virus (HSV) infections can be treated efficiently by the application of antiviral drugs. The herpes family of viruses is responsible for causing a wide variety of diseases in humans. The standard therapy for the management of such infections includes acyclovir (ACV) and penciclovir (PCV) with their respective prodrugs valaciclovir and famciclovir. Though effective, long term prophylaxis with the current drugs leads to development of drug-resistant viral isolates, particularly in immunocompromised patients. Moreover, some drugs are associated with dose-limiting toxicities which limit their further utility. Therefore, there is a need to develop new antiherpetic compounds with different mechanisms of action which will be safe and effective against emerging drug resistant viral isolates. Significant advances have been made towards the design and development of novel antiviral therapeutics during the last decade. As evident by their excellent antiviral activities, pharmaceutical companies are moving forward with several new compounds into various phases of clinical trials. This review provides an overview of structure and life cycle of HSV, progress in the development of new therapies, update on the advances in emerging therapeutics under clinical development and related recent patents for the treatment of Herpes simplex virus infections. PMID:23331181

  20. Anisakis antigens detected in fish muscle infested with Anisakis simplex L3.

    PubMed

    Solas, M Teresa; García, Maria Luisa; Rodriguez-Mahillo, Ana I; Gonzalez-Munoz, Miguel; de las Heras, Cristina; Tejada, Margarita

    2008-06-01

    Anisakis simplex is a fish parasite that is a public health risk to those consuming raw or poorly cooked marine fish and cephalopods because of the possibility of becoming infested with live larvae. In humans, penetration of the larvae into the gastrointestinal track can cause acute and chronic symptoms and allergic anisakiasis. Excretion and secretion products released by the larvae are thought to play a role in migration through the tissues and induce an immunoglobulin E-mediated immune response. The aim of this preliminary study was to detect parasite antigens and allergens in fish tissues surrounding the migrating larvae. Hake and anchovy fillets were artificially parasitized with Anisakis larvae and stored in chilled conditions for 5 days. Larvae were evaluated for fluorescence, fish muscle tissue was examined with transmission electron microscopy, and immunohistochemical reactions of two rabbit polyclonal antisera against a parasite crude extract and the allergen Ani s 4 were recorded. Larvae immediately migrated into the fish muscle, and no emission of bluish fluorescence was observed. Fish muscle areas in contact with the parasite showed disruptions in the structure and inclusion of granules within sarcomeres. Both parasite antigens and the Ani s 4 allergen were located in areas close to the larvae and where sarcomere structure was preserved. These findings indicate that parasite antigens and allergens are dispersed into the muscle and might cause allergic symptoms such as dyspnea, vomiting, diarrhea, urticaria, angioedema, or anaphylaxis in some individuals sensitive to A. simplex. PMID:18592760

  1. Immunological Signaling During Herpes Simplex Virus-2 and Cytomegalovirus Vaginal Shedding After Initiation of Antiretroviral Treatment

    PubMed Central

    Nason, Martha C.; Patel, Eshan U.; Kirkpatrick, Allison R.; Prodger, Jessica L.; Shahabi, Kamnoosh; Tobian, Aaron A. R.; Gianella, Sara; Kalibbala, Sarah; Ssebbowa, Paschal; Kaul, Rupert; Gray, Ronald H.; Quinn, Thomas C.; Serwadda, David; Reynolds, Steven J.; Redd, Andrew D.

    2016-01-01

    Vaginal proinflammatory cytokine expression during herpes virus reactivation was examined in human immunodeficiency virus-infected women before and after initiation of antiretroviral therapy (ART). Vaginal swabs were screened for levels of cytokines interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, tumor necrosis factor (TNF)-α, and interferon-γ. The relative risk (RR) of herpes simplex virus-2 or cytomegalovirus (CMV) shedding being associated with cytokine levels above the median were estimated. Herpes simplex virus-2 shedding was significantly associated with higher levels of IL-6 (RR = 1.4, P = .003) and TNF-α (RR = 1.3, P = .010), whereas CMV shedding was associated with higher IL-6 (RR = 1.3, P = .006) and IL-2 (RR = 1.4, P = .01). The association of viral shedding with higher IL-6 levels suggests that herpes virus reactivation may be playing a role in immune activation after ART initiation. PMID:27191006

  2. An extended study of seroprevalence of anti-Anisakis simplex IgE antibodies in Norwegian blood donors.

    PubMed

    Lin, A H; Nepstad, I; Florvaag, E; Egaas, E; Van Do, T

    2014-01-01

    During the last decade, cases of the fish parasite Anisakis simplex infection and allergy in human have increased in countries with high fish consumption. Our aim was to perform an extended seroprevalence study of anti-IgE antibodies against this parasite in Norway, one of the high fish-consuming countries. At the Department of Immunology and Transfusion Medicine and the Laboratory of Clinical Biochemistry, Haukeland University Hospital, Bergen, Norway, two main groups of anonymized serum samples were collected; the first (n = 993) from recently recruited blood donors (designated 'BDO') and the second (n = 414) from patient with total IgE levels ≥1000 kU/l (designated 'IGE+'). The sera were analysed by the ImmunoCAP(®) method for total IgE and IgE antibodies against A. simplex, house dust mite (HDM), shrimp, cod, crab, brine shrimp and shrimp tropomyosin. The A. simplex positive sera were further tested by an enzyme-linked immunosorbent assay (ELISA) method, which uses 2 recombinant (r) major allergens, rAni s 1 and rAni s 7 as target antigens. SDS-PAGE and Western immunoblotting analyses were also performed. Whereas the prevalences by ImmunoCAP(®) were 0.4% and 16.2% in the BDO and IGE+ groups, respectively, analyses with recombinant allergens showed only 0.0% and 0.2%. Cross-reactivity and immunoblotting analyses suggested that most of the ImmunoCAP(®) positive sera were probably false-positive due to cross-sensitization to shrimp and HDM. However, positivity due to other A. simplex antigens should also be considered. Compared with other high fish-consuming countries, we observed a very low seroprevalence of anti-Anisakis IgE antibodies in a Norwegian population. PMID:24219706

  3. The function of herpes simplex virus genes: a primer for genetic engineering of novel vectors.

    PubMed Central

    Roizman, B

    1996-01-01

    Herpes simplex virus vectors are being developed for delivery and expression of human genes to the central nervous system, selective destruction of cancer cells, and as carriers for genes encoding antigens that induce protective immunity against infectious agents. Vectors constructed to meet these objectives must differ from wild-type virus with respect to host range, reactivation from latency, and expression of viral genes. The vectors currently being developed are (i) helper free amplicons, (ii) replication defective viruses, and (iii) genetically engineered replication competent viruses with restricted host range. Whereas the former two types of vectors require stable, continuous cell lines expressing viral genes for their replication, the replication competent viruses will replicate on approved primary human cell strains. PMID:8876131

  4. The Function of Herpes Simplex Virus Genes: A Primer for Genetic Engineering of Novel Vectors

    NASA Astrophysics Data System (ADS)

    Roizman, Bernard

    1996-10-01

    Herpes simplex virus vectors are being developed for delivery and expression of human genes to the central nervous system, selective destruction of cancer cells, and as carriers for genes encoding antigens that induce protective immunity against infectious agents. Vectors constructed to meet these objectives must differ from wild-type virus with respect to host range, reactivation from latency, and expression of viral genes. The vectors currently being developed are (i) helper free amplicons, (ii) replication defective viruses, and (iii) genetically engineered replication competent viruses with restricted host range. Whereas the former two types of vectors require stable, continuous cell lines expressing viral genes for their replication, the replication competent viruses will replicate on approved primary human cell strains.

  5. Epidermal Growth Factor Receptor-PI3K Signaling Controls Cofilin Activity To Facilitate Herpes Simplex Virus 1 Entry into Neuronal Cells

    PubMed Central

    Zheng, Kai; Xiang, Yangfei; Wang, Xiao; Wang, Qiaoli; Zhong, Meigong; Wang, Shaoxiang; Wang, Xiaoyan; Fan, Jianglin; Kitazato, Kaio; Wang, Yifei

    2014-01-01

    ABSTRACT Herpes simplex virus type 1 (HSV-1) establishes latency in neurons and can cause severe disseminated infection with neurological impairment and high mortality. This neurodegeneration is thought to be tightly associated with virus-induced cytoskeleton disruption. Currently, the regulation pattern of the actin cytoskeleton and the involved molecular mechanisms during HSV-1 entry into neurons remain unclear. Here, we demonstrate that the entry of HSV-1 into neuronal cells induces biphasic remodeling of the actin cytoskeleton and an initial inactivation followed by the subsequent activation of cofilin, a member of the actin depolymerizing factor family that is critical for actin reorganization. The disruption of F-actin dynamics or the modulation of cofilin activity by mutation, knockdown, or overexpression affects HSV-1 entry efficacy and virus-mediated cell ruffle formation. Binding of the HSV-1 envelope initiates the epidermal growth factor receptor (EGFR)-phosphatidylinositide 3-kinase (PI3K) signaling pathway, which leads to virus-induced early cofilin phosphorylation and F-actin polymerization. Moreover, the extracellular signal-regulated kinase (ERK) kinase and Rho-associated, coiled-coil-containing protein kinase 1 (ROCK) are recruited as downstream mediators of the HSV-1-induced cofilin inactivation pathway. Inhibitors specific for those kinases significantly reduce the virus infectivity without affecting virus binding to the target cells. Additionally, lipid rafts are clustered to promote EGFR-associated signaling cascade transduction. We propose that HSV-1 hijacks cofilin to initiate infection. These results could promote a better understanding of the pathogenesis of HSV-1-induced neurological diseases. PMID:24425731

  6. A next step in adeno-associated virus-mediated gene therapy for neurological diseases: regulation and targeting

    PubMed Central

    Chtarto, Abdelwahed; Bockstael, Olivier; Tshibangu, Terence; Dewitte, Olivier; Levivier, Marc; Tenenbaum, Liliane

    2013-01-01

    Recombinant adeno-associated virus (rAAV) vectors mediating long term transgene expression are excellent gene therapy tools for chronic neurological diseases. While rAAV2 was the first serotype tested in the clinics, more efficient vectors derived from the rh10 serotype are currently being evaluated and other serotypes are likely to be tested in the near future. In addition, aside from the currently used stereotaxy-guided intraparenchymal delivery, new techniques for global brain transduction (by intravenous or intra-cerebrospinal injections) are very promising. Various strategies for therapeutic gene delivery to the central nervous system have been explored in human clinical trials in the past decade. Canavan disease, a genetic disease caused by an enzymatic deficiency, was the first to be approved. Three gene transfer paradigms for Parkinson's disease have been explored: converting L-dopa into dopamine through AADC gene delivery in the putamen; synthesizing GABA through GAD gene delivery in the overactive subthalamic nucleus and providing neurotrophic support through neurturin gene delivery in the nigro-striatal pathway. These pioneer clinical trials demonstrated the safety and tolerability of rAAV delivery in the human brain at moderate doses. Therapeutic effects however, were modest, emphasizing the need for higher doses of the therapeutic transgene product which could be achieved using more efficient vectors or expression cassettes. This will require re-addressing pharmacological aspects, with attention to which cases require either localized and cell-type specific expression or efficient brain-wide transgene expression, and when it is necessary to modulate or terminate the administration of transgene product. The ongoing development of targeted and regulated rAAV vectors is described. PMID:23331189

  7. Correction of multiple striated muscles in murine Pompe disease through adeno-associated virus-mediated gene therapy.

    PubMed

    Sun, Baodong; Young, Sarah P; Li, Ping; Di, Chunhui; Brown, Talmage; Salva, Maja Z; Li, Songtao; Bird, Andrew; Yan, Zhen; Auten, Richard; Hauschka, Stephen D; Koeberl, Dwight D

    2008-08-01

    Glycogen storage disease type II (Pompe disease; MIM 232300) stems from the deficiency of acid alpha-glucosidase (GAA; acid maltase; EC 3.2.1.20), which primarily involves cardiac and skeletal muscles. An adeno-associated virus 2/8 (AAV2/8) vector containing the muscle creatine kinase (MCK) (CK1) reduced glycogen content by approximately 50% in the heart and quadriceps in GAA-knockout (GAA-KO) mice; furthermore, an AAV2/8 vector containing the hybrid alpha-myosin heavy chain enhancer-/MCK enhancer-promoter (MHCK7) cassette reduced glycogen content by >95% in heart and >75% in the diaphragm and quadriceps. Transduction with an AAV2/8 vector was higher in the quadriceps than in the gastrocnemius. An AAV2/9 vector containing the MHCK7 cassette corrected GAA deficiency in the distal hindlimb, and glycogen accumulations were substantially cleared by human GAA (hGAA) expression therein; however, the analogous AAV2/7 vector achieved much lower efficacy. Administration of the MHCK7-containing vectors significantly increased striated muscle function as assessed by increased Rotarod times at 18 weeks after injection, whereas the CK1-containing vector did not increase Rotarod performance. Importantly, type IIb myofibers in the extensor digitalis longus (EDL) were transduced, thereby correcting a myofiber type that is unresponsive to enzyme replacement therapy. In summary, AAV8 and AAV9-pseudotyped vectors containing the MHCK7 regulatory cassette achieved enhanced efficacy in Pompe disease mice. PMID:18560415

  8. [Adeno-associated virus mediated T-bet gene transfer into SGC-7901 cell to regulate IFN-gamma production].

    PubMed

    Qiu, Gufeng; Wang, Suoying; Wang, Shengjun; Shao, Qixiang; Ma, Jie; Yang, Ming; Xu, Xiaopeng; Mao, Chaoming; Su, Zhaoliang; Huang, Xinxiang; Xu, Huaxi

    2009-06-01

    In order to investigate the effect of T-bet on malignant cells, we selected SGC-7901, a kind of human gastric carcinoma cell line, and used gene clone technique and adeno-associated virus (AAV) packing technology, thus obtaining a recombinant rAAV-eGFP-T-bet and T-bet gene-transfected SGC-7901 cells. Then the function of T-bet gene-infected SGC-7901 cells was researched by detecting the levels of IFN-gamma and T-bet production. The results showed: (1) It was verified that rAAV-T-bet's packing was completed; (2) After SGC-7901 cells was transfected by rAAV-eGFP-T-bet, a green fluorescence was found in about 30%-40% SGC-7901s, and the gene of 1670 bp (T-bet) and 388 bp (IFN-gamma) were generated from SGC-7901s cells; (3) The proteins of IFN-gamma and T-bet secreted by SGC-7901 cells were also detected. These reveal that SGC-7901 cell is efficiently infected by rAAV encoding T-bet, which can induce transfected cells to secret IFN-gamma. It may be useful in the researches on cancer immune therapy of transfecting T-bet gene. PMID:19634682

  9. Adeno-associated-virus-mediated transduction of the mammary gland enables sustained production of recombinant proteins in milk

    PubMed Central

    Wagner, Stefan; Thresher, Rosemary; Bland, Ross; Laible, Götz

    2015-01-01

    Biopharming for the production of recombinant pharmaceutical proteins in the mammary gland of transgenic animals is an attractive but laborious alternative compared to mammalian cell fermentation. The disadvantage of the lengthy process of genetically modifying an entire animal could be circumvented with somatic transduction of only the mammary epithelium with recombinant, replication-defective viruses. While other viral vectors offer very limited scope for this approach, vectors based on adeno-associated virus (AAV) appear to be ideal candidates because AAV is helper-dependent, does not induce a strong immune response and has no association with disease. Here, we sought to test the suitability of recombinant AAV (rAAV) for biopharming. Using reporter genes, we showed that injected rAAV efficiently transduced mouse mammary cells. When rAAV encoding human myelin basic protein (hMBP) was injected into the mammary glands of mice and rabbits, this resulted in the expression of readily detectable protein levels of up to 0.5 g/L in the milk. Furthermore we demonstrated that production of hMBP persisted over extended periods and that protein expression could be renewed in a subsequent lactation by re-injection of rAAV into a previously injected mouse gland. PMID:26463440

  10. Adeno-associated-virus-mediated transduction of the mammary gland enables sustained production of recombinant proteins in milk.

    PubMed

    Wagner, Stefan; Thresher, Rosemary; Bland, Ross; Laible, Götz

    2015-01-01

    Biopharming for the production of recombinant pharmaceutical proteins in the mammary gland of transgenic animals is an attractive but laborious alternative compared to mammalian cell fermentation. The disadvantage of the lengthy process of genetically modifying an entire animal could be circumvented with somatic transduction of only the mammary epithelium with recombinant, replication-defective viruses. While other viral vectors offer very limited scope for this approach, vectors based on adeno-associated virus (AAV) appear to be ideal candidates because AAV is helper-dependent, does not induce a strong immune response and has no association with disease. Here, we sought to test the suitability of recombinant AAV (rAAV) for biopharming. Using reporter genes, we showed that injected rAAV efficiently transduced mouse mammary cells. When rAAV encoding human myelin basic protein (hMBP) was injected into the mammary glands of mice and rabbits, this resulted in the expression of readily detectable protein levels of up to 0.5 g/L in the milk. Furthermore we demonstrated that production of hMBP persisted over extended periods and that protein expression could be renewed in a subsequent lactation by re-injection of rAAV into a previously injected mouse gland. PMID:26463440

  11. Adeno-associated virus-mediated expression of β-hexosaminidase prevents neuronal loss in the Sandhoff mouse brain.

    PubMed

    Sargeant, Timothy J; Wang, Susan; Bradley, Josephine; Smith, Nicolas J C; Raha, Animesh A; McNair, Rosamund; Ziegler, Robin J; Cheng, Seng H; Cox, Timothy M; Cachón-González, Maria Begoña

    2011-11-15

    Sandhoff disease, a GM2 gangliosidosis caused by a deficiency in β-hexosaminidase, is characterized by progressive neurodegeneration. Although loss of neurons in association with lysosomal storage of glycosphingolipids occurs in patients with this disease, the molecular pathways that lead to the accompanying neurological defects are unclear. Using an authentic murine model of GM2 gangliosidosis, we examined the pattern of neuronal loss in the central nervous system and investigated the effects of gene transfer using recombinant adeno-associated viral vectors expressing β-hexosaminidase subunits (rAAV2/1-Hex). In 4-month-old Sandhoff mice with neurological deficits, cells staining positively for the apoptotic signature in the TUNEL reaction were found in the ventroposterior medial and ventroposterior lateral (VPM/VPL) nuclei of the thalamus. There was progressive loss of neuronal density in this region with age. Comparable loss of neuronal density was identified in the lateral vestibular nucleus of the brainstem and a small but statistically significant loss was present in the ventral spinal cord. Loss of neurons was not detected in other regions that were analysed. Administration of rAAV2/1-Hex into the brain of Sandhoff mice prevented the decline in neuronal density in the VPM/VPL. Preservation of neurons in the VPM/VPL was variable at the humane endpoint in treated animals, but correlated directly with increased lifespan. Loss of neurons was localized to only a few regions in the Sandhoff brain and was prevented by rAAV-mediated transfer of β-hexosaminidase gene function at considerable distances from the site of vector administration. PMID:21852247

  12. Adeno-Associated Virus-Mediated Correction of a Canine Model of Glycogen Storage Disease Type Ia

    PubMed Central

    Weinstein, David A.; Correia, Catherine E.; Conlon, Thomas; Specht, Andrew; Verstegen, John; Onclin-Verstegen, Karine; Campbell-Thompson, Martha; Dhaliwal, Gurmeet; Mirian, Layla; Cossette, Holly; Falk, Darin J.; Germain, Sean; Clement, Nathalie; Porvasnik, Stacy; Fiske, Laurie; Struck, Maggie; Ramirez, Harvey E.; Jordan, Juan; Andrutis, Karl; Chou, Janice Y.; Byrne, Barry J.

    2010-01-01

    Abstract Glycogen storage disease type Ia (GSDIa; von Gierke disease; MIM 232200) is caused by a deficiency in glucose-6-phosphatase-α. Patients with GSDIa are unable to maintain glucose homeostasis and suffer from severe hypoglycemia, hepatomegaly, hyperlipidemia, hyperuricemia, and lactic acidosis. The canine model of GSDIa is naturally occurring and recapitulates almost all aspects of the human form of disease. We investigated the potential of recombinant adeno-associated virus (rAAV) vector-based therapy to treat the canine model of GSDIa. After delivery of a therapeutic rAAV2/8 vector to a 1-day-old GSDIa dog, improvement was noted as early as 2 weeks posttreatment. Correction was transient, however, and by 2 months posttreatment the rAAV2/8-treated dog could no longer sustain normal blood glucose levels after 1 hr of fasting. The same animal was then dosed with a therapeutic rAAV2/1 vector delivered via the portal vein. Two months after rAAV2/1 dosing, both blood glucose and lactate levels were normal at 4 hr postfasting. With more prolonged fasting, the dog still maintained near-normal glucose concentrations, but lactate levels were elevated by 9 hr, indicating that partial correction was achieved. Dietary glucose supplementation was discontinued starting 1 month after rAAV2/1 delivery and the dog continues to thrive with minimal laboratory abnormalities at 23 months of age (18 months after rAAV2/1 treatment). These results demonstrate that delivery of rAAV vectors can mediate significant correction of the GSDIa phenotype and that gene transfer may be a promising alternative therapy for this disease and other genetic diseases of the liver. PMID:20163245

  13. MicroRNA-19b-3p Modulates Japanese Encephalitis Virus-Mediated Inflammation via Targeting RNF11

    PubMed Central

    Ashraf, Usama; Zhu, Bibo; Ye, Jing; Wan, Shengfeng; Nie, Yanru; Chen, Zheng; Cui, Min; Wang, Chong; Duan, Xiaodong; Zhang, Hao; Chen, Huanchun

    2016-01-01

    ABSTRACT Japanese encephalitis virus (JEV) can invade the central nervous system and consequently induce neuroinflammation, which is characterized by profound neuronal cell damage accompanied by astrogliosis and microgliosis. Albeit microRNAs (miRNAs) have emerged as major regulatory noncoding RNAs with profound effects on inflammatory response, it is unknown how astrocytic miRNAs regulate JEV-induced inflammation. Here, we found the involvement of miR-19b-3p in regulating the JEV-induced inflammatory response in vitro and in vivo. The data demonstrated that miR-19b-3p is upregulated in cultured cells and mouse brain tissues during JEV infection. Overexpression of miR-19b-3p led to increased production of inflammatory cytokines, including tumor necrosis factor alpha, interleukin-6, interleukin-1β, and chemokine (C-C motif) ligand 5, after JEV infection, whereas knockdown of miR-19b-3p had completely opposite effects. Mechanistically, miR-19b-3p modulated the JEV-induced inflammatory response via targeting ring finger protein 11, a negative regulator of nuclear factor kappa B signaling. We also found that inhibition of ring finger protein 11 by miR-19b-3p resulted in accumulation of nuclear factor kappa B in the nucleus, which in turn led to higher production of inflammatory cytokines. In vivo silencing of miR-19b-3p by a specific antagomir reinvigorates the expression level of RNF11, which in turn reduces the production of inflammatory cytokines, abrogates gliosis and neuronal cell death, and eventually improves the survival rate in the mouse model. Collectively, our results demonstrate that miR-19b-3p positively regulates the JEV-induced inflammatory response. Thus, miR-19b-3p targeting may constitute a thought-provoking approach to rein in JEV-induced inflammation. IMPORTANCE Japanese encephalitis virus (JEV) is one of the major causes of acute encephalitis in humans worldwide. The pathological features of JEV-induced encephalitis are inflammatory reactions and

  14. Oral Manifestations and Dental Management of Epidermolysis Bullosa Simplex.

    PubMed

    Scheidt, Lisa; Sanabe, Mariane Emi; Diniz, Michele Baffi

    2015-01-01

    Epidermolysis bullosa (EB) is a group of hereditary chronic disorders, characterized by fragility of the skin and mucous membranes in response to minor mechanical trauma. The objective of this study was to report the case of a young girl diagnosed with epidermolysis bullosa simplex (EBS), transmitted by an autosomal dominant gene. Cutaneous findings included blisters and dystrophy following minimal friction. Recurrent blisters and vesicle formation on the hard palate were the main oral findings. In conclusion, publications concerning the oral and clinical manifestations of EBS are important for providing knowledge and an early multidisciplinary approach that prevents blister formation and improves these patients' quality of life, with the dentist playing an important role in oral health management. How to cite this article: Scheidt L, Sanabe ME, Diniz MB. Oral Manifestations and Dental Management of Epidermolysis Bullosa Simplex. Int J Clin Pediatr Dent 2015;8(3):239-241. PMID:26604545

  15. Herpes simplex encephalitis in a domestic rabbit (Oryctolagus cuniculus).

    PubMed

    Grest, P; Albicker, P; Hoelzle, L; Wild, P; Pospischil, A

    2002-05-01

    An adult domestic rabbit showing neurological signs was subjected to euthanasia. At necropsy, macroscopical lesions were absent. Histopathologically, extensive lesions were seen, particularly in the cerebral cortex. Non-suppurative meningitis was present and there was lymphocytic and plasmacytic perivascular cuffing in the neuropil. The cerebral cortex showed extensive segmental neuronal and glial necrosis. Within the necrotic areas, large amphophilic intranuclear inclusion bodies were present in neurons and glial cells. Immunohistochemically, neurons and glial cells in the affected areas were labelled by polyclonal antibodies against both herpes simplex virus-1 (HSV-1) and HSV-2. The agent was classified as HSV-1 by polymerase chain reaction analysis. This is only the second reported natural case of herpes simplex infection in a rabbit. PMID:12056779

  16. Oral Manifestations and Dental Management of Epidermolysis Bullosa Simplex

    PubMed Central

    Scheidt, Lisa; Sanabe, Mariane Emi

    2015-01-01

    ABSTRACT Epidermolysis bullosa (EB) is a group of hereditary chronic disorders, characterized by fragility of the skin and mucous membranes in response to minor mechanical trauma. The objective of this study was to report the case of a young girl diagnosed with epidermolysis bullosa simplex (EBS), transmitted by an autosomal dominant gene. Cutaneous findings included blisters and dystrophy following minimal friction. Recurrent blisters and vesicle formation on the hard palate were the main oral findings. In conclusion, publications concerning the oral and clinical manifestations of EBS are important for providing knowledge and an early multidisciplinary approach that prevents blister formation and improves these patients’ quality of life, with the dentist playing an important role in oral health management. How to cite this article: Scheidt L, Sanabe ME, Diniz MB. Oral Manifestations and Dental Management of Epidermolysis Bullosa Simplex. Int J Clin Pediatr Dent 2015;8(3):239-241. PMID:26604545

  17. Burning mouth syndrome due to herpes simplex virus type 1.

    PubMed

    Nagel, Maria A; Choe, Alexander; Traktinskiy, Igor; Gilden, Don

    2015-01-01

    Burning mouth syndrome is characterised by chronic orofacial burning pain. No dental or medical cause has been found. We present a case of burning mouth syndrome of 6 months duration in a healthy 65-year-old woman, which was associated with high copy numbers of herpes simplex virus type 1 (HSV-1) DNA in the saliva. Her pain resolved completely after antiviral treatment with a corresponding absence of salivary HSV-1 DNA 4 weeks and 6 months later. PMID:25833911

  18. The Broader Autism Phenotype in Simplex and Multiplex Families

    ERIC Educational Resources Information Center

    Gerdts, Jennifer A.; Bernier, Raphael; Dawson, Geraldine; Estes, Annette

    2013-01-01

    Mothers, fathers, and siblings from 87 multiplex (M-mothers, M-fathers, and M-siblings) and 41 simplex (S-mothers, S-fathers, and S-siblings) Autism spectrum disorder families were assessed using the Broader Phenotype Autism Symptom Scale. S-mothers, S-fathers, and S-siblings showed more social interest and were more expressive in their use of…

  19. Herpes simplex virus infects most cell types in vitro: clues to its success

    PubMed Central

    2011-01-01

    Herpes simplex virus (HSV) type-1 and type-2 have evolved numerous strategies to infect a wide range of hosts and cell types. The result is a very successful prevalence of the virus in the human population infecting 40-80% of people worldwide. HSV entry into host cell is a multistep process that involves the interaction of the viral glycoproteins with various cell surface receptors. Based on the cell type, HSV enter into host cell using different modes of entry. The combination of various receptors and entry modes has resulted in a virus that is capable of infecting virtually all cell types. Identifying the common rate limiting steps of the infection may help the development of antiviral agents that are capable of preventing the virus entry into host cell. In this review we describe the major features of HSV entry that have contributed to the wide susceptibility of cells to HSV infection. PMID:22029482

  20. The effect of cyclin-dependent kinases inhibitor treatment on experimental herpes simplex encephalitis mice.

    PubMed

    Zhou, Yu; Zeng, Yan-Ping; Zhou, Qin; Guan, Jing-Xia; Lu, Zu-Neng

    2016-08-01

    Herpes simplex encephalitis(HSE) is the most common and serious viral encephalitis in humans. There is a lack of effective medication to date for HSE. A better understanding of the mediators of tissue damage is essential for finding new targets for therapeutic intervention. In this project, we explored the effect of cyclin-dependent kinases inhibitor olomoucine treatment on experimental HSE mice. The following results were obtained: (1) olomoucine increased survival in HSE mice; (2) olomoucine inhibited microglial activation and reduced HSV-1-induced cytokines release; (3) olomoucine prevented neural cells apoptosis and attenuated brain tissue pathological changes following HSV-1 infection; (4) olomoucine reduced brain edema and improved neurological function in HSE. Overall, olomoucine can induce a blunted inflammatory response, maintain the blood vessel wall intact, improve neurological function and increase survival in HSE mice. PMID:27241721

  1. Understanding natural herpes simplex virus immunity to inform next-generation vaccine design

    PubMed Central

    Sandgren, Kerrie J; Bertram, Kirstie; Cunningham, Anthony L

    2016-01-01

    Incremental advances in our knowledge of how natural immune control of herpes simplex virus (HSV) develops have yielded insight as to why previous vaccine attempts have only been partially successful, however, our understanding of these pathways, particularly in humans, is still incomplete. Further elucidation of the innate immune events that are responsible for stimulating these effector responses is required to accurately inform vaccine design. An enhanced understanding of the mechanism of action of novel adjuvants will also facilitate the rational choice of adjuvant to optimise such responses. Here we review the reasons for the hitherto partial HSV vaccine success and align these with our current knowledge of how natural HSV immunity develops. In particular, we focus on the innate immune response and the role of dendritic cells in inducing protective T-cell responses and how these pathways might be recapitulated in a vaccine setting. PMID:27525067

  2. Polyhydroxylated sulfated steroids derived from 5α-cholestanes as antiviral agents against herpes simplex virus.

    PubMed

    Pujol, Carlos A; Sepúlveda, Claudia S; Richmond, Victoria; Maier, Marta S; Damonte, Elsa B

    2016-07-01

    Twelve polyhydroxylated sulfated steroids synthesized from a 5α-cholestane skeleton with different substitutions in C-2, C-3 and C-6 were evaluated for cytotoxicity and antiviral activity against herpes simplex virus (HSV) by a virus plaque reduction assay. Four compounds elicited a selective inhibitory effect against HSV. The disodium salt of 2β,3α-dihydroxy-6E-hydroximine-5α-cholestane-2,3-disulfate, named compound 7, was the most effective inhibitor of HSV-1, HSV-2 and pseudorabies virus (PrV) strains, including acyclovir-resistant variants, in human and monkey cell lines. Preliminary mechanistic studies demonstrated that compound 7 did not affect the initial steps of virus entry but inhibited a subsequent event in the infection process of HSV. PMID:27101075

  3. Abnormal organization of keratin intermediate filaments in cultured keratinocytes of epidermolysis bullosa simplex.

    PubMed

    Kitajima, Y; Inoue, S; Yaoita, H

    1989-01-01

    Distinctive abnormality in the organization of keratin intermediate filaments (KIFs) was found for the first time in cultured epidermal keratinocytes from two patients with hereditary epidermolysis bullosa simplex (EBS), which showed cleavages above the basement membrane zone due to the fragility of basal cells. KIFs in EBS keratinocytes revealed an irregular radial arrangement composed of sparse but thick KIF bundles. Furthermore, these KIF bundles in many cells changed into numerous ball-like keratin aggregates and disappeared beyond these keratin aggregates in the peripheral cytoplasm. Electron microscopy of cultured EBS keratinocytes showed that many ball-like structures consisting of fine filaments or granules or homogeneous substances were scattered in the peripheral regions of the cell attaching to the dish, and intermediate filaments appeared to be emanating from or surrounding the structures. These ball-like keratin aggregates have never been observed in normal human keratinocytes. PMID:2471468

  4. MOTIVATION INTERNALIZATION AND SIMPLEX STRUCTURE IN SELF-DETERMINATION THEORY.

    PubMed

    Ünlü, Ali; Dettweiler, Ulrich

    2015-12-01

    Self-determination theory, as proposed by Deci and Ryan, postulated different types of motivation regulation. As to the introjected and identified regulation of extrinsic motivation, their internalizations were described as "somewhat external" and "somewhat internal" and remained undetermined in the theory. This paper introduces a constrained regression analysis that allows these vaguely expressed motivations to be estimated in an "optimal" manner, in any given empirical context. The approach was even generalized and applied for simplex structure analysis in self-determination theory. The technique was exemplified with an empirical study comparing science teaching in a classical school class versus an expeditionary outdoor program. Based on a sample of 84 German pupils (43 girls, 41 boys, 10 to 12 years old), data were collected using the German version of the Academic Self-Regulation Questionnaire. The science-teaching format was seen to not influence the pupils' internalization of identified regulation. The internalization of introjected regulation differed and shifted more toward the external pole in the outdoor teaching format. The quantification approach supported the simplex structure of self-determination theory, whereas correlations may disconfirm the simplex structure. PMID:26595290

  5. MONSS: A multi-objective nonlinear simplex search approach

    NASA Astrophysics Data System (ADS)

    Zapotecas-Martínez, Saúl; Coello Coello, Carlos A.

    2016-01-01

    This article presents a novel methodology for dealing with continuous box-constrained multi-objective optimization problems (MOPs). The proposed algorithm adopts a nonlinear simplex search scheme in order to obtain multiple elements of the Pareto optimal set. The search is directed by a well-distributed set of weight vectors, each of which defines a scalarization problem that is solved by deforming a simplex according to the movements described by Nelder and Mead's method. Considering an MOP with n decision variables, the simplex is constructed using n+1 solutions which minimize different scalarization problems defined by n+1 neighbor weight vectors. All solutions found in the search are used to update a set of solutions considered to be the minima for each separate problem. In this way, the proposed algorithm collectively obtains multiple trade-offs among the different conflicting objectives, while maintaining a proper representation of the Pareto optimal front. In this article, it is shown that a well-designed strategy using just mathematical programming techniques can be competitive with respect to the state-of-the-art multi-objective evolutionary algorithms against which it was compared.

  6. Reactivation of herpes simplex virus-1 following epilepsy surgery☆

    PubMed Central

    de Almeida, Sérgio Monteiro; Crippa, Ana; Cruz, Cristina; de Paola, Luciano; de Souza, Luciana Paula; Noronha, Lucia; Torres, Luis Fernando Bleggi; Koneski, Julio A.S.; Pessa, Luis Felipe Cavalli; Nogueira, Meri Bordignon; Raboni, Sonia Mara; Silvado, Carlos Eduardo; Vidal, Luine Rosele

    2015-01-01

    Purpose The present study reports a case of encephalitis due to herpes simplex virus-1 (HSV-1), following surgical manipulation of the site of a primary infection. Methods Herpes simplex virus-1 infection was confirmed by CSF PCR and DNA sequencing. Results The patient was an 11-year-old girl who required temporal lobe surgery for epilepsy. She had meningoencephalitis due to HSV at the age of 20 months, and she was treated with acyclovir. Three years later, the patient developed uncontrolled seizures that became more frequent and changed in character at 11 years of age. On the 12th postoperative day, she developed fever and seizures, and she was diagnosed with HSV-1 by positive CSF PCR. She was treated with acyclovir (30 mg/kg/day for 21 days). In this report, we describe the patient and review the relevant literature. Conclusion The authors stress the potential risk of reactivation of HSV encephalitis after intracranial surgery. Herpes simplex virus encephalitis must be considered in neurosurgical patients who develop postoperative seizures and fever. PMID:26543809

  7. Analysis of Cortical Shape in Children with Simplex Autism

    PubMed Central

    Dierker, Donna L.; Feczko, Eric; Pruett, John R.; Petersen, Steven E.; Schlaggar, Bradley L.; Constantino, John N.; Harwell, John W.; Coalson, Timothy S.; Van Essen, David C.

    2015-01-01

    We used surface-based morphometry to test for differences in cortical shape between children with simplex autism (n = 34, mean age 11.4 years) and typical children (n = 32, mean age 11.3 years). This entailed testing for group differences in sulcal depth and in 3D coordinates after registering cortical midthickness surfaces to an atlas target using 2 independent registration methods. We identified bilateral differences in sulcal depth in restricted portions of the anterior-insula and frontal-operculum (aI/fO) and in the temporoparietal junction (TPJ). The aI/fO depth differences are associated with and likely to be caused by a shape difference in the inferior frontal gyrus in children with simplex autism. Comparisons of average midthickness surfaces of children with simplex autism and those of typical children suggest that the significant sulcal depth differences represent local peaks in a larger pattern of regional differences that are below statistical significance when using coordinate-based analysis methods. Cortical regions that are statistically significant before correction for multiple measures are peaks of more extended, albeit subtle regional differences that may guide hypothesis generation for studies using other imaging modalities. PMID:24165833

  8. Down-RANKing the Threat of HSV-1: RANKL Upregulates MHC-Class-I-Restricted Anti-Viral Immunity in Herpes Simplex Virus Infection.

    PubMed

    Finsterbusch, Katja; Piguet, Vincent

    2015-11-01

    Herpes simplex virus (HSV-1) is a major cause of viral skin infection in humans. Klenner and colleagues now show that the epidermal receptor activator of NFκB ligand (RANKL) is critical for the induction of anti-viral CD8(+) effector T cells (CTL) during cutaneous HSV-1 infection. Activation via RANKL prevents Langerhans cell apoptosis, thus leading to enhanced antigen transport to regional lymph nodes, increasing the CTL-priming capacity of lymph node dendritic cells. PMID:26548487

  9. Anti-inflammatory and anti-proliferative activities of the wild edible cruciferous: Diplotaxis simplex.

    PubMed

    Jdir, Hamida; Khemakham, Bassem; Najjaa, Hanen; Chakroun, Mouna; Jridi, Mourad; Ben Arfa, Abdelkarim; Ben Ali, Yassine; Zouari, Nacim

    2016-10-01

    Context The present study deals with new biological properties of the wild edible Diplotaxis simplex (Viv.) Spreng (Brassicaceae). Objectives The current study evaluates the antioxidant, the anti-inflammatory and the anti-cancer properties of ethyl acetate and ethanol extracts from D. simplex flowers. Materials and methods The anti-proliferative activity of the extracts (10-70 μg/mL) was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) against human colon cancer cell line Caco-2. The anti-inflammatory potential was evaluated by the inhibitory effect of the extracts (1.5-7.5 mg/mL) on phospholipase A2 activity as well as on carrageenan-induced paw oedema in mice. Extracts (200 mg/kg) or indomethacin (50 mg/kg) as positive control were injected intraperitoneally for albino mice prior to the induction of the oedema by carrageenan. Antioxidant activities were investigated using various complementary methods. Results Flower extracts contained a high level of polyphenolics (17.10-52.70 mg GAE/g) and flavonoids (74.20-100.60 mg QE/g), which correlate with its appreciable antioxidant potential in β-carotene peroxidation (IC50 value: 12.50-27.10 μg/mL), DPPH(•) radical-scavenging (IC50 value: 0.20-0.40 mg/mL), Fe(3+ )reducing (EC50 value: 0.10-0.14 mg/mL) and Fe(2+ )chelating (IC50 value: 0.20-0.60 mg/mL) assays. These extracts were effective in inhibiting cancer cell growth (IC50 value: 62.0-63.25 μg/mL). Besides, the ethyl acetate extract inhibited phospholipase A2 activity (IC50 value: 2.97 mg/mL) and reduced the paw oedema in mice (from 0.38 ± 0.01 to 0.24 ± 0.01 cm), 4 h post-carrageenan challenge. Conclusion These data suggest that D. simplex may be useful as a candidate in the treatment of inflammation and the colon cancer. PMID:26916801

  10. JPLEX: Java Simplex Implementation with Branch-and-Bound Search for Automated Test Assembly

    ERIC Educational Resources Information Center

    Park, Ryoungsun; Kim, Jiseon; Dodd, Barbara G.; Chung, Hyewon

    2011-01-01

    JPLEX, short for Java simPLEX, is an automated test assembly (ATA) program. It is a mixed integer linear programming (MILP) solver written in Java. It reads in a configuration file, solves the minimization problem, and produces an output file for postprocessing. It implements the simplex algorithm to create a fully relaxed solution and…

  11. [Role of herpes simplex virus in the development of exudative erythema multiforme].

    PubMed

    Samgin, M A; Ivanov, O L; Kuzheleva, S A; Biriukov, A V; L'vov, N D

    1990-03-01

    The paper presents analysis of current knowledge on etiology and immunopathogenesis of multiform exudative erythema (MEE). Among a variety of pathogenetic actions of herpes simplex on immune system are those relevant to MEE onset. These variants are dealt with in detail. The view on MEE as resultant from herpes simplex infection promises appearance of new prospective modes of etiotropic therapy. PMID:2370760

  12. The Dynamics of HCF-1 Modulation of Herpes Simplex Virus Chromatin during Initiation of Infection

    PubMed Central

    Vogel, Jodi L.; Kristie, Thomas M.

    2013-01-01

    Successful infection of herpes simplex virus is dependent upon chromatin modulation by the cellular coactivator host cell factor-1 (HCF-1). This review focuses on the multiple chromatin modulation components associated with HCF-1 and the chromatin-related dynamics mediated by this coactivator that lead to the initiation of herpes simplex virus (HSV) immediate early gene expression. PMID:23698399

  13. Simplex GPS and InSAR Inversion Software

    NASA Technical Reports Server (NTRS)

    Donnellan, Andrea; Parker, Jay W.; Lyzenga, Gregory A.; Pierce, Marlon E.

    2012-01-01

    Changes in the shape of the Earth's surface can be routinely measured with precisions better than centimeters. Processes below the surface often drive these changes and as a result, investigators require models with inversion methods to characterize the sources. Simplex inverts any combination of GPS (global positioning system), UAVSAR (uninhabited aerial vehicle synthetic aperture radar), and InSAR (interferometric synthetic aperture radar) data simultaneously for elastic response from fault and fluid motions. It can be used to solve for multiple faults and parameters, all of which can be specified or allowed to vary. The software can be used to study long-term tectonic motions and the faults responsible for those motions, or can be used to invert for co-seismic slip from earthquakes. Solutions involving estimation of fault motion and changes in fluid reservoirs such as magma or water are possible. Any arbitrary number of faults or parameters can be considered. Simplex specifically solves for any of location, geometry, fault slip, and expansion/contraction of a single or multiple faults. It inverts GPS and InSAR data for elastic dislocations in a half-space. Slip parameters include strike slip, dip slip, and tensile dislocations. It includes a map interface for both setting up the models and viewing the results. Results, including faults, and observed, computed, and residual displacements, are output in text format, a map interface, and can be exported to KML. The software interfaces with the QuakeTables database allowing a user to select existing fault parameters or data. Simplex can be accessed through the QuakeSim portal graphical user interface or run from a UNIX command line.

  14. Linearized dynamics from the 4-simplex Regge action

    SciTech Connect

    Dittrich, Bianca; Freidel, Laurent; Speziale, Simone

    2007-11-15

    We study the relation between the Hessian matrix of the Riemannian Regge action on a 4-simplex and linearized quantum gravity. We give an explicit formula for the Hessian as a function of the geometry, and show that it has a single zero mode. We then use a 3D lattice model to show that (i) the zero mode is a remnant of the continuum diffeomorphism invariance, and (ii) we recover the complete free graviton propagator in the continuum limit. The results help clarify the structure of the boundary state needed in the recent calculations of the graviton propagator in loop quantum gravity, and, in particular, its role in fixing the gauge.

  15. Herpes Simplex Virus Oncolytic Therapy for Pediatric Malignancies

    PubMed Central

    Friedman, Gregory K; Pressey, Joseph G; Reddy, Alyssa T; Markert, James M; Gillespie, G Yancey

    2009-01-01

    Despite improving survival rates for children with cancer, a subset of patients exist with disease resistant to traditional therapies such as surgery, chemotherapy, and radiation. These patients require newer, targeted treatments used alone or in combination with more traditional approaches. Oncolytic herpes simplex virus (HSV) is one of these newer therapies that offer promise for several difficult to treat pediatric malignancies. The potential benefit of HSV therapy in pediatric solid tumors including brain tumors, neuroblastomas, and sarcomas is reviewed along with the many challenges that need to be addressed prior to moving oncolytic HSV therapy from the laboratory to the beside in the pediatric population. PMID:19367259

  16. Herpes simplex virus hepatitis 4 years after liver transplantation.

    PubMed

    Bissig, Karl-Dimiter; Zimmermann, Arthur; Bernasch, Dirke; Furrer, Hansjakob; Dufour, Jean-FranCois

    2003-01-01

    If not promptly recognized and treated, herpes simplex virus (HSV) hepatitis is associated with a high mortality. A patient transplanted for primary sclerosing cholangitis required, 4 years later, a colectomy for a steroid-resistant flare of ulcerative colitis. He subsequently developed fever, with genital and oral ulcerations. He was hospitalized for diabetic decompensation with massive elevation of serum aminotransferases. Examination revealed vesicles on the hands. Liver biopsy showed Cowdry type B inclusions. Therapy with acyclovir was immediately initiated and the patient recovered. This case illustrates the diagnostic importance of mucocutaneous lesions in the assessment of complications after liver transplantation. PMID:14614611

  17. Lichen Simplex Chronicus That Accompanies Anogenital Warts during the Childhood.

    PubMed

    Seçilmiş Kerimoğlu, Ozlem; Doğan, Nasuh Utku; Tazegül, Aybike; Karameşe, Mehtap; Beyhekim, Hasan; Celik, Cetin

    2012-01-01

    Anogenital warts and lichen simplex chronicus (LSC) are rarely seen during the childhood. A 9-year-old girl has been presented to hospital by her parents with itching in the anogenital area. There were anogenital warts and a different erythematous lesion in the perianal region. On the pulpa of the right thumb, there was a wart extending under the nail. The lesions are surgically removed. The results of the histopathological examination were reported as condyloma acuminata and LSC. Children with anogenital warts should be examined carefully to discover the transmission route and other possible concomitant cutaneous diseases. PMID:23118760

  18. Lichen Simplex Chronicus That Accompanies Anogenital Warts during the Childhood

    PubMed Central

    Seçilmiş Kerimoğlu, Özlem; Doğan, Nasuh Utku; Tazegül, Aybike; Karameşe, Mehtap; Beyhekim, Hasan; Çelik, Çetin

    2012-01-01

    Anogenital warts and lichen simplex chronicus (LSC) are rarely seen during the childhood. A 9-year-old girl has been presented to hospital by her parents with itching in the anogenital area. There were anogenital warts and a different erythematous lesion in the perianal region. On the pulpa of the right thumb, there was a wart extending under the nail. The lesions are surgically removed. The results of the histopathological examination were reported as condyloma acuminata and LSC. Children with anogenital warts should be examined carefully to discover the transmission route and other possible concomitant cutaneous diseases. PMID:23118760

  19. Delivery of herpes simplex virus-based vectors to stem cells.

    PubMed

    Wolfe, Darren; Wechuck, James B; Krisky, David M; Goff, Julie P; Goins, William F; Ozuer, Ali; Epperly, Michael E; Greenberger, Joel S; Fink, David J; Glorioso, Joseph C

    2004-01-01

    In contrast to traditional drugs that generally act by altering existing gene product function, gene therapy aims to target the root cause of the disease by altering the genetic makeup of the cell to treat the disease. Researchers have adapted several classes of viruses as gene-transfer vectors, taking advantage of natural viral mechanisms designed to efficiently and effectively deliver DNA to the host-cell nucleus. Among these, the human herpesviruses are excellent candidate vectors for a variety of applications. Herpes simplex virus type 1 (HSV-1) is a particularly attractive gene-transfer vehicle because natural infection in humans includes a latent state in which the viral genome persists in a nonintegrated form without causing disease in an immune-competent host. HSV-1 is a large DNA virus with a broad host range that can be engineered to accommodate multiple or large therapeutic transgenes (4). HSV vectors may be generally useful for gene transfer to a variety of tissues in which short-term or extended transgene expression of therapeutic transgenes achieve a therapeutic effect. We have used therapeutic vectors to successfully treat human disease models in animals, including cancer, Parkinson's disease, and nerve damage (5-10). PMID:14970603

  20. Intracerebral propagation of Alzheimer's disease: strengthening evidence of a herpes simplex virus etiology

    PubMed Central

    Ball, Melvyn J.; Lukiw, Walter J.; Kammerman, Eli M.; Hill, James M.

    2012-01-01

    Background A faulty human protein, abnormally phosphorylated tau, was recently publicized to spread “like a virus” from neuron to neuron in Alzheimer patients' brains. For several decades, we have been amassing arguments showing that herpes simplex virus type 1 (HSV-1), not p-tau, propagates this inter-neuronal, trans-synaptic pathological cascade. Methods We reiterate convincing data from our own (and other) laboratories, reviewing the first anatomic foothold neurofibrillary tangles gain in brainstem and/or entorhinal cortex; the chronic immunosurveillance cellularity of the trigeminal ganglia wherein HSV-1 awakens from latency to reactivate; the inabilities of p-tau protein's physical properties to promote it to jump synapses; the amino-acid homology between human p-tau and VP22, a key target for phosphorylation by HSV serine/threonine-protein kinase UL13; and the exosomic secretion of HSV-1-infected cells' L-particles, attesting to the cell-to-cell passage of microRNAs of herpes viruses. Results The now-maturing construct that reactivated HSV-1 best accounts for the intracerebral propagation of AD changes in the human brain should at last seem highly attractive. This hypothesis might even explain statins' apparent mechanism in some studies for lowering AD incidence. Conclusion Provided that funding agencies will quickly ignite a new realm of investigation, the rejuvenated enthusiasm for testing this optimistic construct holds incalculable potential for rapid, efficacious clinical application, through already available and relatively safe anti-viral therapeutics. PMID:23159044

  1. Herpes simplex virus colitis complicating ulcerative colitis: A case report and brief review on superinfections.

    PubMed

    Schunter, Marco Oliver; Walles, Thorsten; Fritz, Peter; Meyding-Lamadé, Uta; Thon, Klaus-Peter; Fellermann, Klaus; Stange, Eduard Friedrich; Lamadé, Wolfram

    2007-09-01

    In patients with inflammatory bowel disease herpes simplex virus infection has been described as a major cause of morbidity and mortality, especially in immunocompromised individuals. Here we present the case of a 35-year old woman with an exacerbation of ulcerative colitis caused by herlpes simplex virus infection (HSV-2). The diagnosis was confirmed histologically following subtotal colectomy. After intravenous treatment with aciclovir for 2 weeks postoperative hematochezia stopped. Herpes simplex virus colitis is a rare but potentially fatal complication of immunosuppressive treatment in patients with inflammatory bowel disease. Prompt diagnosis and efficient antiviral therapy are mandatory to improve prognosis. PMID:21172183

  2. Clinical and biological differences between recurrent herpes simplex virus and varicella-zoster virus infections

    SciTech Connect

    Straus, S.E. )

    1989-12-01

    The major features that distinguish recurrent herpes simplex virus infections from zoster are illustrated in this article by two case histories. The clinical and epidemiologic features that characterize recurrent herpes simplex virus and varicella-zoster virus infections are reviewed. It is noted that herpesvirus infections are more common and severe in patients with cellular immune deficiency. Each virus evokes both humoral and cellular immune response in the course of primary infection. DNA hybridization studies with RNA probes labelled with sulfur-35 indicate that herpes simplex viruses persist within neurons, and that varicella-zoster virus is found in the satellite cells that encircle the neurons.

  3. Isolation of a protein kinase induced by herpes simplex virus type 1

    SciTech Connect

    Blue, W.T.; Stobbs, D.G.

    1981-04-01

    Researchers have isolated a new cyclic AMP-independent protein kinase activity induced in HeLa cells by infection with herpes simplex virus type 1. Induction of the enzyme does not occur in cells treated with cycloheximide at the time of infection, or in cells infected with UV-inactivated herpes simplex virus type 1. The amount of enzyme induced in infected cells is dependent upon the multiplicity of infection. An enzyme with identical properties to the appearing in infected HeLa cells is also induced by herpes simplex virus type 1 in BHK cells.

  4. The Immune Response to Herpes Simplex Virus Encephalitis in Mice Is Modulated by Dietary Vitamin E12

    PubMed Central

    Sheridan, Patricia A.; Beck, Melinda A.

    2008-01-01

    Herpes simplex virus encephalitis (HSE) is the most common fatal sporadic encephalitis in humans. HSE is primarily caused by herpes simplex virus (HSV)-1 infection of the brain. HSE results in increased levels of oxidative stress, including the production of reactive oxygen species, free radicals, and neuroinflammation. The most biologically active form of vitamin E (VE) is α-tocopherol (α-TOC). In cellular membranes, α-TOC prevents lipid peroxidation by scavenging free radicals and functioning as an antioxidant. Supplementation with VE has been shown to decrease immunosenescence, improve immune function, and may be neuroprotective. To determine how VE deficiency and VE supplementation would alter the pathogenesis of HSE, we placed weanling male BALB/cByJ mice on VE-deficient (VE-D), VE-adequate (VE-A), or 10× VE-supplemented diets for 4 wk, and then infected the mice intranasally with HSV-1. VE-D mice had more severe symptoms of encephalitis than VE-A mice, including weight loss, keratitis, hunched posture, and morbidity. VE-D mice had increased cytokine and chemokine expression in the brain and increased viral titers. In contrast, VE supplementation failed to decrease cytokine production and had no effect on viral titer. We demonstrated that adequate levels of VE are important in limiting HSE pathology and that 10× supplementation does not enhance protection. PMID:18156415

  5. In vitro assessment of the cell-mediated immune response to herpes simplex virus in man

    SciTech Connect

    Clouse, K.A.B.

    1986-01-01

    These studies demonstrated that human peripheral blood mononuclear cells (PBMC) from individuals sensitized to herpes simplex virus type 1 (HSV-1) were capable of producing interleukin 2 (IL 2) following in vitro stimulation with HSV antigen. IL 2 activity was detected by the direct addition of the murine IL 2-dependent cell line, CTLL-20, to ..gamma..-irradiated cultures of HSV-1 antigen-stimulated PBMC. It was found that PBMC from sensitized individuals produced IL 2 in a dose-dependent manner after in vitro stimulation with HSV antigen. Furthermore, IL 2 production in response to viral antigen correlated with viral antigen-induced proliferation of PBMC. It was also shown that contact with HSV-1 antigen induced the expression of IL 2 receptors on a small percentage of human PBMC. While this suggested that IL 2 receptor expression was associated with viral antigen-induced proliferation responses, the level of induced IL 2 receptor expression remained close to the lower limit of detectability for cytofluorographic analysis. Experiments to elucidate the role of the macrophage (MO) in the response to viral antigen revealed that HSV antigen-induced IL 2 production by sensitized T lymphocytes was dependent on the presence of an accessory MO. To investigate the signals provided to T lymphocytes by accessory cells, MOs were pulsed with HSV antigen and treated with paraformaldehyde. This allowed HSV antigen display, but prevented monokine (IL 1) secretion. The treated MOs could no longer induce sensitized lymphocytes to produce IL 2.

  6. Transient fasting enhances replication of oncolytic herpes simplex virus in glioblastoma.

    PubMed

    Esaki, Shinichi; Rabkin, Samuel D; Martuza, Robert L; Wakimoto, Hiroaki

    2016-01-01

    Short-term nutritional restriction (fasting) has been shown to enhance the efficacy of chemotherapy by sensitizing cancer cells and protecting normal cells in a variety of cancer models, including glioblastoma (GBM). Cancer cells, unlike normal cells, respond to fasting by promoting oncogenic signaling and protein synthesis. We hypothesized that fasting would increase the replication of oncolytic herpes simplex virus (oHSV) in GBM. Patient-derived GBM cell lines were fasted by growth in glucose and fetal calf serum restricted culture medium. "Transient fasting", 24-hour fasting followed by 24-hour recovery in complete medium, increased late virus gene expression and G47Δ yields about 2-fold in GBM cells, but not in human astrocytes, and enhanced G47Δ killing of GBM cells. Mechanistically, "transient fasting" suppressed phosphorylation of the subunit of eukaryotic initiation factor 2α (eIF2α) and c-Jun N-terminal kinases (JNK) in GBM cells, but not in astrocytes. Pharmacological inhibition of JNK also increased G47Δ yield. In vivo, transient fasting (48-hour food restriction and 24-hour recovery) doubled luciferase activity after intratumoral G47Δ-US11fluc injection into orthotopic GBM xenografts. Thus, "transient fasting" increases G47Δ replication and oncolytic activity in human GBM cells. These results suggest that "transient fasting" may be effectively combined to enhance oncolytic HSV therapy of GBM. PMID:27186404

  7. Transient fasting enhances replication of oncolytic herpes simplex virus in glioblastoma

    PubMed Central

    Esaki, Shinichi; Rabkin, Samuel D; Martuza, Robert L; Wakimoto, Hiroaki

    2016-01-01

    Short-term nutritional restriction (fasting) has been shown to enhance the efficacy of chemotherapy by sensitizing cancer cells and protecting normal cells in a variety of cancer models, including glioblastoma (GBM). Cancer cells, unlike normal cells, respond to fasting by promoting oncogenic signaling and protein synthesis. We hypothesized that fasting would increase the replication of oncolytic herpes simplex virus (oHSV) in GBM. Patient-derived GBM cell lines were fasted by growth in glucose and fetal calf serum restricted culture medium. “Transient fasting”, 24-hour fasting followed by 24-hour recovery in complete medium, increased late virus gene expression and G47Δ yields about 2-fold in GBM cells, but not in human astrocytes, and enhanced G47Δ killing of GBM cells. Mechanistically, “transient fasting” suppressed phosphorylation of the subunit of eukaryotic initiation factor 2α (eIF2α) and c-Jun N-terminal kinases (JNK) in GBM cells, but not in astrocytes. Pharmacological inhibition of JNK also increased G47Δ yield. In vivo, transient fasting (48-hour food restriction and 24-hour recovery) doubled luciferase activity after intratumoral G47Δ-US11fluc injection into orthotopic GBM xenografts. Thus, “transient fasting” increases G47Δ replication and oncolytic activity in human GBM cells. These results suggest that “transient fasting” may be effectively combined to enhance oncolytic HSV therapy of GBM. PMID:27186404

  8. Detection and typing of herpes simplex viruses by using recombinant immunoglobulin fragments produced in bacteria.

    PubMed Central

    Cattani, P; Rossolini, G M; Cresti, S; Santangelo, R; Burton, D R; Williamson, R A; Sanna, P P; Fadda, G

    1997-01-01

    Thirty-seven bacterial clones producing human recombinant monoclonal antibody Fab fragments (rFabs) reactive to herpes simplex virus (HSV) antigens were selected from a human combinatorial antibody library constructed in a phage-display vector by a panning procedure against an HSV lysate. Thirty-four of the HSV-specific rFabs were able to specifically recognize HSV-infected cells in indirect immunofluorescence (IF) assays; of these, 25 recognized cells infected by either HSV type 1 (HSV-1) or HSV-2, while 9 recognized only HSV-1-infected cells. One HSV type-common rFab (rFab H37) and one HSV-1-specific rFab (rFab H85) were further evaluated as reagents for viral detection and typing by IF staining in 134 HSV-positive (72 HSV-1 and 62 HSV-2) viral cultures from clinical specimens. The results obtained with these two rFabs were fully consistent with those obtained with a commercial preparation of fluorescein-labeled anti-HSV type-specific murine monoclonal antibodies. The detection sensitivity with the type-common rFab in indirect IF assays was higher overall than that provided by the type-specific murine monoclonal antibodies. Preparations of rFabs suitable for IF staining can be easily and inexpensively obtained in a clinical microbiology laboratory from Escherichia coli cultures. Similar HSV-specific rFabs, therefore, could be advantageous for in vitro diagnostic purposes. PMID:9163470

  9. Herpes simplex virus 2 meningitis: a retrospective cohort study.

    PubMed

    Miller, Stephanie; Mateen, Farrah J; Aksamit, Allen J

    2013-04-01

    Herpes simplex virus 2 is a leading cause of viral meningitis and the most commonly recognized infectious cause of benign, recurrent meningitis. We report a retrospective, observational cohort study of patients with herpes simplex virus type 2 (HSV-2) meningitis, confirmed by polymerase chain reaction (PCR) in the cerebrospinal fluid (CSF). The terms "herpes simplex," "meningitis," or "encephalitis" were searched in the medical records system of the Mayo Clinic in Rochester, Minnesota (1995-2008). Patients were included if they had a clinical diagnosis of meningitis and HSV-2 detected by PCR in the CSF. There were 28 patients with 33 episodes identified (83 % female; mean age at presentation of meningitis 36 years, range 17-53; mean time to HSV2 detection from symptom onset 3 days, range 0-6; history of genital herpes 23 %). No patient took oral antiviral treatment at the time of presentation. Episodes were most likely to include headache (100 %), photophobia (47 %), self-reported fever (45 %), meningismus (44 %), and nausea and/or vomiting (29 %). CSF at the time of meningitis was notable for elevated protein (mean 156 g/dL, range 60-258) and white cell count (mean 504 cells/μL, range 86-1,860) with normal glucose (mean 54 mg/dL, range 32-80). Mollaret cells were never detected. Neuroimaging was most often normal (83 %) when performed, although some cases showed nonspecific (14 %) or meningeal changes (3 %). There was no consistent relationship to genital herpes. The duration of treatment with intravenous acyclovir ranged from 3 to 14 days for the first meningitic episode (daily dose range from 500 to 1,000 mg and total dose range from 500 mg q8h for 3 days to 800 mg q8h for 14 days). For subsequent episodes, the duration of treatment of intravenous acyclovir ranged from less than 1 to 14 days (total dose range from 1,390 mg for 1 day to 900 mg q8h for 10 days). The dose of valacyclovir ranged from 500 mg once daily to 500 mg four times daily. The median duration

  10. The Telomerase Inhibitor MST-312 Interferes with Multiple Steps in the Herpes Simplex Virus Life Cycle

    PubMed Central

    Haberichter, Jarod; Roberts, Scott; Abbasi, Imran; Dedthanou, Phonphanh; Pradhan, Prajakta

    2015-01-01

    ABSTRACT The life cycle of herpes simplex virus (HSV) has the potential to be further manipulated to yield novel, more effective therapeutic treatments. Recent research has demonstrated that HSV-1 can increase telomerase activity and that expression of the catalytic component of telomerase, telomerase reverse transcriptase (TERT), alters sensitivity to HSV-dependent apoptosis. Telomerase is a cellular enzyme that synthesizes nucleotide repeats at the ends of chromosomes (telomeres), which prevents shortening of the 3′ ends of DNA with each cell division. Once telomeres reach a critical length, cells undergo senescence and apoptosis. Here, we used a cell-permeable, reversible inhibitor of the telomerase enzyme, MST-312, to investigate telomerase activity during HSV infection. Human mammary epithelial cells immortalized through TERT expression and human carcinoma HEp-2 cells were infected with the KOS1.1 strain of HSV-1 in the presence of MST-312. MST-312 treatment reduced the number of cells displaying a cytopathic effect and the accumulation of immediate early and late viral proteins. Moreover, the presence of 20 μM to 100 μM MST-312 during infection led to a 2.5- to 5.5-log10 decrease in viral titers. MST-312 also inhibited the replication of HSV-2 and a recent clinical isolate of HSV-1. Additionally, we determined that MST-312 has the largest impact on viral events that take place prior to 5 h postinfection (hpi). Furthermore, MST-312 treatment inhibited virus replication, as measured by adsorption assays and quantification of genome replication. Together, these findings demonstrate that MST-312 interferes with the HSV life cycle. Further investigation into the mechanism for MST-312 is warranted and may provide novel targets for HSV therapies. IMPORTANCE Herpes simplex virus (HSV) infections can lead to cold sores, blindness, and brain damage. Identification of host factors that are important for the virus life cycle may provide novel targets for HSV

  11. Encephalitis herpes simplex: aural rehabilitation following bilateral deafness.

    PubMed

    Montano, J J; Melley, C C; Karam, D B

    1983-10-01

    Aural rehabilitation is a critical and often neglected aspect of a hearing-impaired patient's total rehabilitation. This case description illustrates the need for implementation of aural rehabilitation services. A 59-year-old woman exhibited bilateral profound sensorineural hearing loss following the onset of encephalitis herpes simplex. Auditory amplification attempts were unsuccessful. Aural rehabilitation was initiated immediately, and she was seen for lipreading and vibrotactile stimulation training. Goals progressed from identification of single words within a category to phonemic recognition. Vibrotactile stimulation was used to facilitate environmental awareness. Therapy goals reflected the patient's increased motivation to communicate within her environment. This patient's communicative status is viewed on a continuum: from success in individual treatment goals, extending to successful communication within the structure of the entire rehabilitation setting, and finally to functional communication within her home environment. PMID:6625883

  12. Autophagy Stimulation Abrogates Herpes simplex Virus-1 Infection

    PubMed Central

    Yakoub, Abraam M.; Shukla, Deepak

    2015-01-01

    Herpes simplex virus-1 (HSV-1) is a double-stranded DNA virus that causes life-long infections. HSV-1 infections may lead to herpetic stromal keratitis that may advance to corneal blindness. HSV-1 infections can also cause fatal conditions, such as herpes encephalitis, or neonatal disease. A major virulence mechanism of HSV-1 is the control of autophagy, an innate immune defense strategy that could otherwise degrade viral particles. Here, to investigate a new mechanism for antiviral therapy, we tested the effect of various autophagy inducers (physiological and pharmacological) on infection. Autophagy stimulation was confirmed to significantly suppress HSV-1 infection in various cell types, without affecting cell viability. This study establishes the importance of autophagy for regulating HSV-1 infection, and provides a proof-of-principle evidence for a novel antiviral mechanism. PMID:25856282

  13. Herpes simplex virus 1 induces de novo phospholipid synthesis

    SciTech Connect

    Sutter, Esther; Oliveira, Anna Paula de; Tobler, Kurt; Schraner, Elisabeth M.; Sonda, Sabrina; Kaech, Andres; Lucas, Miriam S.; Ackermann, Mathias; Wild, Peter

    2012-08-01

    Herpes simplex virus type 1 capsids bud at nuclear membranes and Golgi membranes acquiring an envelope composed of phospholipids. Hence, we measured incorporation of phospholipid precursors into these membranes, and quantified changes in size of cellular compartments by morphometric analysis. Incorporation of [{sup 3}H]-choline into both nuclear and cytoplasmic membranes was significantly enhanced upon infection. [{sup 3}H]-choline was also part of isolated virions even grown in the presence of brefeldin A. Nuclei expanded early in infection. The Golgi complex and vacuoles increased substantially whereas the endoplasmic reticulum enlarged only temporarily. The data suggest that HSV-1 stimulates phospholipid synthesis, and that de novo synthesized phospholipids are inserted into nuclear and cytoplasmic membranes to i) maintain membrane integrity in the course of nuclear and cellular expansion, ii) to supply membrane constituents for envelopment of capsids by budding at nuclear membranes and Golgi membranes, and iii) to provide membranes for formation of transport vacuoles.

  14. Proposal of Evolutionary Simplex Method for Global Optimization Problem

    NASA Astrophysics Data System (ADS)

    Shimizu, Yoshiaki

    To make an agile decision in a rational manner, role of optimization engineering has been notified increasingly under diversified customer demand. With this point of view, in this paper, we have proposed a new evolutionary method serving as an optimization technique in the paradigm of optimization engineering. The developed method has prospects to solve globally various complicated problem appearing in real world applications. It is evolved from the conventional method known as Nelder and Mead’s Simplex method by virtue of idea borrowed from recent meta-heuristic method such as PSO. Mentioning an algorithm to handle linear inequality constraints effectively, we have validated effectiveness of the proposed method through comparison with other methods using several benchmark problems.

  15. A note concerning multivariate total positivity on the simplex

    SciTech Connect

    Rayens, W.S.

    1996-12-31

    Although compositional data arise frequently in many different disciplines, relatively little is known about families of parametric densities that reside on a simplex, which is the natural sample space for such data. An exception to this is a recent paper by Gupta and Richards wherein the Liouville family is defined and discussed. They sought to characterize dependence properties within this new family using, among other ideas, multivariate total positivity. Further investigation reveals that their results are not very useful. In fact, it is shown that there does not exist a Liouville density, as defined by Gupta and Richards, that is also multivariate totally positive of order 2. Fatal flaws associated with an obvious alternative to their definition are discussed.

  16. Fine scale association mapping of disease loci using simplex families.

    PubMed

    Morris, A P; Whittaker, J C

    2000-05-01

    We present a new method for the fine scale mapping of disease loci based on samples of simplex families, each containing an affected child. The method is based on a generalisation of a single locus allele transmission model to multiple marker loci. The model is developed under the assumption of a single ancestral mutation and allows for the calculation of posterior probabilities that each allele at a particular marker was present on the founder chromosome. We illustrate the method using simulated family data for cystic fibrosis and Huntingtons disease, for which the locations of mutations in the disease genes are now known. For both diseases, our new method provides good estimates of the location of the mutations. PMID:11246474

  17. Fulminant hepatitis following primary herpes simplex virus infection.

    PubMed

    Al Midani, A; Pinney, J; Field, N; Atkinson, C; Haque, T; Harber, M

    2011-01-01

    Fulminant hepatic failure (FHF) is a rare but well-recognized complication of primary herpes simplex virus (HSV) infection in immunocompromised patients. Here, we report two cases of acute hepatitis and FHF secondary to primary HSV type 1 infection following renal transplantation in the absence of any mucocutaneous manifestation. High levels of HSV type-1 DNA were detected in the blood. Both patients were seronegative for HSV 1 and HSV 2 immunoglobulin G (IgG) before transplantation, whereas the donor of patient 1 was HSV 1 IgG-positive but had no viremia and the donor of patient 2 was HSV-seronegative. Patient 1 recovered with acyclovir and immunoglobulin whereas patient 2 did not respond and succumbed to death. HSV-seronegative patients are potentially at risk of developing severe primary HSV disease following transplantation, particularly in the absence of routine anti-viral prophylaxis. HSV infection should always be excluded in transplant patients with hepatic dysfunction. PMID:21196623

  18. Immunological Aspects of Acute and Recurrent Herpes Simplex Keratitis

    PubMed Central

    Hus, Iwona

    2014-01-01

    Herpes simplex keratitis (HSK) belongs to the major causes of visual morbidity worldwide and available methods of treatment remain unsatisfactory. Primary infection occurs usually early in life and is often asymptomatic. Chronic visual impairment and visual loss are caused by corneal scaring, thinning, and vascularization connected with recurrent HSV infections. The pathogenesis of herpetic keratitis is complex and is still not fully understood. According to the current knowledge, corneal scarring and vascularization are the result of chronic inflammatory reaction against HSV antigens. In this review we discuss the role of innate and adaptive immunities in acute and recurrent HSV ocular infection and present the potential future targets for novel therapeutical options based on immune interventions. PMID:25276842

  19. Lytic Promoters Express Protein during Herpes Simplex Virus Latency

    PubMed Central

    Russell, Tiffany A.; Tscharke, David C.

    2016-01-01

    Herpes simplex virus (HSV) has provided the prototype for viral latency with previously well-defined acute or lytic and latent phases. More recently, the deep quiescence of HSV latency has been questioned with evidence that lytic genes can be transcribed in this state. However, to date the only evidence that these transcripts might be translated has come from immunological studies that show activated T cells persist in the nervous system during latency. Here we use a highly sensitive Cre-marking model to show that lytic and latent phases are less clearly defined in two significant ways. First, around half of the HSV spread leading to latently infected sites occurred beyond the initial acute infection and second, we show direct evidence that lytic promoters can drive protein expression during latency. PMID:27348812

  20. Herpes Simplex Virus-2 Esophagitis in a Young Immunocompetent Adult

    PubMed Central

    Kadayakkara, Deepak K.; Candelaria, Angela; Kwak, Ye Eun; Loeser, Caroline

    2016-01-01

    Herpes simplex esophagitis (HSE) is commonly identified in immunosuppressed patients. It is rare among immunocompetent patients and almost all of the reported cases are due to HSV-1 infection. HSV-2 esophagitis is extremely rare. We report the case of a young immunocompetent male who presented with dysphagia, odynophagia, and epigastric pain. Endoscopy showed multitudes of white nummular lesions in the distal esophagus initially suspected to be candida esophagitis. However, classic histopathological findings of multinucleated giant cells with eosinophilic intranuclear inclusions and positive HSV-2 IgM confirmed the diagnosis of HSV-2 esophagitis. The patient rapidly responded to acyclovir treatment. Although HSV-2 is predominantly associated with genital herpes, it can cause infections in other parts of the body previously attributed to only HSV-1 infection. PMID:27195158

  1. Herpes Simplex Virus-2 Esophagitis in a Young Immunocompetent Adult.

    PubMed

    Kadayakkara, Deepak K; Candelaria, Angela; Kwak, Ye Eun; Loeser, Caroline

    2016-01-01

    Herpes simplex esophagitis (HSE) is commonly identified in immunosuppressed patients. It is rare among immunocompetent patients and almost all of the reported cases are due to HSV-1 infection. HSV-2 esophagitis is extremely rare. We report the case of a young immunocompetent male who presented with dysphagia, odynophagia, and epigastric pain. Endoscopy showed multitudes of white nummular lesions in the distal esophagus initially suspected to be candida esophagitis. However, classic histopathological findings of multinucleated giant cells with eosinophilic intranuclear inclusions and positive HSV-2 IgM confirmed the diagnosis of HSV-2 esophagitis. The patient rapidly responded to acyclovir treatment. Although HSV-2 is predominantly associated with genital herpes, it can cause infections in other parts of the body previously attributed to only HSV-1 infection. PMID:27195158

  2. Analysis of test data on the simplex strapdown navigation system

    NASA Technical Reports Server (NTRS)

    1976-01-01

    The results of a study of test data taken on the simplex strapdown navigation system were presented. That system consisted of the following components: strapdown platform, altimeter, digital computer, tape recorder, typewriter, and power source. The objective of these tests was to isolate error sources which may cause degradation of the system's accuracy and to recommend appropriate changes to the system test procedures or computer software. The following recommendations were made: (1) addition of a gyro compassing alignment program into the navigation program, (2) addition of line drivers at the signal processor end of the transmission line, (3) need for extensive laboratory testing to determine sensor misalignments, biases, and scale factors, (4) need to stabilize the power source to prevent transients during power transfer, (5) need to isolate and eliminate the source of the large noise inputs.

  3. Fatal Neonatal Herpes Simplex Infection Likely from Unrecognized Breast Lesions.

    PubMed

    Field, Scott S

    2016-02-01

    Type 1 herpes simplex virus (HSV-1) is very prevalent yet in rare circumstances can lead to fatal neonatal disease. Genital acquisition of type 2 HSV is the usual mode for neonatal herpes, but HSV-1 transmission by genital or extragenital means may result in greater mortality rates. A very rare scenario is presented in which the mode of transmission was likely through breast lesions. The lesions were seen by nurses as well as the lactation consultant and obstetrician in the hospital after delivery of the affected baby but not recognized as possibly being caused by herpes. The baby died 9 days after birth with hepatic failure and disseminated intravascular coagulation. Peripartum health care workers need to be aware of potential nongenital (including from the breast[s]) neonatal herpes acquisition, which can be lethal. PMID:26185119

  4. Advance in herpes simplex viruses for cancer therapy.

    PubMed

    Liu, Shanglong; Dai, Meihua; You, Lei; Zhao, Yupei

    2013-04-01

    Oncolytic virotherapy is an attractive approach that uses live viruses to selectively kill cancer cells. Oncolytic viruses can be genetically engineered to induce cell lyses through virus replication and cytotoxic protein expression. Herpes simplex virus (HSV) has become one of the most widely clinically used oncolytic agent. Various types of HSV have been studied in basic or clinical research. Combining oncolytic virotherapy with chemotherapy or radiotherapy generally produces synergic action with unclear molecular mechanisms. Arming HSV with therapeutic transgenes is a promising strategy and can be used to complement conventional therapies. As an efficient gene delivery system, HSV has been successfully used to deliver various immunomodulatory molecules. Arming HSV with therapeutic genes merits further investigation for potential clinical application. PMID:23564184

  5. Disseminated herpes simplex infection during pregnancy, rare but important to recognise

    PubMed Central

    Hussain, Nawar Younis; Uriel, Alison; Mammen, Catherine; Bonington, Alec

    2014-01-01

    Disseminated herpes simplex virus (HSV) infection during pregnancy is a rare, but potentially fatal condition. We present a case where prompt treatment with intravenous acyclovir resulted in a successful outcome for both mother and baby. PMID:25320695

  6. Bionomics of Orasema simplex (Hymenoptera: Eucharitidae) a parasitoid of Solenopsis fire ants (Hymenoptera: Formicidae) in Argentina

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Biological characteristics of the parasitoid Orasema simplex Heraty (Hymenoptera: Eucharitidae), a potential candidate for the biological control of fire ants in the United States were investigated. Female survivorship, fertility and oviposition preferences were studied in the laboratory. Naturally ...

  7. PARAMETERS DISTINGUISHING HERPES SIMPLEX VIRUS TYPE 2-TRANSFORMED TUMORIGENIC AND NONTUMORIGENIC RAT CELLS

    EPA Science Inventory

    A newly developed experimental model system was used to determine in vitro transformation-specific parameters which correlate with tumorigenicity. The data suggested that clonal herpes simplex virus type 2-transformed syngeneic rat embryo cells with intermediate, transformed rat ...

  8. Transmission Disequilibrium of Small CNVs in Simplex Autism

    PubMed Central

    Krumm, Niklas; O’Roak, Brian J.; Karakoc, Emre; Mohajeri, Kiana; Nelson, Ben; Vives, Laura; Jacquemont, Sebastien; Munson, Jeff; Bernier, Raphe; Eichler, Evan E.

    2013-01-01

    We searched for disruptive, genic rare copy-number variants (CNVs) among 411 families affected by sporadic autism spectrum disorder (ASD) from the Simons Simplex Collection by using available exome sequence data and CoNIFER (Copy Number Inference from Exome Reads). Compared to high-density SNP microarrays, our approach yielded ∼2× more smaller genic rare CNVs. We found that affected probands inherited more CNVs than did their siblings (453 versus 394, p = 0.004; odds ratio [OR] = 1.19) and that the probands’ CNVs affected more genes (921 versus 726, p = 0.02; OR = 1.30). These smaller CNVs (median size 18 kb) were transmitted preferentially from the mother (136 maternal versus 100 paternal, p = 0.02), although this bias occurred irrespective of affected status. The excess burden of inherited CNVs among probands was driven primarily by sibling pairs with discordant social-behavior phenotypes (p < 0.0002, measured by Social Responsiveness Scale [SRS] score), which contrasts with families where the phenotypes were more closely matched or less extreme (p > 0.5). Finally, we found enrichment of brain-expressed genes unique to probands, especially in the SRS-discordant group (p = 0.0035). In a combined model, our inherited CNVs, de novo CNVs, and de novo single-nucleotide variants all independently contributed to the risk of autism (p < 0.05). Taken together, these results suggest that small transmitted rare CNVs play a role in the etiology of simplex autism. Importantly, the small size of these variants aids in the identification of specific genes as additional risk factors associated with ASD. PMID:24035194

  9. Transmission disequilibrium of small CNVs in simplex autism.

    PubMed

    Krumm, Niklas; O'Roak, Brian J; Karakoc, Emre; Mohajeri, Kiana; Nelson, Ben; Vives, Laura; Jacquemont, Sebastien; Munson, Jeff; Bernier, Raphe; Eichler, Evan E

    2013-10-01

    We searched for disruptive, genic rare copy-number variants (CNVs) among 411 families affected by sporadic autism spectrum disorder (ASD) from the Simons Simplex Collection by using available exome sequence data and CoNIFER (Copy Number Inference from Exome Reads). Compared to high-density SNP microarrays, our approach yielded ∼2× more smaller genic rare CNVs. We found that affected probands inherited more CNVs than did their siblings (453 versus 394, p = 0.004; odds ratio [OR] = 1.19) and that the probands' CNVs affected more genes (921 versus 726, p = 0.02; OR = 1.30). These smaller CNVs (median size 18 kb) were transmitted preferentially from the mother (136 maternal versus 100 paternal, p = 0.02), although this bias occurred irrespective of affected status. The excess burden of inherited CNVs among probands was driven primarily by sibling pairs with discordant social-behavior phenotypes (p < 0.0002, measured by Social Responsiveness Scale [SRS] score), which contrasts with families where the phenotypes were more closely matched or less extreme (p > 0.5). Finally, we found enrichment of brain-expressed genes unique to probands, especially in the SRS-discordant group (p = 0.0035). In a combined model, our inherited CNVs, de novo CNVs, and de novo single-nucleotide variants all independently contributed to the risk of autism (p < 0.05). Taken together, these results suggest that small transmitted rare CNVs play a role in the etiology of simplex autism. Importantly, the small size of these variants aids in the identification of specific genes as additional risk factors associated with ASD. PMID:24035194

  10. Effects of herpes simplex virus on mRNA stability.

    PubMed Central

    Strom, T; Frenkel, N

    1987-01-01

    Herpes simplex virus virions contain one or more functions which mediate shutoff of host protein synthesis, disaggregation of host polyribosomes, and degradation of host mRNA. We studied aspects of the host shutoff mechanism by using herpes simplex virus type 1 mutants deficient in virion-induced shutoff of host protein synthesis (G. S. Read and N. Frenkel, J. Virol. 46:498-512, 1983). Shutoff of host protein synthesis by the wild-type virus was associated with degradation of host mRNAs, including beta-actin, alpha-tubulin, and heat shock protein 70. In contrast, the virion host shutoff (vhs) mutants were deficient to various degrees in their ability to induce host mRNA degradation; the extent of mRNA degradation correlated well with the extent of inhibition of host protein synthesis. This finding suggests that inhibition of host protein synthesis and degradation of host mRNA were mediated by the same virion-associated function. Virion-induced degradation of host mRNA was not prevented by inhibitors of ribosome translocation, nor could it be augmented, for mutant vhs-1, by drugs which disaggregate polyribosomes. This suggests that mRNA in polyribosomes, as well as nonpolyribosomal mRNA, is susceptible to virion-induced degradation. Finally, the half-life of viral transcripts was also prolonged in cells infected with the vhs-1 mutant virus, suggesting that the vhs function indiscriminately decreased the half-lives of both host and viral mRNAs. The vhs function may thus play a dual role in virus infection. (i) It inhibits host gene expression, and (ii) it enables rapid transitions in the expression of viral genes which are sequentially transcribed as infection progresses. Images PMID:3035220

  11. Gasification of Simplex briquets: briquet production. Vol. 1. Final report

    SciTech Connect

    Not Available

    1983-04-01

    A 7-ton/hr briquetting plant was installed at International Briquetting in Baltimore, Maryland, and used to produce 360 tons of Simplex briquets from Pittsburgh No. 8 seam, Champion No. 1 mine caking coal and shredded, air-classified Baltimore County refuse. The production of these briquets was funded by the Department of Energy, through the US Bureau of Mines, and a consortium comprised of the New York State Energy Research and Development Authority and the Empire State Electric Energy Research Company. This report describes the briquetting plant and discusses the problems that were encountered in producing the briquets. The following modifications are recommended for future Simplex briquetting plants: drying equipment should be installed on the RDF feed system to ensure that the RDF moisture is below 18%; the crushed coal must be dried to less than 4% moisture to ensure its free flow in the bins; magnets should be installed above the coal and RDF feed conveyors to remove any tramp metal; a 3/4-inch screen should be installed over the coal feed bin to remove any oversize rocks or lump coal; the RDF handling system and turbulizer discharge to the press should all be enclosed for dust control (the enclosures should be vented to a baghouse); only heavy duty apron conveyors should be used where belt conveyors are needed; briquetts should be cured if they are going to be stored in containers where they might sweat; and a screen with 1 1/4-inch openings should be used to remove the fines from 2 1/4-inch briquets (this screen should be sufficiently large to prevent briquets from crowding together on the screen).

  12. Anti-N-Methyl-D-Aspartate Receptor Antibody Mediated Neurologic Relapse Post Herpes Simplex Encephalitis: A Case Series.

    PubMed

    Geoghegan, Sarah; Walsh, Aoibhinn; King, Mary D; Lynch, Bryan; Webb, David; Twomey, Eilish; Ronan Leahy, T; Butler, Karina; Gavin, Patrick

    2016-08-01

    Despite the advent of antiviral therapy, herpes simplex encephalitis (HSE) remains a devastating condition with significant morbidity and mortality. Neurologic relapse after initial improvement is generally attributed to herpes simplex virus reactivation. In 2013, inflammation caused by anti-N-methyl-D-aspartate receptor antibodies was reported in association with cases of neurologic relapse after herpes simplex encephalitis. We present 3 such cases and discuss diagnostic and management dilemmas. PMID:27171680

  13. Effects of Herpes Simplex Virus Vector–Mediated Enkephalin Gene Therapy on Bladder Overactivity and Nociception

    PubMed Central

    Yokoyama, Hitoshi; Oguchi, Tomohiko; Goins, William F.; Goss, James R.; Nishizawa, Osamu; de Groat, William C.; Wolfe, Darren; Krisky, David M.; Glorioso, Joseph C.

    2013-01-01

    Abstract We previously reported the effects of herpes simplex virus (HSV) vector–mediated enkephalin on bladder overactivity and pain. In this study, we evaluated the effects of vHPPE (E1G6-ENK), a newly engineered replication-deficient HSV vector encoding human preproenkephalin (hPPE). vHPPE or control vector was injected into the bladder wall of female rats 2 weeks prior to the following studies. A reverse-transcription PCR study showed high hPPE transgene levels in L6 dorsal root ganglia innervating the bladder in the vHPPE group. The number of freezing behaviors, which is a nociceptive reaction associated with bladder pain, was also significantly lower in the vHPPE group compared with the control group. The number of L6 spinal cord c-fos–positive cells and the urinary interleukin (IL)-1β and IL-6 levels after resiniferatoxin (RTx) administration into the bladder of the vHPPE group were significantly lower compared with those of the control vector–injected group. In continuous cystometry, the vHPPE group showed a smaller reduction in intercontraction interval after RTx administration into the bladder. This antinociceptive effect was antagonized by naloxone hydrochloride. Thus, the HSV vector vHPPE encoding hPPE demonstrated physiological improvement in visceral pain induced by bladder irritation. Gene therapy may represent a potentially useful treatment modality for bladder hypersensitive disorders such as bladder pain syndrome/interstitial cystitis. PMID:23316929

  14. Herpes simplex viral-vector design for efficient transduction of nonneuronal cells without cytotoxicity.

    PubMed

    Miyagawa, Yoshitaka; Marino, Pietro; Verlengia, Gianluca; Uchida, Hiroaki; Goins, William F; Yokota, Shinichiro; Geller, David A; Yoshida, Osamu; Mester, Joseph; Cohen, Justus B; Glorioso, Joseph C

    2015-03-31

    The design of highly defective herpes simplex virus (HSV) vectors for transgene expression in nonneuronal cells in the absence of toxic viral-gene activity has been elusive. Here, we report that elements of the latency locus protect a nonviral promoter against silencing in primary human cells in the absence of any viral-gene expression. We identified a CTCF motif cluster 5' to the latency promoter and a known long-term regulatory region as important elements for vigorous transgene expression from a vector that is functionally deleted for all five immediate-early genes and the 15-kb internal repeat region. We inserted a 16.5-kb expression cassette for full-length mouse dystrophin and report robust and durable expression in dystrophin-deficient muscle cells in vitro. Given the broad cell tropism of HSV, our design provides a nontoxic vector that can accommodate large transgene constructs for transduction of a wide variety of cells without vector integration, thereby filling an important void in the current arsenal of gene-therapy vectors. PMID:25775541

  15. Genetic studies of cell fusion induced by herpes simplex virus type 1

    SciTech Connect

    Read, G.S.; Person, S.; Keller, P.M.

    1980-07-01

    Eight cell fusion-causing syn mutants were isolated from the KOS strain of herpes simplex virus type 1. Unlike the wild-type virus, the mutants produced plaques containing multinucleated cells, or syncytia. Fusion kinetics curves were established with a Coulter Counter assay for the mutants and wild-type virus in single infections of human embryonic lung (HEL) cells, for the mutants and wild-type virus in mixed infections (dominance test), and for pairs of mutants in mixed infection and proceeded with an exponential decrease in the number of small single cells. At some later time that was characteristic of the mutant, there was a significant reduction in the rate of fusion for all but possibly one of the mutants. Although the wild-type virus did not produce syncytial plaques, it did induce a small amount of fusion that stopped abruptly about 2 h after it started. These data are consistent with the hypothesis that both mutants and wild type induce an active fusion inducer and that the activity of this inducer is subsequently inhibited. The extent of fusion is apparently determined by the length of the interval during which the fusion inducer is active. That fusion is actively inhibited in wild-type infections is indicated by the observation that syn mutant-infected cells fused more readily with uninfected cells than with wild type-infected cells.

  16. VP22 herpes simplex virus protein can transduce proteins into stem cells.

    PubMed

    Gabanyi, I; Lojudice, F H; Kossugue, P M; Rebelato, E; Demasi, M A; Sogayar, M C

    2013-02-01

    The type I herpes simplex virus VP22 tegument protein is abundant and well known for its ability to translocate proteins from one cell to the other. In spite of some reports questioning its ability to translocate proteins by attributing the results observed to fixation artifacts or simple attachment to the cell membrane, VP22 has been used to deliver several proteins into different cell types, triggering the expected cell response. However, the question of the ability of VP22 to enter stem cells has not been addressed. We investigated whether VP22 could be used as a tool to be applied in stem cell research and differentiation due to its capacity to internalize other proteins without altering the cell genome. We generated a VP22.eGFP construct to evaluate whether VP22 could be internalized and carry another protein with it into two different types of stem cells, namely adult human dental pulp stem cells and mouse embryonic stem cells. We generated a VP22.eGFP fusion protein and demonstrated that, in fact, it enters stem cells. Therefore, this system may be used as a tool to deliver various proteins into stem cells, allowing stem cell research, differentiation and the generation of induced pluripotent stem cells in the absence of genome alterations. PMID:23369972

  17. Potential role of tenofovir vaginal gel for reduction of risk of herpes simplex virus in females

    PubMed Central

    Tan, DHS

    2012-01-01

    A surprising result of the groundbreaking CAPRISA-004 trial, which demonstrated the efficacy of vaginal tenofovir 1% gel in reducing the risk of human immunodeficiency virus (HIV)-1 infection by 39% in heterosexual women, was the added benefit of this microbicide in reducing acquisition of herpes simplex virus type 2 (HSV-2) by 51%. HSV-2 is the most common cause of genital ulcer disease worldwide, and is responsible for considerable morbidity among women and neonates. The virus is further implicated in increasing the risk of both HIV acquisition and transmission, and may have additional adverse consequences in HIV-coinfected persons, making HSV-2 prevention an important clinical and public health objective. While tenofovir had not previously been widely considered to be an anti-herpes drug, in vitro activity against HSV is well documented, raising interest in potential future applications of tenofovir and its prodrugs in HSV-2 control. This article reviews the currently available data for tenofovir as an anti-herpes agent, as well as unanswered questions about delivery systems, drug formulation, rectal administration, drug resistance, and clinical applications. PMID:22927765

  18. Structural analysis of herpes simplex virus by optical super-resolution imaging

    PubMed Central

    Laine, Romain F.; Albecka, Anna; van de Linde, Sebastian; Rees, Eric J.; Crump, Colin M.; Kaminski, Clemens F.

    2015-01-01

    Herpes simplex virus type-1 (HSV-1) is one of the most widespread pathogens among humans. Although the structure of HSV-1 has been extensively investigated, the precise organization of tegument and envelope proteins remains elusive. Here we use super-resolution imaging by direct stochastic optical reconstruction microscopy (dSTORM) in combination with a model-based analysis of single-molecule localization data, to determine the position of protein layers within virus particles. We resolve different protein layers within individual HSV-1 particles using multi-colour dSTORM imaging and discriminate envelope-anchored glycoproteins from tegument proteins, both in purified virions and in virions present in infected cells. Precise characterization of HSV-1 structure was achieved by particle averaging of purified viruses and model-based analysis of the radial distribution of the tegument proteins VP16, VP1/2 and pUL37, and envelope protein gD. From this data, we propose a model of the protein organization inside the tegument. PMID:25609143

  19. Quantification of the host response proteome after herpes simplex virus type 1 infection.

    PubMed

    Berard, Alicia R; Coombs, Kevin M; Severini, Alberto

    2015-05-01

    Viruses employ numerous host cell metabolic functions to propagate and manage to evade the host immune system. For herpes simplex virus type 1 (HSV1), a virus that has evolved to efficiently infect humans without seriously harming the host in most cases, the virus-host interaction is specifically interesting. This interaction can be best characterized by studying the proteomic changes that occur in the host during infection. Previous studies have been successful at identifying numerous host proteins that play important roles in HSV infection; however, there is still much that we do not know. This study identifies host metabolic functions and proteins that play roles in HSV infection, using global quantitative stable isotope labeling by amino acids in cell culture (SILAC) proteomic profiling of the host cell combined with LC-MS/MS. We showed differential proteins during early, mid and late infection, using both cytosolic and nuclear fractions. We identified hundreds of differentially regulated proteins involved in fundamental cellular functions, including gene expression, DNA replication, inflammatory response, cell movement, cell death, and RNA post-transcriptional modification. Novel differentially regulated proteins in HSV infections include some previously identified in other virus systems, as well as fusion protein, involved in malignant liposarcoma (FUS) and hypoxia up-regulated 1 protein precursor (HYOU1), which have not been identified previously in any virus infection. PMID:25815715

  20. Genetic Diversity within Alphaherpesviruses: Characterization of a Novel Variant of Herpes Simplex Virus 2

    PubMed Central

    Désiré, Nathalie; Marlet, Julien; Dacheux, Laurent; Seang, Sophie; Caumes, Eric; Bourhy, Hervé; Agut, Henri; Boutolleau, David

    2015-01-01

    ABSTRACT Very low levels of variability have been reported for the herpes simplex virus 2 (HSV-2) genome. We recently described a new genetic variant of HSV-2 (HSV-2v) characterized by a much higher degree of variability for the UL30 gene (DNA polymerase) than observed for the HG52 reference strain. Retrospective screening of 505 clinical isolates of HSV-2 by a specific real-time PCR assay targeting the UL30 gene led to the identification of 13 additional HSV-2v isolates, resulting in an overall prevalence of 2.8%. Phylogenetic analyses on the basis of microsatellite markers and gene sequences showed clear differences between HSV-2v and classical HSV-2. Thirteen of the 14 patients infected with HSV-2v originated from West or Central Africa, and 9 of these patients were coinfected with HIV. These results raise questions about the origin of this new virus. Preliminary results suggest that HSV-2v may have acquired genomic segments from chimpanzee alphaherpesvirus (ChHV) by recombination. IMPORTANCE This article deals with the highly topical question of the origin of this new HSV-2 variant identified in patients with HIV coinfection originating mostly from West or Central Africa. HSV-2v clearly differed from classical HSV-2 isolates in phylogenetic analyses and may be linked to simian ChHV. This new HSV-2 variant highlights the possible occurrence of recombination between human and simian herpesviruses under natural conditions, potentially presenting greater challenges for the future. PMID:26401046

  1. Activity of Tea Tree (Melaleuca alternifolia) Essential Oil against L3 Larvae of Anisakis simplex

    PubMed Central

    Langa, Elisa; Murillo, Paula

    2014-01-01

    Nematicidal activity of Melaleuca alternifolia essential oil, commonly known as tea tree oil (TTO), was assayed in vitro against L3 larvae of Anisakis simplex. The results showed a mortality of 100% for concentrations between 7 and 10 μL/mL after 48 h of incubation, obtaining an LD50 value of 4.53 μL/mL after 24 hours and 4.27 μL/mL after 48 hours. Concentration-dependent inhibition of acetylcholinesterase was observed for tea tree essential oil showing inhibition values of 100% at 100 μL/mL. This fact suggests that TTO may act as an AChE inhibitor. Terpinen-4-ol was discarded as main larvicide compound as it did not show larvicidal or anticholinesterase activity. The data obtained suggest that the essential oil of Melaleuca alternifolia may have a great therapeutic potential for the treatment of human anisakiasis. PMID:24967378

  2. Infected cell protein 0 functional domains and their coordination in herpes simplex virus replication.

    PubMed

    Gu, Haidong

    2016-02-12

    Herpes simplex virus 1 (HSV-1) is a ubiquitous human pathogen that establishes latent infection in ganglia neurons. Its unique life cycle requires a balanced "conquer and compromise" strategy to deal with the host anti-viral defenses. One of HSV-1 α (immediate early) gene products, infected cell protein 0 (ICP0), is a multifunctional protein that interacts with and modulates a wide range of cellular defensive pathways. These pathways may locate in different cell compartments, which then migrate or exchange factors upon stimulation, for the purpose of a concerted and effective defense. ICP0 is able to simultaneously attack multiple host pathways by either degrading key restrictive factors or modifying repressive complexes. This is a viral protein that contains an E3 ubiquitin ligase, translocates among different cell compartments and interacts with major defensive complexes. The multiple functional domains of ICP0 can work independently and at the same time coordinate with each other. Dissecting the functional domains of ICP0 and delineating the coordination of these domains will help us understand HSV-1 pathogenicity as well as host defense mechanisms. This article focuses on describing individual ICP0 domains, their biochemical properties and their implication in HSV-1 infection. By putting individual domain functions back into the picture of host anti-viral defense network, this review seeks to elaborate the complex interactions between HSV-1 and its host. PMID:26870669

  3. Herpes simplex viral-vector design for efficient transduction of nonneuronal cells without cytotoxicity

    PubMed Central

    Miyagawa, Yoshitaka; Marino, Pietro; Verlengia, Gianluca; Uchida, Hiroaki; Goins, William F.; Yokota, Shinichiro; Geller, David A.; Yoshida, Osamu; Mester, Joseph; Cohen, Justus B.; Glorioso, Joseph C.

    2015-01-01

    The design of highly defective herpes simplex virus (HSV) vectors for transgene expression in nonneuronal cells in the absence of toxic viral-gene activity has been elusive. Here, we report that elements of the latency locus protect a nonviral promoter against silencing in primary human cells in the absence of any viral-gene expression. We identified a CTCF motif cluster 5′ to the latency promoter and a known long-term regulatory region as important elements for vigorous transgene expression from a vector that is functionally deleted for all five immediate-early genes and the 15-kb internal repeat region. We inserted a 16.5-kb expression cassette for full-length mouse dystrophin and report robust and durable expression in dystrophin-deficient muscle cells in vitro. Given the broad cell tropism of HSV, our design provides a nontoxic vector that can accommodate large transgene constructs for transduction of a wide variety of cells without vector integration, thereby filling an important void in the current arsenal of gene-therapy vectors. PMID:25775541

  4. Infected cell protein 0 functional domains and their coordination in herpes simplex virus replication

    PubMed Central

    Gu, Haidong

    2016-01-01

    Herpes simplex virus 1 (HSV-1) is a ubiquitous human pathogen that establishes latent infection in ganglia neurons. Its unique life cycle requires a balanced “conquer and compromise” strategy to deal with the host anti-viral defenses. One of HSV-1 α (immediate early) gene products, infected cell protein 0 (ICP0), is a multifunctional protein that interacts with and modulates a wide range of cellular defensive pathways. These pathways may locate in different cell compartments, which then migrate or exchange factors upon stimulation, for the purpose of a concerted and effective defense. ICP0 is able to simultaneously attack multiple host pathways by either degrading key restrictive factors or modifying repressive complexes. This is a viral protein that contains an E3 ubiquitin ligase, translocates among different cell compartments and interacts with major defensive complexes. The multiple functional domains of ICP0 can work independently and at the same time coordinate with each other. Dissecting the functional domains of ICP0 and delineating the coordination of these domains will help us understand HSV-1 pathogenicity as well as host defense mechanisms. This article focuses on describing individual ICP0 domains, their biochemical properties and their implication in HSV-1 infection. By putting individual domain functions back into the picture of host anti-viral defense network, this review seeks to elaborate the complex interactions between HSV-1 and its host. PMID:26870669

  5. Houttuynia cordata Targets the Beginning Stage of Herpes Simplex Virus Infection

    PubMed Central

    Hung, Pei-Yun; Ho, Bing-Ching; Lee, Szu-Yuan; Chang, Sui-Yuan; Kao, Chuan-Liang; Lee, Shoei-Sheng; Lee, Chun-Nan

    2015-01-01

    Herpes simplex virus (HSV), a common latent virus in humans, causes certain severe diseases. Extensive use of acyclovir (ACV) results in the development of drug-resistant HSV strains, hence, there is an urgent need to develop new drugs to treat HSV infection. Houttuynia cordata (H. cordata), a natural herbal medicine, has been reported to exhibit anti-HSV effects which is partly NF-κB-dependent. However, the molecular mechanisms by which H. cordata inhibits HSV infection are not elucidated thoroughly. Here, we report that H. cordata water extracts (HCWEs) inhibit the infection of HSV-1, HSV-2, and acyclovir-resistant HSV-1 mainly via blocking viral binding and penetration in the beginning of infection. HCWEs also suppress HSV replication. Furthermore, HCWEs attenuate the first-wave of NF-κB activation, which is essential for viral gene expressions. Further analysis of six compounds in HCWEs revealed that quercetin and isoquercitrin inhibit NF-κB activation and additionally, quercetin also has an inhibitory effect on viral entry. These results indicate that HCWEs can inhibit HSV infection through multiple mechanisms and could be a potential lead for development of new drugs for treating HSV. PMID:25643242

  6. Houttuynia cordata targets the beginning stage of herpes simplex virus infection.

    PubMed

    Hung, Pei-Yun; Ho, Bing-Ching; Lee, Szu-Yuan; Chang, Sui-Yuan; Kao, Chuan-Liang; Lee, Shoei-Sheng; Lee, Chun-Nan

    2015-01-01

    Herpes simplex virus (HSV), a common latent virus in humans, causes certain severe diseases. Extensive use of acyclovir (ACV) results in the development of drug-resistant HSV strains, hence, there is an urgent need to develop new drugs to treat HSV infection. Houttuynia cordata (H. cordata), a natural herbal medicine, has been reported to exhibit anti-HSV effects which is partly NF-κB-dependent. However, the molecular mechanisms by which H. cordata inhibits HSV infection are not elucidated thoroughly. Here, we report that H. cordata water extracts (HCWEs) inhibit the infection of HSV-1, HSV-2, and acyclovir-resistant HSV-1 mainly via blocking viral binding and penetration in the beginning of infection. HCWEs also suppress HSV replication. Furthermore, HCWEs attenuate the first-wave of NF-κB activation, which is essential for viral gene expressions. Further analysis of six compounds in HCWEs revealed that quercetin and isoquercitrin inhibit NF-κB activation and additionally, quercetin also has an inhibitory effect on viral entry. These results indicate that HCWEs can inhibit HSV infection through multiple mechanisms and could be a potential lead for development of new drugs for treating HSV. PMID:25643242

  7. Oligonucleotides Designed to Inhibit TLR9 Block Herpes Simplex Virus type 1 Infection at Multiple Steps

    PubMed Central

    Sauter, Monica M.; Gauger, Joshua J. L.; Brandt, Curtis R.

    2014-01-01

    Herpes simplex virus type 1 (HSV-1) is an important human pathogen which requires activation of nuclear factor–kappa B (NFκB) during its replication cycle. The persistent nature of HSV-1 infection, and the emergence of drug-resistant strains, highlights the importance of research to develop new antiviral agents. Toll-like receptors (TLR) play a prominent role during the early antiviral response by recognizing viral nucleic acid and gene products, activating NFκB, and stimulating the production of inflammatory cytokines. We demonstrate a significant effect on HSV-1 replication in ARPE-19 and Vero cells when oligonucleotides designed to inhibit TLR9 are added 2 hours prior to infection. A greater than 90% reduction in the yield of infectious virus was achieved at oligonucleotide concentrations of 10 to 20 micromolar. TLR9 inhibitory oligonucleotides prevented expression of essential immediate early herpes gene products as determined by immunofluorescence microscopy and Western blotting. TLR9 oligonucleotides also interfered with viral attachment and entry. A TLR9 inhibitory oligonucleotide containing five adjacent guanosine residues (G-ODN) exhibited virucidal activity and inhibited HSV-1 replication when added post-infection. The antiviral effect of the TLR9 inhibitory oligonucleotides did not depend on the presence of TLR9 protein, suggesting a mechanism of inhibition that is not TLR9 specific. TLR9 inhibitory oligonucleotides also reduced NFκB activity in nuclear extracts. Studies using these TLR inhibitors in the context of viral infection should be interpreted with caution. PMID:24995383

  8. Quantitative autoradiographic mapping of herpes simplex virus encephalitis with a radiolabeled antiviral drug

    SciTech Connect

    Saito, Y.; Price, R.W.; Rottenberg, D.A.; Fox, J.J.; Su, T.L.; Watanabe, K.A.; Philips, F.S.

    1982-09-17

    2'-Fluoro-5-methyl-1-..beta..-D-arabinosyluracil (FMAU) labeled with carbon-14 was used to image herpes simplex virus type 1-infected regions of rat brain by quantitative autoradiography. FMAU is a potent antiviral pyrimidine nucleoside which is selectively phosphorylated by virus-coded thymidine kinase. When the labeled FMAU was administered 6 hours before the rats were killed, the selective uptake and concentration of the drug and its metabolites by infected cells (defined by immunoperoxidase staining of viral antigens) allowed quantitative definition and mapping of HSV-1-infected structures in autoradiograms of brain sections. These results shown that quantitative autoradiography can be used to characterize the local metabolism of antiviral drugs by infected cells in vivo. They also suggest that the selective uptake of drugs that exploit viral thymidine kinase for their antiviral effect can, by appropriate labeling, be used in conjunction with clinical neuroimaging techniques to define infected regions of human brain, thereby providing a new approach to the diagnosis of herpes encephalitis in man.

  9. Herpes simplex virus vectors overexpressing the glucose transporter gene protect against seizure-induced neuron loss.

    PubMed Central

    Lawrence, M S; Ho, D Y; Dash, R; Sapolsky, R M

    1995-01-01

    We have generated herpes simplex virus (HSV) vectors vIE1GT and v alpha 4GT bearing the GLUT-1 isoform of the rat brain glucose transporter (GT) under the control of the human cytomegalovirus ie1 and HSV alpha 4 promoters, respectively. We previously reported that such vectors enhance glucose uptake in hippocampal cultures and the hippocampus. In this study we demonstrate that such vectors can maintain neuronal metabolism and reduce the extent of neuron loss in cultures after a period of hypoglycemia. Microinfusion of GT vectors into the rat hippocampus also reduces kainic acid-induced seizure damage in the CA3 cell field. Furthermore, delivery of the vector even after onset of the seizure is protective, suggesting that HSV-mediated gene transfer for neuroprotection need not be carried out in anticipation of neurologic crises. Using the bicistronic vector v alpha 22 beta gal alpha 4GT, which coexpresses both GT and the Escherichia coli lacZ marker gene, we further demonstrate an inverse correlation between the extent of vector expression in the dentate and the amount of CA3 damage resulting from the simultaneous delivery of kainic acid. Images Fig. 2 Fig. 5 PMID:7638175

  10. Distinct Impact of Two Keratin Mutations Causing Epidermolysis Bullosa Simplex on Keratinocyte Adhesion and Stiffness.

    PubMed

    Homberg, Melanie; Ramms, Lena; Schwarz, Nicole; Dreissen, Georg; Leube, Rudolf E; Merkel, Rudolf; Hoffmann, Bernd; Magin, Thomas M

    2015-10-01

    Keratin filaments constitute the major component of the epidermal cytoskeleton from heterodimers of type I and type II keratin subunits. Missense mutations in keratin 5 or keratin 14, highly expressed in the basal epidermis, cause the severe skin blistering disease epidermolysis bullosa simplex (EBS) in humans by rendering the keratin cytoskeleton sensitive to mechanical stress; yet, the mechanisms by which individual mutations cause cell fragility are incompletely understood. Here, we compared the K14p.Arg125Pro with the K5p.Glu477Asp mutation, both giving rise to severe generalized EBS, by stable expression in keratin-free keratinocytes. This revealed distinctly different effects on keratin cytoskeletal organization, in agreement with in vivo observations, thus validating the cell system. Although the K14p.Arg125Pro mutation led to impaired desmosomes, downregulation of desmosomal proteins, and weakened epithelial sheet integrity upon shear stress, the K5p.Glu477Asp mutation did not impair these functions, although causing EBS with squamous cell carcinoma in vivo. Atomic force microscopy demonstrated that K14 mutant cells were even less resistant against deformation compared with keratin-free keratinocytes. Thus, a keratin mutation causing EBS compromises cell stiffness to a greater extent than the lack of keratins. Finally, re-expression of K14 in K14 mutant cells did not rescue the above defects. Collectively, our findings have implications for EBS therapy approaches. PMID:25961909

  11. Alternative Entry Receptors for Herpes Simplex Virus and Their Roles in Disease

    PubMed Central

    Taylor, Joann M.; Lin, Erick; Susmarski, Nanette; Yoon, Miri; Zago, Anna; Ware, Carl F.; Pfeffer, Klaus; Miyoshi, Jun; Takai, Yoshimi; Spear, Patricia G.

    2007-01-01

    SUMMARY Either herpesvirus entry mediator (HVEM, TNFRSF14) or nectin-1 (PVRL1) is sufficient for herpes simplex virus (HSV) infection of cultured cells. The contribution of individual receptors to infection in vivo and to disease is less clear. To assess this, Tnfrsf14 −/− and/or Pvrl1 −/− mice were challenged intravaginally with HSV-2. Infection of the vaginal epithelium occurred in the absence of either HVEM or nectin-1, but was virtually undetectable when both receptors were absent, indicating that either HVEM or nectin-1 was necessary. Absence of nectin-1 (but not HVEM) reduced efficiency of infection of the vaginal epithelium and viral spread to the nervous system, attenuating neurological disease and preventing external lesion development. While nectin-1 proved not to be essential for infection of the nervous system, it is required for the full manifestations of disease. This study illustrates the value of mutant mice for understanding receptor contributions to disease caused by a human virus. PMID:18005714

  12. Isolation of virus from brain after immunosuppression of mice with latent herpes simplex

    NASA Astrophysics Data System (ADS)

    Kastrukoff, Lorne; Long, Carol; Doherty, Peter C.; Wroblewska, Zofia; Koprowski, Hilary

    1981-06-01

    Herpes simplex virus (HSV) is usually present in a latent form in the trigeminal ganglion of man1-3. Various stress factors may induce virus reactivation, which is manifest by a lip lesion (innervated from the trigeminal ganglion) and the production of infectious virus. The considerable experimental efforts to define the conditions that lead to the reactivation of latent HSV have concentrated on isolating virus either from the original extraneural site of virus inoculation, or from cell-free homogenates of sensory ganglia from latently infected animals4-15. Recent DNA hybridization experiments resulted in the demonstration of the presence of HSV genomes in the brain tissue of both latently infected mice, and of humans who showed no clinical symptoms of HSV (ref. 16 and N. Fraser, personal communication). This led us to consider the possibility that HSV may be present in brain tissue as the result of either reactivation of the virus in brain cells or the passage of reactivated virus from trigeminal ganglia through the brain stem to the brain. The presence of infectious HSV in brain tissue has not previously been demonstrated; yet this could be a factor in chronic, relapsing neurological diseases such as multiple sclerosis. We have now shown experimentally that mice carrying latent HSV in their trigeminal ganglia may, following massive immunosuppression, express infectious virus in the central nervous system (CNS).

  13. Structural analysis of herpes simplex virus by optical super-resolution imaging

    NASA Astrophysics Data System (ADS)

    Laine, Romain F.; Albecka, Anna; van de Linde, Sebastian; Rees, Eric J.; Crump, Colin M.; Kaminski, Clemens F.

    2015-01-01

    Herpes simplex virus type-1 (HSV-1) is one of the most widespread pathogens among humans. Although the structure of HSV-1 has been extensively investigated, the precise organization of tegument and envelope proteins remains elusive. Here we use super-resolution imaging by direct stochastic optical reconstruction microscopy (dSTORM) in combination with a model-based analysis of single-molecule localization data, to determine the position of protein layers within virus particles. We resolve different protein layers within individual HSV-1 particles using multi-colour dSTORM imaging and discriminate envelope-anchored glycoproteins from tegument proteins, both in purified virions and in virions present in infected cells. Precise characterization of HSV-1 structure was achieved by particle averaging of purified viruses and model-based analysis of the radial distribution of the tegument proteins VP16, VP1/2 and pUL37, and envelope protein gD. From this data, we propose a model of the protein organization inside the tegument.

  14. Woodylides A–C, New Cytotoxic Linear Polyketides from the South China Sea Sponge Plakortis simplex

    PubMed Central

    Yu, Hao-Bing; Liu, Xiang-Fang; Xu, Ying; Gan, Jian-Hong; Jiao, Wei-Hua; Shen, Yang; Lin, Hou-Wen

    2012-01-01

    Three new polyketides, woodylides A–C (1–3), were isolated from the ethanol extract of the South China Sea sponge Plakortis simplex. The structures were elucidated by spectroscopic data (IR, 1D and 2D NMR, and HRESIMS). The absolute configurations at C-3 of 1 and 3 were determined by the modified Mosher’s method. Antifungal, cytotoxic, and PTP1B inhibitory activities of these polyketides were evaluated. Compounds 1 and 3 showed antifungal activity against fungi Cryptococcus neoformans with IC50 values of 3.67 and 10.85 µg/mL, respectively. In the cytotoxicity test, compound 1 exhibited a moderate effect against the HeLa cell line with an IC50 value of 11.2 µg/mL, and compound 3 showed cytotoxic activity against the HCT-116 human colon tumor cell line and PTP1B inhibitory activity with IC50 values of 9.4 and 4.7 µg/mL, respectively. PMID:22822354

  15. The role of herpes simplex virus-1 thymidine kinase alanine 168 in substrate specificity.

    PubMed

    Candice L, Willmon; Django, Sussman; Margaret E, Black

    2008-01-01

    Herpes simplex virus type 1 (HSV) thymidine kinase (TK) has been widely used in suicide gene therapy for the treatment of cancer due to its broad substrate specificity and the inability of the endogenous human TK to phosphorylate guanosine analogs such as ganciclovir (GCV). The basis of suicide gene therapy is the introduction of a gene that encodes a prodrug-activating enzyme into tumor cells. After administration, the prodrug is selectively converted to a toxic drug by the suicide gene product thereby bringing about the eradication of the cancer cells. A major drawback to this therapy is the low activity the enzyme displays towards the prodrugs, requiring high prodrug doses that result in adverse side effects. Earlier studies revealed two HSV TK variants (SR39 and mutant 30) derived by random mutagenesis with enhanced activities towards GCV in vitro and in vivo. While these mutants contain multiple amino acid substitutions, molecular modeling suggests that substitutions at alanine 168 (A168) may be responsible for the observed increase in prodrug sensitivity. To evaluate this, site-directed mutagenesis was used to individually substitute A168 with phenylalanine or tyrosine to reflect the mutations found in SR39 and mutant 30, respectively. Additionally, kinetic parameters and the ability of these mutants to sensitize tumor cells to GCV in comparison to wild-type thymidine kinase were determined. PMID:18949076

  16. Frequent Release of Low Amounts of Herpes Simplex Virus From Neurons: Results of a Mathematical Model

    PubMed Central

    Schiffer, Joshua T.; Abu-Raddad, Laith; Mark, Karen E.; Zhu, Jia; Selke, Stacy; Magaret, Amalia; Wald, Anna; Corey, Lawrence

    2010-01-01

    Herpes Simplex Virus-2 (HSV-2) is a sexually transmitted infection that is the leading cause of genital ulcers worldwide. Infection is life long and is characterized by repeated asymptomatic and symptomatic shedding episodes of virus that are initiated when virus is released from neurons into the genital tract. The pattern of HSV-2 release from neurons into the genital tract is poorly understood. We fit a mathematical model of HSV-2 pathogenesis to curves generated from daily quantification of HSV in mucosal swabs performed from patients with herpetic genital ulcers. We used virologic parameters derived from model fitting for stochastic model simulations. These simulations reproduced previously documented estimates for shedding frequency, and herpetic lesion diameter and frequency. The most realistic model output occurred when we assumed minimal amounts of daily neuronal virus introduction. In our simulations, small changes in average total quantity of HSV-2 released from neurons influenced detectable shedding frequency, while changes in frequency of neuronal HSV-2 release had little effect. Frequent HSV-2 shedding episodes in humans are explained by nearly constant release of small numbers of viruses from neurons that terminate in the genital tract. PMID:20161655

  17. Functional IRF3 deficiency in a patient with herpes simplex encephalitis

    PubMed Central

    Andersen, Line Lykke; Mørk, Nanna; Reinert, Line S.; Kofod-Olsen, Emil; Narita, Ryo; Jørgensen, Sofie E.; Skipper, Kristian A.; Höning, Klara; Gad, Hans Henrik; Østergaard, Lars; Ørntoft, Torben F.; Hornung, Veit; Paludan, Søren R.; Mikkelsen, Jacob Giehm; Fujita, Takashi; Christiansen, Mette; Hartmann, Rune

    2015-01-01

    Herpes simplex encephalitis (HSE) in children has previously been linked to defects in type I interferon (IFN) production downstream of Toll-like receptor 3. Here, we describe a novel genetic etiology of HSE by identifying a heterozygous loss-of-function mutation in the IFN regulatory factor 3 (IRF3) gene, leading to autosomal dominant (AD) IRF3 deficiency by haploinsufficiency, in an adolescent female patient with HSE. IRF3 is activated by most pattern recognition receptors recognizing viral infections and plays an essential role in induction of type I IFN. The identified IRF3 R285Q amino acid substitution results in impaired IFN responses to HSV-1 infection and particularly impairs signaling through the TLR3–TRIF pathway. In addition, the R285Q mutant of IRF3 fails to become phosphorylated at S386 and undergo dimerization, and thus has impaired ability to activate transcription. Finally, transduction with WT IRF3 rescues the ability of patient fibroblasts to express IFN in response to HSV-1 infection. The identification of IRF3 deficiency in HSE provides the first description of a defect in an IFN-regulating transcription factor conferring increased susceptibility to a viral infection in the CNS in humans. PMID:26216125

  18. Latent Herpes Simplex Virus Infection of Sensory Neurons Alters Neuronal Gene Expression

    PubMed Central

    Kramer, Martha F.; Cook, W. James; Roth, Frederick P.; Zhu, Jia; Holman, Holly; Knipe, David M.; Coen, Donald M.

    2003-01-01

    The persistence of herpes simplex virus (HSV) and the diseases that it causes in the human population can be attributed to the maintenance of a latent infection within neurons in sensory ganglia. Little is known about the effects of latent infection on the host neuron. We have addressed the question of whether latent HSV infection affects neuronal gene expression by using microarray transcript profiling of host gene expression in ganglia from latently infected versus mock-infected mouse trigeminal ganglia. 33P-labeled cDNA probes from pooled ganglia harvested at 30 days postinfection or post-mock infection were hybridized to nylon arrays printed with 2,556 mouse genes. Signal intensities were acquired by phosphorimager. Mean intensities (n = 4 replicates in each of three independent experiments) of signals from mock-infected versus latently infected ganglia were compared by using a variant of Student's t test. We identified significant changes in the expression of mouse neuronal genes, including several with roles in gene expression, such as the Clk2 gene, and neurotransmission, such as genes encoding potassium voltage-gated channels and a muscarinic acetylcholine receptor. We confirmed the neuronal localization of some of these transcripts by using in situ hybridization. To validate the microarray results, we performed real-time reverse transcriptase PCR analyses for a selection of the genes. These studies demonstrate that latent HSV infection can alter neuronal gene expression and might provide a new mechanism for how persistent viral infection can cause chronic disease. PMID:12915567

  19. Invasion of Herpes Simplex Virus Type 1 into Murine Epidermis: An Ex Vivo Infection Study.

    PubMed

    Rahn, Elena; Petermann, Philipp; Thier, Katharina; Bloch, Wilhelm; Morgner, Jessica; Wickström, Sara A; Knebel-Mörsdorf, Dagmar

    2015-12-01

    Herpes simplex virus type 1 (HSV-1) invades its human host via the skin or mucosa. We aim to understand how HSV-1 overcomes the barrier function of the host epithelia, and for this reason, we established an ex vivo infection assay initially with murine skin samples. Here, we report how tissue has to be prepared to be susceptible to HSV-1 infection. Most efficient infection of the epidermis was achieved by removing the dermis. HSV-1 initially invaded the basal epidermal layer, and from there, spreading to the suprabasal layers was observed. Strikingly, in resting stage hair follicles, only the hair germ was infected, whereas the quiescent bulge stem cells (SCs) were resistant to infection. However, during the growth phase, infected cells were also detected in the activated bulge SCs. We demonstrated that cell proliferation was not a precondition for HSV-1 invasion, but SC activation was required as shown by infection of aberrantly activated bulge SCs in integrin-linked kinase (ILK)-deficient hair follicles. These results suggest that the status of the bulge SCs determines whether HSV-1 can reach its receptors, whereas the receptors on basal keratinocytes are accessible irrespective of their proliferation status. PMID:26203638

  20. Viral forensic genomics reveals the relatedness of classic herpes simplex virus strains KOS, KOS63, and KOS79.

    PubMed

    Bowen, Christopher D; Renner, Daniel W; Shreve, Jacob T; Tafuri, Yolanda; Payne, Kimberly M; Dix, Richard D; Kinchington, Paul R; Gatherer, Derek; Szpara, Moriah L

    2016-05-01

    Herpes simplex virus 1 (HSV-1) is a widespread global pathogen, of which the strain KOS is one of the most extensively studied. Previous sequence studies revealed that KOS does not cluster with other strains of North American geographic origin, but instead clustered with Asian strains. We sequenced a historical isolate of the original KOS strain, called KOS63, along with a separately isolated strain attributed to the same source individual, termed KOS79. Genomic analyses revealed that KOS63 closely resembled other recently sequenced isolates of KOS and was of Asian origin, but that KOS79 was a genetically unrelated strain that clustered in genetic distance analyses with HSV-1 strains of North American/European origin. These data suggest that the human source of KOS63 and KOS79 could have been infected with two genetically unrelated strains of disparate geographic origins. A PCR RFLP test was developed for rapid identification of these strains. PMID:26950505

  1. Natural killer cell receptor expression in patients with severe and recurrent Herpes simplex virus-1 (HSV-1) infections.

    PubMed

    Carter, C; Savic, S; Cole, J; Wood, P

    2007-04-01

    Herpes simplex virus-1 (HSV-1) is an important human pathogen which in a minority of people causes severe infections. In immunocompetent hosts the infection is self limiting. However, a small minority of people have frequent attacks. As NK cells have been implicated in host protection against HSV-1, the aim of this study was to compare NK cell receptor expression in healthy controls and in patients suffering from recurrent HSV-1 reactivations using monoclonal antibodies against NK cell receptors and 3 colour flow cytometry. Eighteen patients were recruited into the study and the results were compared to a control group. The results obtained showed that overall there was no statistical difference between patient and control groups in the expression of the NK cell receptors. There were however, individuals in the patient group (in particular, two members of one family) with significantly reduced level of activating receptors compared to the control group. PMID:17706187

  2. Reversible Nerve Damage and Corneal Pathology in Murine Herpes Simplex Stromal Keratitis

    PubMed Central

    Yun, Hongmin; Rowe, Alexander M.; Lathrop, Kira L.; Harvey, Stephen A. K.

    2014-01-01

    ABSTRACT Herpes simplex virus type 1 (HSV-1) shedding from sensory neurons can trigger recurrent bouts of herpes stromal keratitis (HSK), an inflammatory response that leads to progressive corneal scarring and blindness. A mouse model of HSK is often used to delineate immunopathogenic mechanisms and bears many of the characteristics of human disease, but it tends to be more chronic and severe than human HSK. Loss of blink reflex (BR) in human HSK is common and due to a dramatic retraction of corneal sensory nerve termini in the epithelium and the nerve plexus at the epithelial/stromal interface. However, the relationship between loss of BR due to nerve damage and corneal pathology associated with HSK remains largely unexplored. Here, we show a similar retraction of corneal nerves in mice with HSK. Indeed, we show that much of the HSK-associated corneal inflammation in mice is actually attributable to damage to the corneal nerves and accompanying loss of BR and can be prevented or ameliorated by tarsorrhaphy (suturing eyelids closed), a clinical procedure commonly used to prevent corneal exposure and desiccation. In addition, we show that HSK-associated nerve retraction, loss of BR, and severe pathology all are reversible and regulated by CD4+ T cells. Thus, defining immunopathogenic mechanisms of HSK in the mouse model will necessitate distinguishing mechanisms associated with the immunopathologic response to the virus from those associated with loss of corneal sensation. Based on our findings, investigation of a possible contribution of nerve damage and BR loss to human HSK also appears warranted. IMPORTANCE HSK in humans is a potentially blinding disease characterized by recurrent inflammation and progressive scarring triggered by viral release from corneal nerves. Corneal nerve damage is a known component of HSK, but the causes and consequences of HSK-associated nerve damage remain obscure. We show that desiccation of the corneal surface due to nerve damage and

  3. Evaluation of PD 404,182 as an Anti-HIV and Anti-Herpes Simplex Virus Microbicide

    PubMed Central

    Chamoun-Emanuelli, Ana M.; Bobardt, Michael; Moncla, Bernard; Mankowski, Marie K.; Ptak, Roger G.

    2014-01-01

    PD 404,182 (PD) is a synthetic compound that was found to compromise HIV integrity via interaction with a nonenvelope protein viral structural component (A. M. Chamoun et al., Antimicrob. Agents Chemother. 56:672–681, 2012). The present study evaluates the potential of PD as an anti-HIV microbicide and establishes PD's virucidal activity toward another pathogen, herpes simplex virus (HSV). We show that the anti-HIV-1 50% inhibitory concentration (IC50) of PD, when diluted in seminal plasma, is ∼1 μM, similar to the IC50 determined in cell culture growth medium, and that PD retains full anti-HIV-1 activity after incubation in cervical fluid at 37°C for at least 24 h. In addition, PD is nontoxic toward vaginal commensal Lactobacillus species (50% cytotoxic concentration [CC50], >300 μM), freshly activated human peripheral blood mononuclear cells (CC50, ∼200 μM), and primary CD4+ T cells, macrophages, and dendritic cells (CC50, >300 μM). PD also exhibited high stability in pH-adjusted Dulbecco's phosphate-buffered saline with little to no activity loss after 8 weeks at pH 4 and 42°C, indicating suitability for formulation for transportation and storage in developing countries. Finally, for the first time, we show that PD inactivates herpes simplex virus 1 (HSV-1) and HSV-2 at submicromolar concentrations. Due to the prevalence of HSV infection, the ability of PD to inactivate HSV may provide an additional incentive for use as a microbicide. The ability of PD to inactivate both HIV-1 and HSV, combined with its low toxicity and high stability, warrants additional studies for the evaluation of PD's microbicidal candidacy in animals and humans. PMID:24217696

  4. Evaluation of PD 404,182 as an anti-HIV and anti-herpes simplex virus microbicide.

    PubMed

    Chamoun-Emanuelli, Ana M; Bobardt, Michael; Moncla, Bernard; Mankowski, Marie K; Ptak, Roger G; Gallay, Philippe; Chen, Zhilei

    2014-01-01

    PD 404,182 (PD) is a synthetic compound that was found to compromise HIV integrity via interaction with a nonenvelope protein viral structural component (A. M. Chamoun et al., Antimicrob. Agents Chemother. 56:672-681, 2012). The present study evaluates the potential of PD as an anti-HIV microbicide and establishes PD's virucidal activity toward another pathogen, herpes simplex virus (HSV). We show that the anti-HIV-1 50% inhibitory concentration (IC50) of PD, when diluted in seminal plasma, is ∼1 μM, similar to the IC50 determined in cell culture growth medium, and that PD retains full anti-HIV-1 activity after incubation in cervical fluid at 37°C for at least 24 h. In addition, PD is nontoxic toward vaginal commensal Lactobacillus species (50% cytotoxic concentration [CC50], >300 μM), freshly activated human peripheral blood mononuclear cells (CC50, ∼200 μM), and primary CD4(+) T cells, macrophages, and dendritic cells (CC50, >300 μM). PD also exhibited high stability in pH-adjusted Dulbecco's phosphate-buffered saline with little to no activity loss after 8 weeks at pH 4 and 42°C, indicating suitability for formulation for transportation and storage in developing countries. Finally, for the first time, we show that PD inactivates herpes simplex virus 1 (HSV-1) and HSV-2 at submicromolar concentrations. Due to the prevalence of HSV infection, the ability of PD to inactivate HSV may provide an additional incentive for use as a microbicide. The ability of PD to inactivate both HIV-1 and HSV, combined with its low toxicity and high stability, warrants additional studies for the evaluation of PD's microbicidal candidacy in animals and humans. PMID:24217696

  5. Subcell resolution in simplex stochastic collocation for spatial discontinuities

    NASA Astrophysics Data System (ADS)

    Witteveen, Jeroen A. S.; Iaccarino, Gianluca

    2013-10-01

    Subcell resolution has been used in the Finite Volume Method (FVM) to obtain accurate approximations of discontinuities in the physical space. Stochastic methods are usually based on local adaptivity for resolving discontinuities in the stochastic dimensions. However, the adaptive refinement in the probability space is ineffective in the non-intrusive uncertainty quantification framework, if the stochastic discontinuity is caused by a discontinuity in the physical space with a random location. The dependence of the discontinuity location in the probability space on the spatial coordinates then results in a staircase approximation of the statistics, which leads to first-order error convergence and an underprediction of the maximum standard deviation. To avoid these problems, we introduce subcell resolution into the Simplex Stochastic Collocation (SSC) method for obtaining a truly discontinuous representation of random spatial discontinuities in the interior of the cells discretizing the probability space. The presented SSC-SR method is based on resolving the discontinuity location in the probability space explicitly as function of the spatial coordinates and extending the stochastic response surface approximations up to the predicted discontinuity location. The applications to a linear advection problem, the inviscid Burgers' equation, a shock tube problem, and the transonic flow over the RAE 2822 airfoil show that SSC-SR resolves random spatial discontinuities with multiple stochastic and spatial dimensions accurately using a minimal number of samples.

  6. Herpes Simplex Virus and Varicella-Zoster Virus.

    PubMed

    Levin, Myron J; Weinberg, Adriana; Schmid, D Scott

    2016-06-01

    The most common specimens from immunocompromised patients that are analyzed for detection of herpes simplex virus (HSV) or varicella-zoster virus (VZV) are from skin lesions. Many types of assays are applicable to these samples, but some, such as virus isolation and direct fluorescent antibody testing, are useful only in the early phases of the lesions. In contrast, nucleic acid (NA) detection methods, which generally have superior sensitivity and specificity, can be applied to skin lesions at any stage of progression. NA methods are also the best choice, and sometimes the only choice, for detecting HSV or VZV in blood, cerebrospinal fluid, aqueous or vitreous humor, and from mucosal surfaces. NA methods provide the best performance when reliability and speed (within 24 hours) are considered together. They readily distinguish the type of HSV detected or the source of VZV detected (wild type or vaccine strain). Nucleic acid detection methods are constantly being improved with respect to speed and ease of performance. Broader applications are under study, such as the use of quantitative results of viral load for prognosis and to assess the efficacy of antiviral therapy. PMID:27337486

  7. Herpes simplex virus encephalitis in Peru: a multicentre prospective study.

    PubMed

    Montano, S M; Mori, N; Nelson, C A; Ton, T G N; Celis, V; Ticona, E; Sihuincha, M; Tilley, D H; Kochel, T; Zunt, J R

    2016-06-01

    Herpes simplex virus (HSV) is one of the most commonly identified infectious aetiologies of encephalitis in North America and Europe. The epidemiology of encephalitis beyond these regions, however, is poorly defined. During 2009-2012 we enrolled 313 patients in a multicentre prospective study of encephalitis in Peru, 45 (14·4%) of whom had confirmed HSV infection. Of 38 patients with known HSV type, 84% had HSV-1 and 16% had HSV-2. Patients with HSV infection were significantly more likely to present in the summer months (44·4% vs. 20·0%, P = 0·003) and have nausea (60·0% vs. 39·8%, P = 0·01) and rash (15·6% vs. 5·3%, P = 0·01) compared to patients without HSV infection. These findings highlight differences in the epidemiology and clinical presentation of HSV encephalitis outside of the Northern Hemisphere that warrant further investigation. Furthermore, there is an urgent need for improved HSV diagnostic capacity and availability of intravenous acyclovir in Peru. PMID:26733400

  8. Simplex-in-cell technique for collisionless plasma simulations

    NASA Astrophysics Data System (ADS)

    Kates-Harbeck, Julian; Totorica, Samuel; Zrake, Jonathan; Abel, Tom

    2016-01-01

    We extend the simplex-in-cell (SIC) technique recently introduced in the context of collisionless dark matter fluids [1,2] to the case of collisionless plasmas. The six-dimensional phase space distribution function f (x , v) is represented by an ensemble of three-dimensional manifolds, which we refer to as sheets. The electric potential field is obtained by solving the Poisson equation on a uniform mesh, where the charge density is evaluated by a spatial projection of the phase space sheets. The SIC representation of phase space density facilitates robust, high accuracy numerical evolution of the Vlasov-Poisson system using significantly fewer tracer particles than comparable particle-in-cell (PIC) approaches by reducing the numerical shot-noise associated with the latter. We introduce the SIC formulation and describe its implementation in a new code, which we validate using standard test problems including plasma oscillations, Landau damping, and two stream instabilities in one dimension. Merits of the new scheme are shown to include higher accuracy and faster convergence rates in the number of particles. We finally motivate and outline the efficient application of SIC to higher dimensional problems.

  9. Herpes Simplex Virus Products in Productive and Abortive Infection

    PubMed Central

    Spring, Susan B.; Roizman, Bernard; Schwartz, Jerome

    1968-01-01

    Herpes simplex virus strain MPdk− multiplies in HEp-2 cells, but not in dog kidney (DK) cells. Strain MPdk+sp, a multistep mutant of MPdk−, multiplies in both HEp-2 and DK cells. Stabilized lysates of productively infected cells yield three macromolecular aggregates of viral deoxyribonucleic acid and protein banding in CsCl gradients at densities of 1.285 g/cm3 (α), 1.325 g/cm3 (β), and 1.37 to 1.45 g/cm3 (γ). Similar lysates from abortively infected cells yield only the β and γ bands. Electron microscopic examination revealed that (i) the α band contained enveloped nucleocapsids, whereas the β band contained naked nucleocapsids and particles tentatively identified as internal components of the nucleocapsids, and that (ii) the enveloped virions and reduplication of cellular membranes observed in thin sections of productively infected cells were absent from abortively infected cells. Studies of the surface antigens of infected cells in a cytolytic system described previously revealed that abortively infected cells contained approximately 10-fold less virus-induced surface antigen than did productively infected cells. From these and other data published previously, we concluded that infectious MPdk− virions are not made in DK cells because (i) functional viral products necessary for the envelopment of the nucleocapsid are not made, and (ii) capsid proteins and some nonstructural products specified by the virus malfunction. Images PMID:4316018

  10. Subassemblies and Asymmetry in Assembly of Herpes Simplex Virus Procapsid

    PubMed Central

    Aksyuk, Anastasia A.; Newcomb, William W.; Cheng, Naiqian; Winkler, Dennis C.; Fontana, Juan; Heymann, J. Bernard

    2015-01-01

    ABSTRACT The herpes simplex virus 1 (HSV-1) capsid is a massive particle (~200 MDa; 1,250-Å diameter) with T=16 icosahedral symmetry. It initially assembles as a procapsid with ~4,000 protein subunits of 11 different kinds. The procapsid undergoes major changes in structure and composition as it matures, a process driven by proteolysis and expulsion of the internal scaffolding protein. Assembly also relies on an external scaffolding protein, the triplex, an α2β heterotrimer that coordinates neighboring capsomers in the procapsid and becomes a stabilizing clamp in the mature capsid. To investigate the mechanisms that regulate its assembly, we developed a novel isolation procedure for the metastable procapsid and collected a large set of cryo-electron microscopy data. In addition to procapsids, these preparations contain maturation intermediates, which were distinguished by classifying the images and calculating a three-dimensional reconstruction for each class. Appraisal of the procapsid structure led to a new model for assembly; in it, the protomer (assembly unit) consists of one triplex, surrounded by three major capsid protein (MCP) subunits. The model exploits the triplexes’ departure from 3-fold symmetry to explain the highly skewed MCP hexamers, the triplex orientations at each 3-fold site, and the T=16 architecture. These observations also yielded new insights into maturation. PMID:26443463

  11. Herpes simplex virus induces the replication of foreign DNA

    SciTech Connect

    Danovich, R.M.; Frenkel, N.

    1988-08-01

    Plasmids containing the simian virus 40 (SV40) DNA replication origin and the large T gene are replicated in Vero monkey cells but not in rabbit skin cells. Efficient replication of the plasmids was observed in rabbit cells infected with herpes simplex virus type 1 (HSV-1) and HSV-2. The HSV-induced replication required the large T antigen and the SV40 replication origin. However, it produced concatemeric molecules resembling replicative intermediates of HSV DNA and was sensitive to phosphonoacetate at concentrations known to inhibit the HSV DNA polymerase. Therefore, it involved the HSV DNA polymerase itself or a viral gene product(s) which was expressed following the replication of HSV DNA. Analyses of test plasmids lacking SV40 or HSV DNA sequences showed that, under some conditions. HSV also induced low-level replication of test plasmids containing no known eucaryotic replication origins. Together, these results show that HSV induces a DNA replicative activity which amplifies foreign DNA. The relevance of these findings to the putative transforming potential of HSV is discussed.

  12. Stabilising the Herpes Simplex Virus capsid by DNA packaging

    NASA Astrophysics Data System (ADS)

    Wuite, Gijs; Radtke, Kerstin; Sodeik, Beate; Roos, Wouter

    2009-03-01

    Three different types of Herpes Simplex Virus type 1 (HSV-1) nuclear capsids can be distinguished, A, B and C capsids. These capsids types are, respectively, empty, contain scaffold proteins, or hold DNA. We investigate the physical properties of these three capsids by combining biochemical and nanoindentation techniques. Atomic Force Microscopy (AFM) experiments show that A and C capsids are mechanically indistinguishable whereas B capsids already break at much lower forces. By extracting the pentamers with 2.0 M GuHCl or 6.0 M Urea we demonstrate an increased flexibility of all three capsid types. Remarkably, the breaking force of the B capsids without pentamers does not change, while the modified A and C capsids show a large drop in their breaking force to approximately the value of the B capsids. This result indicates that upon DNA packaging a structural change at or near the pentamers occurs which mechanically reinforces the capsids structure. The reported binding of proteins UL17/UL25 to the pentamers of the A and C capsids seems the most likely candidate for such capsids strengthening. Finally, the data supports the view that initiation of DNA packaging triggers the maturation of HSV-1 capsids.

  13. Bioactive lignan derivatives from the stems of Firmiana simplex.

    PubMed

    Woo, Kyeong Wan; Suh, Won Se; Subedi, Lalita; Kim, Sun Yeou; Kim, Aejung; Lee, Kang Ro

    2016-02-01

    The CHCl3 soluble fraction of the 80% MeOH extract of the stems of Firmiana simplex strongly inhibited nitric oxide production in lipopolysaccharide-activated BV-2 cells. A bioactivity-guided column chromatographic separation yielded two new lignans, firmianols A and B (1-2) together with seventeen known lignans (3-19). The structural elucidation of the new compounds was determined by spectroscopic methods, including 1D, 2D NMR and HR-FAB-MS. All isolated lignans were evaluated for their antineuroinflammatory effects on nitric oxide (NO) production in lipopolysaccharides (LPS)-activated murine microglia BV2 cells. Among the isolated, compounds 14 and 15 showed potent inhibitory activity against NO production (IC50 1.05 and 0.929 μM, respectively) without cell toxicity in murine microglia BV-2 cells. Compounds 11-13 and 17 also exhibited strong inhibitory effects on NO production, with IC50 values ranging from 7.07 to 15.28 μM. PMID:26774654

  14. Position error propagation in the simplex strapdown navigation system

    NASA Technical Reports Server (NTRS)

    1976-01-01

    The results of an analysis of the effects of deterministic error sources on position error in the simplex strapdown navigation system were documented. Improving the long term accuracy of the system was addressed in two phases: understanding and controlling the error within the system, and defining methods of damping the net system error through the use of an external reference velocity or position. Review of the flight and ground data revealed error containing the Schuler frequency as well as non-repeatable trends. The only unbounded terms are those involving gyro bias and azimuth error coupled with velocity. All forms of Schuler-periodic position error were found to be sufficiently large to require update or damping capability unless the source coefficients can be limited to values less than those used in this analysis for misalignment and gyro and accelerometer bias. The first-order effects of the deterministic error sources were determined with a simple error propagator which provided plots of error time functions in response to various source error values.

  15. Herpes simplex virus induces the replication of foreign DNA.

    PubMed Central

    Danovich, R M; Frenkel, N

    1988-01-01

    Plasmids containing the simian virus 40 (SV40) DNA replication origin and the large T gene are replicated efficiently in Vero monkey cells but not in rabbit skin cells. Efficient replication of the plasmids was observed in rabbit skin cells infected with herpes simplex virus type 1 (HSV-1) and HSV-2. The HSV-induced replication required the large T antigen and the SV40 replication origin. However, it produced concatemeric molecules resembling replicative intermediates of HSV DNA and was sensitive to phosphonoacetate at concentrations known to inhibit the HSV DNA polymerase. Therefore, it involved the HSV DNA polymerase itself or a viral gene product(s) which was expressed following the replication of HSV DNA. Analyses of test plasmids lacking SV40 or HSV DNA sequences showed that, under some conditions, HSV also induced low-level replication of test plasmids containing no known eucaryotic replication origins. Together, these results show that HSV induces a DNA replicative activity which amplifies foreign DNA. The relevance of these findings to the putative transforming potential of HSV is discussed. Images PMID:2850486

  16. The herpes simplex virus virion host shutoff function.

    PubMed Central

    Kwong, A D; Frenkel, N

    1989-01-01

    The virion host shutoff (vhs) function of herpes simplex virus (HSV) limits the expression of genes in the infected cells by destabilizing both host and viral mRNAs. vhs function mutants have been isolated which are defective in their ability to degrade host mRNA. Furthermore, the half-life of viral mRNAs is significantly longer in cells infected with the vhs-1 mutant virus than in cells infected with the wild-type (wt) virus. Recent data have shown that the vhs-1 mutation resides within the open reading frame UL41. We have analyzed the shutoff of host protein synthesis in cells infected with a mixture of the wt HSV-1 (KOS) and the vhs-1 mutant virus. The results of these experiments revealed that (i) the wt virus shutoff activity requires a threshold level of input virions per cell and (ii) the mutant vhs-1 virus protein can irreversibly block the wt virus shutoff activity. These results are consistent with a stoichiometric model in which the wt vhs protein interacts with a cellular factor which controls the half-life of cell mRNA. This wt virus interaction results in the destabilization of both host and viral mRNAs. In contrast, the mutant vhs function interacts with the cellular factor irreversibly, resulting in the increased half-life of both host and viral mRNAs. Images PMID:2552156

  17. GPU implementation of the simplex identification via split augmented Lagrangian

    NASA Astrophysics Data System (ADS)

    Sevilla, Jorge; Nascimento, José M. P.

    2015-10-01

    Hyperspectral imaging can be used for object detection and for discriminating between different objects based on their spectral characteristics. One of the main problems of hyperspectral data analysis is the presence of mixed pixels, due to the low spatial resolution of such images. This means that several spectrally pure signatures (endmembers) are combined into the same mixed pixel. Linear spectral unmixing follows an unsupervised approach which aims at inferring pure spectral signatures and their material fractions at each pixel of the scene. The huge data volumes acquired by such sensors put stringent requirements on processing and unmixing methods. This paper proposes an efficient implementation of a unsupervised linear unmixing method on GPUs using CUDA. The method finds the smallest simplex by solving a sequence of nonsmooth convex subproblems using variable splitting to obtain a constraint formulation, and then applying an augmented Lagrangian technique. The parallel implementation of SISAL presented in this work exploits the GPU architecture at low level, using shared memory and coalesced accesses to memory. The results herein presented indicate that the GPU implementation can significantly accelerate the method's execution over big datasets while maintaining the methods accuracy.

  18. Clinical Correlates of Herpes Simplex Virus Viremia Among Hospitalized Adults

    PubMed Central

    Berrington, William R.; Jerome, Keith R.; Cook, Linda; Wald, Anna; Corey, Lawrence; Casper, Corey

    2009-01-01

    Background The quantification of herpes simplex virus (HSV) DNA from the peripheral blood is often used to evaluate patients suspected of having disseminated HSV infection. Few studies have examined the clinical correlates of HSV viremia among adults. Methods We conducted a retrospective analysis of blood samples sent to a reference molecular virology diagnostic facility at a university hospital for quantification of HSV DNA between October 2001 and June 2006. Medical records of patients with detectable HSV DNA were reviewed to abstract relevant clinical characteristics. Results HSV DNA was detected in 37 (4.0%) of 951 samples from 29 individual patients. 19 (65.5%) were >16 years of age, and detailed medical records were available for review from 13 (68.4%) of 19 adults patients. Of the 10 patients whose HSV infection was typed, 6 (60%) had HSV-2, 3 (30%) had HSV-1, and one had evidence of both HSV-1 and HSV-2 infection. All viremic patients were treated with antiviral medications. The most common clinical findings were hepatitis (62%), fever (54%), CNS alterations (46%), skin lesions (38%), abdominal pain (31%), and sepsis (31%). Respiratory failure (23%) was uncommon. Patients with HSV viremia were observed to have a high mortality rate (6 of 10 immunocompromised and 1 of 3 immunocompetent individuals). Conclusions HSV viremia may be associated with a variety of morbid signs and symptoms in hospitalized immunocompetent and immunocompromised adults, and is associated with high rates of mortality, though causality can only be determined by additional studies. PMID:19807272

  19. Seroreactive recombinant herpes simplex virus type 2-specific glycoprotein G.

    PubMed Central

    Parkes, D L; Smith, C M; Rose, J M; Brandis, J; Coates, S R

    1991-01-01

    The herpes simplex virus type 2 (HSV-2) genome codes for an envelope protein, glycoprotein G (gG), which contains predominantly type 2-specific epitopes. A portion of this gG gene has been expressed as a fusion protein in Escherichia coli. Expression was regulated by a lambda phage pL promoter. The 60,000-molecular-weight recombinant protein was purified by ion-exchange chromatography. Amino acid sequence analysis confirmed the N terminus of the purified protein. Mice immunized with recombinant gG developed antibodies reactive with native HSV-2 protein, but not with HSV-1 protein, in an indirect immunofluorescence assay. The serological activity of this purified recombinant gG protein was evaluated by immunoblot assay. This protein was reactive with an HSV-2 gG monoclonal antibody. It was also reactive with HSV-2 rabbit antiserum but not with HSV-1 rabbit antiserum. Of 15 patient serum samples known to have antibody to HSV-2, 14 were reactive with this recombinant type 2-specific gG protein, and none of 15 HSV antibody-negative patient serum samples showed reactivity. In agreement with the expected prevalence of HSV-2 infection, 27.6% of 134 serum samples from random normal individuals had antibodies reactive with recombinant gG. This recombinant gG protein may be of value in detecting HSV-2-specific antibody responses in patients infected with HSV-2. Images PMID:1653787

  20. An unusual presentation of herpes simplex encephalitis with negative PCR.

    PubMed

    Buerger, Kelly J; Zerr, Kayleigh; Salazar, Richard

    2015-01-01

    A 74-year-old man presented with acute right-sided hemiparesis and epilepsia partialis continua in association with fever and confusion. Initial workup revealed possible cerebritis in the left medial frontal lobe without involvement of the temporal lobes. Cerebrospinal fluid (CSF) analysis revealed minimal lymphocytic pleocytosis but negative real-time herpes simplex virus (HSV) PCR. Acyclovir was discontinued on day 5 due to a negative infectious workup and clinical improvement. On day 9 his condition deteriorated and he was transferred to a higher level of acuity for advanced supportive care. Worsening encephalopathy and refractory status epilepticus ensued despite medical care. Repeat CSF analysis showed mild lymphocytic pleocytosis with negative real-time HSV PCR. Brain MRI revealed progression of cortical enhancement. Immunosuppressive therapy and plasma exchange were attempted without clinical response. On day 24, another lumbar puncture showed only mild lymphocytic pleocytosis. Brain MRI showed involvement of the right medial temporal lobe. Subsequently, acyclovir was resumed. The HSV-1 PCR result was positive on day 30. Unfortunately, the patient expired. PMID:26243746

  1. Subcell resolution in simplex stochastic collocation for spatial discontinuities

    SciTech Connect

    Witteveen, Jeroen A.S.; Iaccarino, Gianluca

    2013-10-15

    Subcell resolution has been used in the Finite Volume Method (FVM) to obtain accurate approximations of discontinuities in the physical space. Stochastic methods are usually based on local adaptivity for resolving discontinuities in the stochastic dimensions. However, the adaptive refinement in the probability space is ineffective in the non-intrusive uncertainty quantification framework, if the stochastic discontinuity is caused by a discontinuity in the physical space with a random location. The dependence of the discontinuity location in the probability space on the spatial coordinates then results in a staircase approximation of the statistics, which leads to first-order error convergence and an underprediction of the maximum standard deviation. To avoid these problems, we introduce subcell resolution into the Simplex Stochastic Collocation (SSC) method for obtaining a truly discontinuous representation of random spatial discontinuities in the interior of the cells discretizing the probability space. The presented SSC–SR method is based on resolving the discontinuity location in the probability space explicitly as function of the spatial coordinates and extending the stochastic response surface approximations up to the predicted discontinuity location. The applications to a linear advection problem, the inviscid Burgers’ equation, a shock tube problem, and the transonic flow over the RAE 2822 airfoil show that SSC–SR resolves random spatial discontinuities with multiple stochastic and spatial dimensions accurately using a minimal number of samples.

  2. Simplex Factor Models for Multivariate Unordered Categorical Data

    PubMed Central

    Bhattacharya, Anirban; Dunson, David B.

    2013-01-01

    Gaussian latent factor models are routinely used for modeling of dependence in continuous, binary, and ordered categorical data. For unordered categorical variables, Gaussian latent factor models lead to challenging computation and complex modeling structures. As an alternative, we propose a novel class of simplex factor models. In the single-factor case, the model treats the different categorical outcomes as independent with unknown marginals. The model can characterize flexible dependence structures parsimoniously with few factors, and as factors are added, any multivariate categorical data distribution can be accurately approximated. Using a Bayesian approach for computation and inferences, a Markov chain Monte Carlo (MCMC) algorithm is proposed that scales well with increasing dimension, with the number of factors treated as unknown. We develop an efficient proposal for updating the base probability vector in hierarchical Dirichlet models. Theoretical properties are described, and we evaluate the approach through simulation examples. Applications are described for modeling dependence in nucleotide sequences and prediction from high-dimensional categorical features. PMID:23908561

  3. Treatment of Herpes simplex virus infections with topical antiviral agents.

    PubMed

    Hamuy, R; Berman, B

    1998-01-01

    Clinical studies of topical therapy against Herpes simplex virus (HSV) infections have been reviewed. Idoxuridine (IDU) 15% in dimethyl sulfoxide (DMSO), interferons, and penciclovir result in significant clinical benefit against this virus. IDU reduced pain duration and decreased time to loss of crust in a study of 301 patients. Alpha-interferon has shown synergism with other anti-HSV drugs such as caffeine, trifluorothymidine (TFT), DMSO, and nonoxynol-9. Finally, in a study of over 2,000 patients, application of penciclovir cream, both early and late in the course of HSV infection, decreased the duration of lesions, pain, and viral shedding. Acyclovir (ACV)-resistant strains of HSV are susceptible to (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl) cytosine (HPMPC), and ascorbic acid shows promising effects against HSV. Using a vehicle that enhances skin penetration of a drug or possibly further exploring combination therapy may result in efficacious treatment of HSV. The possibility of topical vaccination or topical gene therapy may also prove beneficial in the future. PMID:9683881

  4. Effect of preexisting anti-herpes immunity on the efficacy of herpes simplex viral therapy in a murine intraperitoneal tumor model.

    PubMed

    Lambright, E S; Kang, E H; Force, S; Lanuti, M; Caparrelli, D; Kaiser, L R; Albelda, S M; Molnar-Kimber, K L

    2000-10-01

    HSV-1716, a replicating nonneurovirulent herpes simplex virus type 1, has shown efficacy in treating multiple types of human tumors in immunodeficient mice. Since the majority of the human population has been previously exposed to herpes simplex virus, the efficacy of HSV-based oncolytic therapy was investigated in an immunocompetent animal tumor model. EJ-6-2-Bam-6a, a tumor cell line derived from h-ras-transformed murine fibroblast, exhibit a diffuse growth pattern in the peritoneal cavity of BALB/c mice and replicate HSV-1716 to titers observed in human tumors. An established intraperitoneal (ip) tumor model of EJ-6-2-Bam-6a in naive and HSV-immunized mice was used to evaluate the efficacy of single or multiple ip administrations of HSV-1716 (4 x 10(6) pfu/treatment) or of carrier cells, which are irradiated, ex vivo virally infected EJ-6-2-Bam-6a cells that can amplify the viral load in situ. All treated groups significantly prolonged survival versus media control with an approximately 40% long-term survival rate (cure) in the multiply treated, HSV-naive animals. Prior immunization of the mice with HSV did not significantly decrease the median survival of the single or multiply treated HSV-1716 or the carrier cell-treated groups. These studies support the development of replication-selective herpes virus mutants for use in localized intraperitoneal malignancies. PMID:11020355

  5. Immunobiology of herpes simplex virus and cytomegalovirus infections of the fetus and newborn

    PubMed Central

    Muller, William J.; Jones, Cheryl A.; Koelle, David M.

    2010-01-01

    Immunologic “immaturity” is often blamed for the increased susceptibility of newborn humans to infection, but the precise mechanisms and details of immunologic development remain somewhat obscure. Herpes simplex virus (HSV) and cytomegalovirus (CMV) are two of the more common severe infectious agents of the fetal and newborn periods. HSV infection in the newborn most commonly occurs after exposure to the virus during delivery, and can lead to a spectrum of clinical disease ranging from isolated skin-eye-mucous membrane infection to severe disseminated multiorgan disease, often including encephalitis. In contrast to HSV, clinically severe CMV infections early in life are usually acquired during the intrauterine period. These infections can result in a range of clinical disease, including hearing loss and neurodevelopmental delay. However, term newborns infected with CMV after delivery are generally asymptomatic, and older children and adults often acquire infection with HSV or CMV with either no or mild clinical symptoms. The reasons for these widely variable clinical presentations are not completely understood, but likely relate to developmental differences in immune responses. This review summarizes recent human and animal studies of the immunologic response of the fetus and newborn to these two infections, in comparison to the responses of older children and adults. The immunologic defense of the newborn against each virus is considered under the broader categories of (i) the placental barrier to infection, (ii) skin and mucosal barriers (including antimicrobial peptides), (iii) innate responses, (iv) humoral responses, and (v) cellular responses. A specific focus is made on recent studies of innate and cellular immunity to HSV and CMV. PMID:20467462

  6. Production of CFTR-null and CFTR-DeltaF508 heterozygous pigs by adeno-associated virus-mediated gene targeting and somatic cell nuclear transfer.

    PubMed

    Rogers, Christopher S; Hao, Yanhong; Rokhlina, Tatiana; Samuel, Melissa; Stoltz, David A; Li, Yuhong; Petroff, Elena; Vermeer, Daniel W; Kabel, Amanda C; Yan, Ziying; Spate, Lee; Wax, David; Murphy, Clifton N; Rieke, August; Whitworth, Kristin; Linville, Michael L; Korte, Scott W; Engelhardt, John F; Welsh, Michael J; Prather, Randall S

    2008-04-01

    Progress toward understanding the pathogenesis of cystic fibrosis (CF) and developing effective therapies has been hampered by lack of a relevant animal model. CF mice fail to develop the lung and pancreatic disease that cause most of the morbidity and mortality in patients with CF. Pigs may be better animals than mice in which to model human genetic diseases because their anatomy, biochemistry, physiology, size, and genetics are more similar to those of humans. However, to date, gene-targeted mammalian models of human genetic disease have not been reported for any species other than mice. Here we describe the first steps toward the generation of a pig model of CF. We used recombinant adeno-associated virus (rAAV) vectors to deliver genetic constructs targeting the CF transmembrane conductance receptor (CFTR) gene to pig fetal fibroblasts. We generated cells with the CFTR gene either disrupted or containing the most common CF-associated mutation (DeltaF508). These cells were used as nuclear donors for somatic cell nuclear transfer to porcine oocytes. We thereby generated heterozygote male piglets with each mutation. These pigs should be of value in producing new models of CF. In addition, because gene-modified mice often fail to replicate human diseases, this approach could be used to generate models of other human genetic diseases in species other than mice. PMID:18324337

  7. A Fast Hyperplane-Based Minimum-Volume Enclosing Simplex Algorithm for Blind Hyperspectral Unmixing

    NASA Astrophysics Data System (ADS)

    Lin, Chia-Hsiang; Chi, Chong-Yung; Wang, Yu-Hsiang; Chan, Tsung-Han

    2016-04-01

    Hyperspectral unmixing (HU) is a crucial signal processing procedure to identify the underlying materials (or endmembers) and their corresponding proportions (or abundances) from an observed hyperspectral scene. A well-known blind HU criterion, advocated by Craig in early 1990's, considers the vertices of the minimum-volume enclosing simplex of the data cloud as good endmember estimates, and it has been empirically and theoretically found effective even in the scenario of no pure pixels. However, such kind of algorithms may suffer from heavy simplex volume computations in numerical optimization, etc. In this work, without involving any simplex volume computations, by exploiting a convex geometry fact that a simplest simplex of N vertices can be defined by N associated hyperplanes, we propose a fast blind HU algorithm, for which each of the N hyperplanes associated with the Craig's simplex of N vertices is constructed from N-1 affinely independent data pixels, together with an endmember identifiability analysis for its performance support. Without resorting to numerical optimization, the devised algorithm searches for the N(N-1) active data pixels via simple linear algebraic computations, accounting for its computational efficiency. Monte Carlo simulations and real data experiments are provided to demonstrate its superior efficacy over some benchmark Craig-criterion-based algorithms in both computational efficiency and estimation accuracy.

  8. Valacyclovir for the prevention of recurrent herpes simplex virus eye disease after excimer laser photokeratectomy.

    PubMed Central

    Asbell, P A

    2000-01-01

    PURPOSE: A variety of factors have been reported as inducing the reactivation of latent herpes simplex virus (HSV), among them stress, trauma, and UV radiation. Excimer laser photorefractive keratectomy (PRK) is a surgical procedure utilizing a 193 nm ultraviolet light to alter the curvature of the cornea and hence correct vision. Reactivation of ocular herpes simplex keratitis following such excimer laser PRK has been reported. All published cases of HSV reactivation following excimer laser treatment in humans are reviewed. The present study evaluates whether stress, trauma of the corneal de-epithelialization prior to the laser, or the excimer laser treatment itself to the stromal bed induces this ocular reactivation of the latent HSV, and whether a systemic antiviral agent, valacyclovir, would prevent such laser PRK-induced reactivation of the HSV. METHODS: Forty-three normal 1.5- to 2.5-kg New Zealand white rabbits were infected on the surface of the cornea with HSV-1, strain RE. The animals were monitored until resolution, and then all animals were divided into 5 treatment groups: (1) de-epithelialization only, intraperitoneal (i.p.) saline for 14 days; (2) de-epithelialization plus laser, i.p. saline for 14 days; (3) de-epithelialization plus laser, valacyclovir 50 mg/kg per day i.p. for 14 days; (4) de-epithelialization plus laser, valacyclovir 100 mg/kg per day i.p. for 14 days; (5) de-epithelialization plus laser, valacyclovir 150 mg/kg per day i.p. for 14 days. Animals were evaluated in a masked fashion by clinical examination biweekly and viral cultures biweekly through day 28. RESULTS: The reactivation rates were as follows: group 1, 0%; group 2, 67%; group 3, 50%; group 4, 17%; and group 5, 0%. Viral titers were negative in animals that had no reactivation but persistently positive in those that had reactivation (day 6 through day 28). CONCLUSIONS: Excimer laser (193 nm) treatment can trigger reactivation of ocular herpes disease (67%) and viral

  9. Virus-Mediated Chemical Changes in Rice Plants Impact the Relationship between Non-Vector Planthopper Nilaparvata lugens Stål and Its Egg Parasitoid Anagrus nilaparvatae Pang et Wang

    PubMed Central

    Gao, Guanchun; Zhou, Xiaojun; Zheng, Xusong; Sun, Yujian; Yang, Yajun; Tian, Junce; Lu, Zhongxian

    2014-01-01

    In order to clarify the impacts of southern rice black-streaked dwarf virus (SRBSDV) infection on rice plants, rice planthoppers and natural enemies, differences in nutrients and volatile secondary metabolites between infected and healthy rice plants were examined. Furthermore, the impacts of virus-mediated changes in plants on the population growth of non-vector brown planthopper (BPH), Nilaparvata lugens, and the selectivity and parasitic capability of planthopper egg parasitoid Anagrus nilaparvatae were studied. The results showed that rice plants had no significant changes in amino acid and soluble sugar contents after SRBSDV infection, and SRBSDV-infected plants had no significant effect on population growth of non-vector BPH. A. nilaparvatae preferred BPH eggs both in infected and healthy rice plants, and tended to parasitize eggs on infected plants, but it had no significant preference for infected plants or healthy plants. GC-MS analysis showed that tridecylic aldehyde occurred only in rice plants infected with SRBSDV, whereas octanal, undecane, methyl salicylate and hexadecane occurred only in healthy rice plants. However, in tests of behavioral responses to these five volatile substances using a Y-tube olfactometer, A. nilaparvatae did not show obvious selectivity between single volatile substances at different concentrations and liquid paraffin in the control group. The parasitic capability of A. nilaparvatae did not differ between SRBSDV-infected plants and healthy plant seedlings. The results suggested that SRBSDV-infected plants have no significant impacts on the non-vector planthopper and its egg parasitoid, A. nilaparvatae. PMID:25141278

  10. The Challenges and Opportunities for Development of a T-Cell Epitope-Based Herpes Simplex Vaccine

    PubMed Central

    Kuo, Tiffany; Wang, Christine; Badakhshan, Tina; Chilukuri, Sravya; BenMohamed, Lbachir

    2014-01-01

    The infections with herpes simplex virus type 1 and type 2 (HSV-1 & HSV-2) have been prevalent since the ancient Greek times. To this day, they still affect a staggering number of over a half billion individuals worldwide. HSV-2 infections cause painful genital herpes, encephalitis, and death in newborns. HSV-1 infections are more prevalent than HSV-2 infections and cause potentially blinding ocular herpes, oro-facial herpes and encephalitis. While genital herpes in mainly caused by HSV-2 infections, in recent years, there is an increase in the proportion of genital herpes caused by HSV-1 infections in young adults, which reach 50% in some western societies. While prophylactic and therapeutic HSV vaccines remain urgently needed for centuries their development has been notoriously difficult. During the most recent National Institute of Health (NIH) workshop titled "Next Generation Herpes Simplex Virus Vaccines: The Challenges and Opportunities", basic researchers, funding agencies, and pharmaceutical representatives gathered: (i) to assess the status of herpes vaccine research; and (ii) to identify the gaps and propose alternative approaches in developing a safe and efficient herpes vaccine. One “common denominator” among previously failed clinical herpes vaccine trials is that they either used a whole virus or whole viral proteins, which contain both pathogenic “symptomatic” and protective “asymptomatic” antigens/epitopes. In this report, we continue to advocate that using an “asymptomatic” epitope-based vaccine strategy that selectively incorporates protective epitopes which: (i) are exclusively recognized, in vitro, by effector memory CD4+ and CD8+ TEM cells from “naturally” protected seropositive asymptomatic individuals; and (ii) protect, in vivo, human leukocyte antigen (HLA) transgenic animal models from ocular and genital herpes infections and diseases, could be the answer to many of the scientific challenges facing HSV vaccine

  11. Adeno-Associated Virus Mediated Delivery of An Engineered Protein that Combines the Complement Inhibitory Properties of CD46, CD55 and CD59

    PubMed Central

    Leaderer, Derek; Cashman, Siobhan M.; Kumar-Singh, Rajendra

    2015-01-01

    Background A variety of disorders are associated with the activation of complement. CD46, CD55 and CD59 are the major membrane associated regulators of complement on human cells. Previously, we have found that independent expression of CD55, CD46 or CD59 through gene transfer protects murine tissues against human complement mediated attack. Herein we investigated the potential of combining the complement regulatory properties of CD46, CD55 and CD59 into single gene products expressed from an adeno-associated virus (AAV) vector in a soluble non-membrane anchored form. Methods Minigenes encoding the complement regulatory domains from CD46, CD55 and CD59 (SACT) or CD55 and CD59 (DTAC) were cloned into an AAV vector. The specific regulatory activity of each component of SACT and DTAC was measured in vitro. The recombinant AAV vectors were injected into the peritoneum of mice and the efficacy of the transgene products for being able to protect murine liver vasculature against human complement, specifically the membrane attack complex (MAC) was measured. Results SACT and DTAC exhibited properties similar to CD46, CD55 and CD59 or CD55 and CD59 respectively in vitro. AAV mediated delivery of SACT or DTAC protected murine liver vasculature from human MAC deposition by 63.2% and 56.7% respectively. Conclusions When delivered to mice in vivo via an AAV vector, SACT and DTAC are capable of limiting human complement mediated damage. SACT and DTAC merit further study as potential therapies for complement mediated disorders when delivered via a gene therapy approach. PMID:25917932

  12. A comparison of herpes simplex virus type 1 and varicella-zoster virus latency and reactivation

    PubMed Central

    Kennedy, Peter G. E.; Rovnak, Joel; Badani, Hussain

    2015-01-01

    Herpes simplex virus type 1 (HSV-1; human herpesvirus 1) and varicella-zoster virus (VZV; human herpesvirus 3) are human neurotropic alphaherpesviruses that cause lifelong infections in ganglia. Following primary infection and establishment of latency, HSV-1 reactivation typically results in herpes labialis (cold sores), but can occur frequently elsewhere on the body at the site of primary infection (e.g. whitlow), particularly at the genitals. Rarely, HSV-1 reactivation can cause encephalitis; however, a third of the cases of HSV-1 encephalitis are associated with HSV-1 primary infection. Primary VZV infection causes varicella (chickenpox) following which latent virus may reactivate decades later to produce herpes zoster (shingles), as well as an increasingly recognized number of subacute, acute and chronic neurological conditions. Following primary infection, both viruses establish a latent infection in neuronal cells in human peripheral ganglia. However, the detailed mechanisms of viral latency and reactivation have yet to be unravelled. In both cases latent viral DNA exists in an ‘end-less’ state where the ends of the virus genome are joined to form structures consistent with unit length episomes and concatemers, from which viral gene transcription is restricted. In latently infected ganglia, the most abundantly detected HSV-1 RNAs are the spliced products originating from the primary latency associated transcript (LAT). This primary LAT is an 8.3 kb unstable transcript from which two stable (1.5 and 2.0 kb) introns are spliced. Transcripts mapping to 12 VZV genes have been detected in human ganglia removed at autopsy; however, it is difficult to ascribe these as transcripts present during latent infection as early-stage virus reactivation may have transpired in the post-mortem time period in the ganglia. Nonetheless, low-level transcription of VZV ORF63 has been repeatedly detected in multiple ganglia removed as close to death as possible. There is

  13. A comparison of herpes simplex virus type 1 and varicella-zoster virus latency and reactivation.

    PubMed

    Kennedy, Peter G E; Rovnak, Joel; Badani, Hussain; Cohrs, Randall J

    2015-07-01

    Herpes simplex virus type 1 (HSV-1; human herpesvirus 1) and varicella-zoster virus (VZV; human herpesvirus 3) are human neurotropic alphaherpesviruses that cause lifelong infections in ganglia. Following primary infection and establishment of latency, HSV-1 reactivation typically results in herpes labialis (cold sores), but can occur frequently elsewhere on the body at the site of primary infection (e.g. whitlow), particularly at the genitals. Rarely, HSV-1 reactivation can cause encephalitis; however, a third of the cases of HSV-1 encephalitis are associated with HSV-1 primary infection. Primary VZV infection causes varicella (chickenpox) following which latent virus may reactivate decades later to produce herpes zoster (shingles), as well as an increasingly recognized number of subacute, acute and chronic neurological conditions. Following primary infection, both viruses establish a latent infection in neuronal cells in human peripheral ganglia. However, the detailed mechanisms of viral latency and reactivation have yet to be unravelled. In both cases latent viral DNA exists in an 'end-less' state where the ends of the virus genome are joined to form structures consistent with unit length episomes and concatemers, from which viral gene transcription is restricted. In latently infected ganglia, the most abundantly detected HSV-1 RNAs are the spliced products originating from the primary latency associated transcript (LAT). This primary LAT is an 8.3 kb unstable transcript from which two stable (1.5 and 2.0 kb) introns are spliced. Transcripts mapping to 12 VZV genes have been detected in human ganglia removed at autopsy; however, it is difficult to ascribe these as transcripts present during latent infection as early-stage virus reactivation may have transpired in the post-mortem time period in the ganglia. Nonetheless, low-level transcription of VZV ORF63 has been repeatedly detected in multiple ganglia removed as close to death as possible. There is increasing

  14. Latency of Herpes Simplex Virus in Absence of Neutralizing Antibody: Model for Reactivation

    NASA Astrophysics Data System (ADS)

    Sekizawa, Tsuyoshi; Openshaw, Harry; Wohlenberg, Charles; Notkins, Abner Louis

    1980-11-01

    Mice inoculated with herpes simplex virus (type 1) by the lip or corneal route and then passively immunized with rabbit antibody to herpes simplex virus developed a latent infection in the trigeminal ganglia within 96 hours. Neutralizing antibody to herpes simplex virus was cleared from the circulation and could not be detected in most of these mice after 2 months. Examination of ganglia from the antibody-negative mice revealed latent virus in over 90 percent of the animals, indicating that serum neutralizing antibody is not necessary to maintain the latent state. When the lips or corneas of these mice were traumatized, viral reactivation occurred in up to 90 percent of the mice, as demonstrated by the appearance of neutralizing antibody. This study provides a model for identifying factors that trigger viral reactivation.

  15. Chronic active destructive herpes simplex encephalitis with recovery of viral DNA 12 years after disease onset.

    PubMed

    Asenbauer, B; McEntagart, M; King, M D; Gallagher, P; Burke, M; Farrell, M A

    1998-06-01

    Acute herpes simplex encephalitis (HSE) carries significant morbidity and mortality even after early treatment with antiviral agents (7). As well as causing acute neurological disease, Herpes viruses are associated with relapsing--remitting (Varicella--Zoster, Epstein-Barr) and chronic (Rasmussen encephalitis) disease processes (1). A two-year-old girl developed acute HSE which was followed by a 10-year neurologic illness characterised by asymmetric spastic tetraparesis, pseudobulbar palsy, the opercular syndrome of Foix-Chavany-Marie (4) and seizures. The neurological signs remained static until the child died suddenly 12 years after disease onset. Neuropathologic examination demonstrated active chronic encephalitis. Herpes simplex virus (HSV) DNA was recovered from formalin-fixed paraffin-embedded brain tissue. This case provides additional evidence for the development of chronic neurological disease attributable to persistence of herpes simplex virus type 1. PMID:9706620

  16. Digital coherent detection research on Brillouin optical time domain reflectometry with simplex pulse codes

    NASA Astrophysics Data System (ADS)

    Hao, Yun-Qi; Ye, Qing; Pan, Zheng-Qing; Cai, Hai-Wen; Qu, Rong-Hui

    2014-11-01

    The digital coherent detection technique has been investigated without any frequency-scanning device in the Brillouin optical time domain reflectometry (BOTDR), where the simplex pulse codes are applied in the sensing system. The time domain signal of every code sequence is collected by the data acquisition card (DAQ). A shift-averaging technique is applied in the frequency domain for the reason that the local oscillator (LO) in the coherent detection is fix-frequency deviated from the primary source. With the 31-bit simplex code, the signal-to-noise ratio (SNR) has 3.5-dB enhancement with the same single pulse traces, accordant with the theoretical analysis. The frequency fluctuation for simplex codes is 14.01 MHz less than that for a single pulse as to 4-m spatial resolution. The results are believed to be beneficial for the BOTDR performance improvement.

  17. Thrust efficiency optimization of the pulsed plasma thruster SIMP-LEX

    NASA Astrophysics Data System (ADS)

    Nawaz, Anuscheh; Albertoni, Riccardo; Auweter-Kurtz, Monika

    2010-08-01

    The effect of electric parameters on the thrust efficiency of an ablative pulsed plasma thruster was studied. Analytically, it was shown that a higher efficiency can be obtained by increasing energy of a bank of capacitors. This can be achieved by changing the inductance per distance of the plasma sheet, or reducing the resistance of the circuit and the mass bit. Further, an optimum discharge time was found when the capacitance and the inductance were varied. A low initial inductance increases the thrust efficiency. Experimentally, these trends can be verified by comparing two thrusters: SIMP-LEX and ADD SIMP-LEX, with their different initial inductances. For ADD SIMP-LEX, the optimal thrust efficiency for different capacities was determined to be 31% at 60μF for a 17 J configuration.

  18. Structure and origin of defective genomes contained in serially passaged herpes simplex virus type 1 (Justin).

    PubMed Central

    Locker, H; Frenkel, N

    1979-01-01

    Restriction enzyme and hybridization analyses have revealed that high-density DNA prepared from passage 15 of serially passaged herpes simplex virus type 1 (Justin) contains three major classes of modified viral DNA molecules, each composed of distinct but closely related types of repeate units. The DNA sequences within the three types of repeat units are colinear with the DNA sequences located at the right end (between coordinates 0.94 and 1.0) of the parental herpes simplex virus type 1 genome. Thus, the three types of repeat units each contain the entire repeat sequence (ac) (which brackets the unique sequences of the small [S] component of herpes simplex virus type 1 DNA) and differ only with respect to the amount of unique S sequences which they contain. The three classes of high-density DNA molecules were found to be stably propagated between passages 6 and 15 of this series. Images PMID:221666

  19. A remarkable autosomal heteromorphism in Pseudoryzomys simplex 2n = 56; FN = 54–55 (Rodentia, Sigmodontinae)

    PubMed Central

    Moreira, Camila Nascimento; Di-Nizo, Camilla Bruno; de Jesus Silva, Maria José; Yonenaga-Yassuda, Yatiyo; Ventura, Karen

    2013-01-01

    Pseudoryzomys simplex, the false rice rat, is a monotypic genus of the Oryzomyini tribe (Sigmodontinae) distributed in part of Bolivia, Paraguay, Argentina and Brazil. Its diploid number has been described as 56 acrocentric chromosomes decreasing in size and no karyotype figure has been depicted. Herein, we present karyotypic data on P. simplex, including chromosome banding and molecular fluorescent in situ hybridization using telomeric sequences and the whole X-chromosome of its sister clade Holochilus brasiliensis (HBR) as probes. A case of remarkable autosomal heteromorphism due to the presence of a whole heterochromatic arm leading to the variability of FN is reported, as well as the occurrence of regions of homology between the X and Y chromosomes (pseudoautosomal regions) after chromosome painting with the HBR X probe on P. simplex metaphases. PMID:23885202

  20. Max-out-in pivot rule with Dantzig's safeguarding rule for the simplex method

    NASA Astrophysics Data System (ADS)

    Tipawanna, Monsicha; Sinapiromsaran, Krung

    2014-03-01

    The simplex method is used to solve linear programming problem by improving the current basic feasible solution. It uses a pivot rule to guide the search in the feasible region. The pivot rule is used to select an entering index in simplex method. Nowadays, many pivot rule have been presented, but no pivot rule shows superior performance than other. Therefore, this is still an active research in linear programming. In this research, we present the max-out-in pivot rule with Dantzig's safeguarding for simplex method. This rule is based on maximum improvement of objective value of the current basic feasible point similar to the Dantzig's rule. We can illustrate by Klee and Minty problems that our rule outperforms that of Dantzig's rule by the number of iterations for solving linear programming problems.

  1. Herpes simplex virus 2 infection impacts stress granule accumulation.

    PubMed

    Finnen, Renée L; Pangka, Kyle R; Banfield, Bruce W

    2012-08-01

    Interference with stress granule (SG) accumulation is gaining increased appreciation as a common strategy used by diverse viruses to facilitate their replication and to cope with translational arrest. Here, we examined the impact of infection by herpes simplex virus 2 (HSV-2) on SG accumulation by monitoring the localization of the SG components T cell internal antigen 1 (TIA-1), Ras-GTPase-activating SH3-domain-binding protein (G3BP), and poly(A)-binding protein (PABP). Our results indicate that SGs do not accumulate in HSV-2-infected cells and that HSV-2 can interfere with arsenite-induced SG accumulation early after infection. Surprisingly, SG accumulation was inhibited despite increased phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), implying that HSV-2 encodes previously unrecognized activities designed to maintain translation initiation downstream of eIF2α. SG accumulation was not inhibited in HSV-2-infected cells treated with pateamine A, an inducer that works independently of eIF2α phosphorylation. The SGs that accumulated following pateamine A treatment of infected cells contained G3BP and PABP but were largely devoid of TIA-1. We also identified novel nuclear structures containing TIA-1 that form late in infection. These structures contain the RNA binding protein 68-kDa Src-associated in mitosis (Sam68) and were noticeably absent in infected cells treated with inhibitors of viral DNA replication, suggesting that they arise as a result of late events in the virus replicative cycle. PMID:22623775

  2. Interactome analysis of herpes simplex virus 1 envelope glycoprotein H.

    PubMed

    Hirohata, Yoshitaka; Kato, Akihisa; Oyama, Masaaki; Kozuka-Hata, Hiroko; Koyanagi, Naoto; Arii, Jun; Kawaguchi, Yasushi

    2015-06-01

    Herpes simplex virus 1 (HSV-1) envelope glycoprotein H (gH) is important for viral entry into cells and nuclear egress of nucleocapsids. To clarify additional novel roles of gH during HSV-1 replication, host cell proteins that interact with gH were screened for by tandem affinity purification coupled with mass spectrometry-based proteomics in 293T cells transiently expressing gH. This screen identified 123 host cell proteins as potential gH interactors. Of these proteins, general control nonderepressive-1 (GCN1), a trans-acting positive effector of GCN2 kinase that regulates phosphorylation of the α subunit of translation initiation factor 2 (eIF2α), was subsequently confirmed to interact with gH in HSV-1-infected cells. eIF2α phosphorylation is known to downregulate protein synthesis, and various viruses have evolved mechanisms to prevent the accumulation of phosphorylated eIF2α in infected cells. Here, it was shown that GCN1 knockdown reduces phosphorylation of eIF2α in HSV-1-infected cells and that the gH-null mutation increases eIF2α in HSV-1-infected cells, whereas gH overexpression in the absence of other HSV-1 proteins reduces eIF2α phosphorylation. These findings suggest that GCN1 can regulate eIF2α phosphorylation in HSV-1-infected cells and that the GCN1-binding viral partner gH is necessary and sufficient to prevent the accumulation of phosphorylated eIF2α. Our database of 123 host cell proteins potentially interacting with gH will be useful for future studies aimed at unveiling further novel functions of gH and the roles of cellular proteins in HSV-1-infected cells. PMID:25808324

  3. Herpes simplex virus type 1 encephalitis in acquired immunodeficiency syndrome.

    PubMed

    Chrétien, F; Bélec, L; Hilton, D A; Flament-Saillour, M; Guillon, F; Wingertsmann, L; Baudrimont, M; de Truchis, P; Keohane, C; Vital, C; Love, S; Gray, F

    1996-10-01

    Herpes simplex (HSV) infection of the central nervous system is uncommon in AIDS and usually has an atypical topography. This review is centred around the case of a 49-year-old homosexual patient with AIDS who died from diffuse encephalopathy. Neuropathological examination revealed necrotic and haemorrhagic changes involving both temporal lobes, insulae and cingulate gyri. Cowdry type A intranuclear inclusion bodies were abundant but inflammation was minimal. Electron microscopy confirmed characteristic herpes virus particles. Immunocyto-chemistry was positive for HSV type 1 and 2. In situ hybridization and PCR, however, were positive for HSV type 1 but excluded HSV type 2. There was associated cytomegalovirus ventriculitis but clearly separated from HSV encephalitis. There were no histological features of HIV encephalitis and HIV could not be demonstrated by immunocytochemistry or by PCR to demonstrate proviral DNA. Apoptotic neurons were numerous in areas with a severe macrophage reaction. Only two pathological cases with characteristic limbic distribution and necrotic haemorrhagic histologic have been reported previously. The rarity of these reports suggests that in advanced AIDS, the immune reaction causing a typical necrotizing encephalitis cannot be mounted. Distinction between HSV type 1 and 2 infection may be difficult by immunocytochemistry and usually requires in situ hybridization, tissue culture or PCR. In AIDS patients, HSV-1 has been identified as responsible for encephalitis whereas HSV-2 has been more responsible for myelitis. Associated productive HIV infection of the CNS was found in none of the cases. In contrast, cytomegalovirus encephalitis was found in nine of 11 cases of AIDS-associated HSV encephalitis. PMID:8930949

  4. A Case Series: Herpes Simplex Virus as an Occupational Hazard

    PubMed Central

    Browning, William D; McCarthy, James P

    2012-01-01

    Statement of the Problem Herpes labialis infections are common and present a serious risk to the dental team. Purpose of the Study The purpose is to make dentists aware of the risks involved with treatment of patients with active herpes labialis. In addition, evidence-based risk-management strategies are presented. Methods and Materials The incidence and natural history of herpes simplex virus type 1 (HSV-1) are reviewed. Four previously unreported case histories are presented to illustrate the impact common sequelae of HSV-1 can have on the dental team. The differences between HSV-1 and the blood-borne diseases which are the focus of universal precautions are discussed. In particular, the highly contagious, highly transmissible nature of HSV-1 and its transmission through aerosols are highlighted. Finally, the need to include protection against aerosols in the profession's understanding of universal precautions is noted. Results The authors suggest limiting the treatment of patients with active lesions to urgent care only, and treating active HSV-1 lesions to reduce time of healing. For four common clinical situations involving HSV-1 infections, evidence-based methods for protecting the dental team and the patient from cross-contamination are also presented. Conclusion While it is clear that the treatment of patients with active herpes labialis lesions increases risk of cross-infection, there are good protocols for controlling this risk. CLINICAL SIGNIFICANCE By bringing common vectors of cross-infection to light and providing evidence-based protocols for preventing them, this article provides practitioners with positive steps that can be taken for controlling the risk of spreading herpes infections to the dental team. (J Esthet Restor Dent 24:61–67, 2012) PMID:22296698

  5. Purification and structural characterization of herpes simplex virus glycoprotein C

    SciTech Connect

    Kikuchi, G.E.; Baker, S.A.; Merajver, S.D.; Coligan, J.E.; Levine, M.; Glorioso, J.C.; Nairn, R.

    1987-01-27

    Purification of herpes simplex virus glycoprotein C (gC) in microgram amounts yielded sufficient material for an analysis of its secondary structure. Purification was facilitated by using the mutant virus gC-3, which bears a point mutation that interrupts the putative hydrophobic membrane anchor sequence, causing the secretion of gC-3 protein into the cell culture medium. gC-3 protein was purified by size fractionation of concentrated culture medium from infected cells on a gel filtration column of Sephacryl S-200, followed by immunoaffinity chromatography on a column constructed of gC-specific monoclonal antibodies cross-linked to a protein A-Sepharose CL-4B matrix. Purified gC-3 had a molecular weight of 130,000 as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the size expected for gC, was reactive with gC-specific monoclonal antibodies in protein immunoblots, and contained amino acid sequences characteristic of gC as determined by radiochemical amino acid microsequence analyses. Polyclonal antisera obtained from a rabbit immunized with gC-3 reacted with wild-type gC in immunoprecipitation, enzyme immunoassay, and immunoelectroblot (western blot) assays. Deglycosylation by treatment with trifluoromethanesulfonic acid reduced the molecular weight of gC-3 by approximately 35%. Analyses of both native and deglycosylated gC-3 by Raman spectroscopy showed that the native molecule consists of about 17%..cap alpha..-helix, 24% ..beta..-sheet, and 60% disordered secondary structures, whereas deglycosylated gC-3 consists of about 8% ..cap alpha..-helix, 10% ..beta..-sheet, 81% disordered structures. These data were in good agreement with the 11% ..cap alpha..-helix, 18% ..beta..-sheet, 61% ..beta..-turn, and 9% disordered structures calculated from Chou-Fasman analysis of the primary sequence of gC-3.

  6. Concurrent chemotherapy inhibits Herpes simplex virus 1 replication and oncolysis

    PubMed Central

    Kulu, Yakup; Kawasaki, Hiroshi; Donahue, James M.; Kasuya, Hideki; Cusack, James C.; Choi, Enid W.; Kuruppu, Darshini K.; Fuchs, Bryan C.; Tanabe, Kenneth K.

    2013-01-01

    Herpes simplex virus 1 (HSV-1) replication in cancer cells leads to their destruction (viral oncolysis) and has been under investigation as an experimental cancer therapy in clinical trials as single agents, and as combinations with chemotherapy. Cellular responses to chemotherapy modulate viral replication, but these interactions are poorly understood. To investigate the effect of chemotherapy on HSV-1 oncolysis, viral replication in cells exposed to 5-fluorouracil (5-FU), irinotecan (CPT-11), methotrexate (MTX) or a cytokine (TNF-α) was examined. Exposure of colon and pancreatic cancer cells to 5-FU, CPT-11, or MTX in vitro significantly antagonizes both HSV-1 replication and lytic oncolysis. Nuclear factor-kappa B (NF-κB) activation is required for efficient viral replication, and experimental inhibition of this response with an IκBα dominant-negative repressor significantly antagonizes HSV-1 replication. Nonetheless cells exposed to 5-FU, CPT-11, TNF-α or HSV-1 activate NF-κB. Cells exposed to MTX do not activate NF-κB, suggesting a possible role for NF-κB inhibition in the decreased viral replication observed following exposure to MTX. The role of eukaryotic initiation factor 2 alpha (eIF-2α) dephosphorylation was examined; HSV-1 mediated eIF-2α dephosphorylation proceeds normally in HT29 cells exposed to 5-FU-, CPT-11-, or MTX. This report demonstrates that cellular responses to chemotherapeutic agents provide an unfavorable environment for HSV-1-mediated oncolysis, and these observations are relevant to the design of both preclinical and clinical studies of HSV-1 oncolysis. PMID:23348635

  7. Simplex didactics: A non-linear trajectory for research in education.

    PubMed

    Sibilio, Maurizio

    2015-12-01

    The concept of simplexity, as proposed by Alain Berthoz, is based on the assumption that solutions elaborated by living organisms to decipher and face complexity could be applicable to all complex adaptive systems. Within the pedagogical and didactic context the proposal of the French physiologist could provide a scientific research trajectory aiming at solving the tension between theory, praxis, descriptive approaches and practical needs. Thus, simplexity seems to be an operational strategy based on the identification of the principles that rule and guide the didactic action through patterns of adaptation, which allow to decipher complexity in terms of data elaboration and decision making among different opportunities. PMID:26746648

  8. Phosphonoacetic Acid-Resistant Herpes Simplex Virus Infection in Hairless Mice1

    PubMed Central

    Klein, Richard J.; Friedman-Kien, Alvin E.

    1975-01-01

    Phosphonoacetic acid (PAA)-resistant type 1 herpes simplex virus population was isolated by repeated passage of the virus in the presence of this inhibitor. Hairless mice infected percutaneously with the inhibitor-resistant or the parental inhibitor-susceptible virus were treated intraperitoneally with PAA and 9-β-d-arabinofuranosyl-adenine by using several different dosage schedules. Whereas 9-β-d-arabinofuranosyl-adenine was effective both in the PAA-susceptible and PAA-resistant herpes simplex virus-induced skin infection, PAA suppressed only the infection induced by the parental PAA-susceptible virus. PMID:166611

  9. A subset of herpes simplex virus replication genes induces DNA amplification within the host cell genome.

    PubMed Central

    Heilbronn, R; zur Hausen, H

    1989-01-01

    Herpes simplex virus (HSV) induces DNA amplification of target genes within the host cell chromosome. To characterize the HSV genes that mediate the amplification effect, combinations of cloned DNA fragments covering the entire HSV genome were transiently transfected into simian virus 40 (SV40)-transformed hamster cells. This led to amplification of the integrated SV40 DNA sequences to a degree comparable to that observed after transfection of intact virion DNA. Transfection of combinations of subclones and of human cytomegalovirus immediate-early promoter-driven expression constructs for individual open reading frames led to the identification of six HSV genes which together were necessary and sufficient for the induction of DNA amplification: UL30 (DNA polymerase), UL29 (major DNA-binding protein), UL5, UL8, UL42, and UL52. All of these genes encode proteins necessary for HSV DNA replication. However, an additional gene coding for an HSV origin-binding protein (UL9) was required for origin-dependent HSV DNA replication but was dispensible for SV40 DNA amplification. Our results show that a subset of HSV replication genes is sufficient for the induction of DNA amplification. This opens the possibility that HSV expresses functions sufficient for DNA amplification but separate from those responsible for lytic viral growth. HSV infection may thereby induce DNA amplification within the host cell genome without killing the host by lytic viral growth. This may lead to persistence of a cell with a new genetic phenotype, which would have implications for the pathogenicity of the virus in vivo. Images PMID:2547992

  10. Oncolytic herpes simplex virus-based strategies: toward a breakthrough in glioblastoma therapy

    PubMed Central

    Ning, Jianfang; Wakimoto, Hiroaki

    2014-01-01

    Oncolytic viruses (OV) are a class of antitumor agents that selectively kill tumor cells while sparing normal cells. Oncolytic herpes simplex virus (oHSV) has been investigated in clinical trials for patients with the malignant brain tumor glioblastoma for more than a decade. These clinical studies have shown the safety of oHSV administration to the human brain, however, therapeutic efficacy of oHSV as a single treatment remains unsatisfactory. Factors that could hamper the anti-glioblastoma efficacy of oHSV include: attenuated potency of oHSV due to deletion or mutation of viral genes involved in virulence, restricting viral replication and spread within the tumor; suboptimal oHSV delivery associated with intratumoral injection; virus infection-induced inflammatory and cellular immune responses which could inhibit oHSV replication and promote its clearance; lack of effective incorporation of oHSV into standard-of-care, and poor knowledge about the ability of oHSV to target glioblastoma stem cells (GSCs). In an attempt to address these issues, recent research efforts have been directed at: (1) design of new engineered viruses to enhance potency, (2) better understanding of the role of the cellular immunity elicited by oHSV infection of tumors, (3) combinatorial strategies with different antitumor agents with a mechanistic rationale, (4) “armed” viruses expressing therapeutic transgenes, (5) use of GSC-derived models in oHSV evaluation, and (6) combinations of these. In this review, we will describe the current status of oHSV clinical trials for glioblastoma, and discuss recent research advances and future directions toward successful oHSV-based therapy of glioblastoma. PMID:24999342

  11. Downstream effects of plectin mutations in epidermolysis bullosa simplex with muscular dystrophy.

    PubMed

    Winter, Lilli; Türk, Matthias; Harter, Patrick N; Mittelbronn, Michel; Kornblum, Cornelia; Norwood, Fiona; Jungbluth, Heinz; Thiel, Christian T; Schlötzer-Schrehardt, Ursula; Schröder, Rolf

    2016-01-01

    Mutations of the human plectin gene (PLEC) on chromosome 8q24 cause autosomal recessive epidermolysis bullosa simplex with muscular dystrophy (EBS-MD). In the present study we analyzed the downstream effects of PLEC mutations on plectin protein expression and localization, the structure of the extrasarcomeric desmin cytoskeleton, protein aggregate formation and mitochondrial distribution in skeletal muscle tissue from three EBS-MD patients. PLEC gene analysis in a not previously reported 35-year-old EBS-MD patient with additional disease features of cardiomyopathy and malignant arrhythmias revealed novel compound heterozygous (p.(Phe755del) and p.(Lys1040Argfs*139)) mutations resulting in complete abolition of plectin protein expression. In contrast, the other two patients with different homozygous PLEC mutations showed preserved plectin protein expression with one only expressing rodless plectin variants, and the other markedly reduced protein levels. Analysis of skeletal muscle tissue from all three patients revealed severe disruption of the extrasarcomeric intermediate filament cytoskeleton, protein aggregates positive for desmin, syncoilin, and synemin, degenerative myofibrillar changes, and mitochondrial abnormalities comprising respiratory chain dysfunction and an altered organelle distribution and amount.Our study demonstrates that EBS-MD causing PLEC mutations universally result in a desmin protein aggregate myopathy phenotype despite marked differences in individual plectin protein expression patterns. Since plectin is the key cytolinker protein that regulates the structural and functional organization of desmin filaments, the defective anchorage and spacing of assembled desmin filaments is the key pathogenetic event that triggers the formation of desmin protein aggregates as well as secondary mitochondrial pathology. PMID:27121971

  12. A Novel Oncolytic Herpes Simplex Virus Type 2 Has Potent Anti-Tumor Activity

    PubMed Central

    Zhuang, Xiufen; Lu, Haizhen; Liang, Jing; Li, Jie; Zhang, Yu; Dong, Ying; Zhang, Youhui; Zhang, Shuren; Liu, Shangmei; Liu, Binlei

    2014-01-01

    Oncolytic viruses are promising treatments for many kinds of solid tumors. In this study, we constructed a novel oncolytic herpes simplex virus type 2: oHSV2. We investigated the cytopathic effects of oHSV2 in vitro and tested its antitumor efficacy in a 4T1 breast cancer model. We compared its effect on the cell cycle and its immunologic impact with the traditional chemotherapeutic agent doxorubicin. In vitro data showed that oHSV2 infected most of the human and murine tumor cell lines and was highly oncolytic. oHSV2 infected and killed 4T1 tumor cells independent of their cell cycle phase, whereas doxorubicin mainly blocked cells that were in S and G2/M phase. In vivo study showed that both oHSV2 and doxorubicin had an antitumor effect, though the former was less toxic. oHSV2 treatment alone not only slowed down the growth of tumors without causing weight loss but also induced an elevation of NK cells and mild decrease of Tregs in spleen. In addition, combination therapy of doxorubicin followed by oHSV2 increased survival with weight loss than oHSV2 alone. The data showed that the oncolytic activity of oHSV2 was similar to oHSV1 in cell lines examined and in vivo. Therefore, we concluded that our virus is a safe and effective therapeutic agent for 4T1 breast cancer and that the sequential use of doxorubicin followed by oHSV2 could improve antitumor activity without enhancing doxorubicin’s toxicity. PMID:24671154

  13. Phenotypic properties of herpes simplex virus 1 containing a derepressed open reading frame P gene.

    PubMed Central

    Lagunoff, M; Randall, G; Roizman, B

    1996-01-01

    Open reading frame P (ORF P) maps in the viral DNA sequences transcribed during latency and is located antisense to the gamma 1 34.5 gene. Earlier studies have shown that the expression of ORF P is repressed by an infected cell protein no. 4 binding site straddling the transcription initiation site. We have made monospecific polyclonal antibodies to the protein and constructed a virus, designated ORF P++, in which the infected cell protein no. 4 binding site has been mutagenized, thereby allowing full expression of an unmodified ORF P gene from its natural promoter. We report the following findings. (i) The native protein forms multiple bands on denaturing polyacrylamide gels suggestive of extensive processing and aggregation of the protein; (ii) the protein accumulates in the nucleus in rod-shaped structures perpendicular to the axis of attachment of the infected cell to the solid matrix; (iii) the virus was highly attenuated on inoculation into mice by the intracerebral or ocular route, and virus was not recovered upon explantation of trigeminal ganglia; (iv) although protein synthesis was not prematurely shut off in the human neuroblastoma cell line SK-N-SH, gamma 1 34.5 protein was not detected in immunoblasts. Analyses of electrophoretically separated denatured RNAs indicated that in cells infected with the ORF P++ virus, there was a large increase in the amount of ORF P RNA and a corresponding decrease in the amount of gamma 1 34.5 RNA. We conclude that either the overproduction of ORF P protein blocks the expression of some herpes simplex virus 1 genes or derepression of the transcription of ORF P has a negative effect on the transcription of the antisense gamma 1 34.5 RNA. PMID:8627705

  14. Genetic studies of cell fusion induced by herpes simplex virus type 1.

    PubMed Central

    Read, G S; Person, S; Keller, P M

    1980-01-01

    Eight cell fusion-causing syn mutants were isolated from the KOS strain of herpes simplex virus type 1. Unlike the wild-type virus, the mutants produced plaques containing multinucleated cells, or syncytia. Fusion kinetics curves were established with a Coulter Counter assay for the mutants and wild-type virus in single infections of human embryonic lung (HEL) cells, for the mutants and wild-type virus in mixed infections (dominance test), and for pairs of mutants in mixed infections (complementation test). In single infections, fusion began 4 to 6 h after infection and proceeded with an exponential decrease in the number of small single cells. At some later time that was characteristic of the mutant, there was a significant reduction in the rate of fusion for all but possibly one of the mutants. Although the wild-type virus did not produce syncytial plaques, it did induce a small amount of fusion that stopped abruptly about 2 h after it started. These data are consistent with the hypothesis that both mutants and wild type induce an active fusion inducer and that the activity of this inducer is subsequently inhibited. The extent of fusion is apparently determined by the length of the interval during which the fusion inducer is active. That fusion is actively inhibited in wild-type infections is indicated by the observation that syn mutant-infected cells fused more readily with uninfected cells than with wild-type infected cells. Fusion was decreased in mixed infections with the mutants and wild-type virus, but the mutants displayed a codominant fusion phenotype. Fusion was not decreased in mixed infection with pairs of mutants, indicating that the mutants, with one possible exception, are members of the same complementation group. A linkage map was established for six of the mutants by analysis of recombination frequencies. PMID:6251259

  15. Quantification of poly(I:C)-mediated protection against genital herpes simplex virus type 2 infection.

    PubMed

    Herbst-Kralovetz, Melissa M; Pyles, Richard B

    2006-10-01

    Alternative strategies for controlling the growing herpes simplex virus type 2 (HSV-2) epidemic are needed. A novel class of immunomodulatory microbicides has shown promise as antiherpetics, including intravaginally applied CpG-containing oligodeoxynucleotides that stimulate toll-like receptor 9 (TLR9). In the current study, we quantified protection against experimental genital HSV-2 infection provided by an alternative nucleic acid-based TLR agonist, polyinosine-poly(C) (PIC) (TLR3 agonist). Using a protection quantification paradigm, groups of mice were PIC treated and then subdivided into groups challenged with escalating doses of HSV-2. Using this paradigm, a temporal window of PIC efficacy for single applications was defined as 1 day prior to (prophylactic) through 4 h after (therapeutic) viral challenge. PIC treatment within this window protected against 10-fold-higher HSV-2 challenges, as indicated by increased 50% infectious dose values relative to those for vehicle-treated controls. Disease resolution and survival were significantly enhanced by repetitive PIC doses. Using optimal PIC regimens, cytokine induction was evaluated in murine vaginal lavages and in human vaginal epithelial cells. Similar induction patterns were observed, with kinetics that explained the limited durability of PIC-afforded protection. Daily PIC delivery courses did not generate sustained cytokine levels in murine vaginal fluids that would be indicative of local immunotoxicity. No evidence of immunotoxicity was observed in selected organs that were analyzed following repetitive vaginal PIC doses. Animal and in vitro data indicate that PIC may prove to be a valuable preventative microbicide and/or therapeutic agent against genital herpes by increasing resistance to HSV-2 and enhancing disease resolution following a failure of prevention. PMID:17005677

  16. A subset of herpes simplex virus replication genes induces DNA amplification within the host cell genome

    SciTech Connect

    Heilbronn, R.; zur Hausen, H. )

    1989-09-01

    Herpes simplex virus (HSV) induces DNA amplification of target genes within the host cell chromosome. To characterize the HSV genes that mediate the amplification effect, combinations of cloned DNA fragments covering the entire HSV genome were transiently transfected into simian virus 40 (SV40)-transformed hamster cells. This led to amplification of the integrated SV40 DNA sequences to a degree comparable to that observed after transfection of intact virion DNA. Transfection of combinations of subclones and of human cytomegalovirus immediate-early promoter-driven expression constructs for individual open reading frames led to the identification of sic HSV genes which together were necessary and sufficient for the induction of DNA amplification: UL30 (DNA polymerase), UL29 (major DNA-binding protein), UL5, UL8, UL42, and UL52. All of these genes encode proteins necessary for HSV DNA replication. However, an additional gene coding for an HSV origin-binding protein (UL9) was required for origin-dependent HSV DNA replication but was dispensable for SV40 DNA amplification. The results show that a subset of HSV replication genes is sufficient for the induction of DNA amplification. This opens the possibility that HSV expresses functions sufficient for DNA amplification but separate from those responsible for lytic viral growth. HSV infection may thereby induce DNA amplification within the host cell genome without killing the host by lytic viral growth. This may lead to persistence of a cell with a new genetic phenotype, which would have implications for the pathogenicity of the virus in vivo.

  17. Quantification of Poly(I:C)-Mediated Protection against Genital Herpes Simplex Virus Type 2 Infection

    PubMed Central

    Herbst-Kralovetz, Melissa M.; Pyles, Richard B.

    2006-01-01

    Alternative strategies for controlling the growing herpes simplex virus type 2 (HSV-2) epidemic are needed. A novel class of immunomodulatory microbicides has shown promise as antiherpetics, including intravaginally applied CpG-containing oligodeoxynucleotides that stimulate toll-like receptor 9 (TLR9). In the current study, we quantified protection against experimental genital HSV-2 infection provided by an alternative nucleic acid-based TLR agonist, polyinosine-poly(C) (PIC) (TLR3 agonist). Using a protection quantification paradigm, groups of mice were PIC treated and then subdivided into groups challenged with escalating doses of HSV-2. Using this paradigm, a temporal window of PIC efficacy for single applications was defined as 1 day prior to (prophylactic) through 4 h after (therapeutic) viral challenge. PIC treatment within this window protected against 10-fold-higher HSV-2 challenges, as indicated by increased 50% infectious dose values relative to those for vehicle-treated controls. Disease resolution and survival were significantly enhanced by repetitive PIC doses. Using optimal PIC regimens, cytokine induction was evaluated in murine vaginal lavages and in human vaginal epithelial cells. Similar induction patterns were observed, with kinetics that explained the limited durability of PIC-afforded protection. Daily PIC delivery courses did not generate sustained cytokine levels in murine vaginal fluids that would be indicative of local immunotoxicity. No evidence of immunotoxicity was observed in selected organs that were analyzed following repetitive vaginal PIC doses. Animal and in vitro data indicate that PIC may prove to be a valuable preventative microbicide and/or therapeutic agent against genital herpes by increasing resistance to HSV-2 and enhancing disease resolution following a failure of prevention. PMID:17005677

  18. Inhibition of host protein synthesis and degradation of cellular mRNAs during infection by influenza and herpes simplex virus

    SciTech Connect

    Inglis, S.C.

    1982-12-01

    Cloned DNA copies of two cellular genes were used to monitor, by blot hybridization, the stability of particular cell mRNAs after infection by influenza virus and herpes virus. The results indicated that the inhibition of host cell protein synthesis that accompanied infection by each virus could be explained by a reduction in the amounts of cellular mRN As in the cytoplasm, and they suggested that this decrease was due to virus-mediated mRNA degradation.

  19. Candidate topical microbicides bind herpes simplex virus glycoprotein B and prevent viral entry and cell-to-cell spread.

    PubMed

    Cheshenko, Natalia; Keller, Marla J; MasCasullo, Veronica; Jarvis, Gary A; Cheng, Hui; John, Minnie; Li, Jin-Hua; Hogarty, Kathleen; Anderson, Robert A; Waller, Donald P; Zaneveld, Lourens J D; Profy, Albert T; Klotman, Mary E; Herold, Betsy C

    2004-06-01

    Topical microbicides designed to prevent acquisition of sexually transmitted infections are urgently needed. Nonoxynol-9, the only commercially available spermicide, damages epithelium and may enhance human immunodeficiency virus transmission. The observation that herpes simplex virus (HSV) and human immunodeficiency virus bind heparan sulfate provided the rationale for the development of sulfated or sulfonated polymers as topical agents. Although several of the polymers have advanced to clinical trials, the spectrum and mechanism of anti-HSV activity and the effects on soluble mediators of inflammation have not been evaluated. The present studies address these gaps. The results indicate that PRO 2000, polystyrene sulfonate, cellulose sulfate, and polymethylenehydroquinone sulfonate inhibit HSV infection 10,000-fold and are active against clinical isolates, including an acyclovir-resistant variant. The compounds formed stable complexes with glycoprotein B and inhibit viral binding, entry, and cell-to-cell spread. The effects may be long lasting due to the high affinity and stability of the sulfated compound-virus complex, as evidenced by surface plasmon resonance studies. The candidate microbicides retained their antiviral activities in the presence of cervical secretions and over a broad pH range. There was little reduction in cell viability following repeated exposure of human endocervical cells to these compounds, although a reduction in secretory leukocyte protease inhibitor levels was observed. These studies support further development and rigorous evaluation of these candidate microbicides. PMID:15155195

  20. Recombinant adeno-associated virus-mediated gene transfer for the potential therapy of adenosine deaminase-deficient severe combined immune deficiency.

    PubMed

    Silver, Jared N; Elder, Melissa; Conlon, Thomas; Cruz, Pedro; Wright, Amy J; Srivastava, Arun; Flotte, Terence R

    2011-08-01

    Severe combined immune deficiency due to adenosine deaminase (ADA) deficiency is a rare, potentially fatal pediatric disease, which results from mutations within the ADA gene, leading to metabolic abnormalities and ultimately profound immunologic and nonimmunologic defects. In this study, recombinant adeno-associated virus (rAAV) vectors based on serotypes 1 and 9 were used to deliver a secretory version of the human ADA (hADA) gene to various tissues to promote immune reconstitution following enzyme expression in a mouse model of ADA deficiency. Here, we report that a single-stranded rAAV vector, pTR2-CB-Igκ-hADA, (1) facilitated successful gene delivery to multiple tissues, including heart, skeletal muscle, and kidney, (2) promoted ectopic expression of hADA, and (3) allowed enhanced serum-based enzyme activity over time. Moreover, the rAAV-hADA vector packaged in serotype 9 capsid drove partial, prolonged, and progressive immune reconstitution in ADA-deficient mice. Overview Summary Gene therapies for severe combined immune deficiency due to adenosine deaminase (ADA) deficiency (ADA-SCID) over two decades have exclusively involved retroviral vectors targeted to lymphocytes and hematopoietic progenitor cells. These groundbreaking gene therapies represented an unprecedented revolution in clinical medicine but in most cases did not fully correct the immune deficiency and came with the potential risk of insertional mutagenesis. Alternatively, recombinant adeno-associated virus (rAAV) vectors have gained attention as valuable tools for gene transfer, having demonstrated no pathogenicity in humans, minimal immunogenicity, long-term efficacy, ease of administration, and broad tissue tropism (Muzyczka, 1992 ; Flotte et al., 1993 ; Kessler et al., 1996 ; McCown et al., 1996 ; Lipkowitz et al., 1999 ; Marshall, 2001 ; Chen et al., 2003 ; Conlon and Flotte, 2004 ; Griffey et al., 2005 ; Pacak et al., 2006 ; Stone et al., 2008 ; Liu et al., 2009 ; Choi et al., 2010

  1. Non-nucleosidic inhibition of Herpes simplex virus DNA polymerase: mechanistic insights into the anti-herpetic mode of action of herbal drug withaferin A

    PubMed Central

    2011-01-01

    Background Herpes Simplex Virus 1 and 2 causes several infections in humans including cold sores and encephalitis. Previous antiviral studies on herpes viruses have focussed on developing nucleoside analogues that can inhibit viral polymerase and terminate the replicating viral DNA. However, these drugs bear an intrinsic non-specificity as they can also inhibit cellular polymerase apart from the viral one. The present study is an attempt to elucidate the action mechanism of naturally occurring withaferin A in inhibiting viral DNA polymerase, thus providing an evidence for its development as a novel anti-herpetic drug. Results Withaferin A was found to bind very similarly to that of the previously reported 4-oxo-DHQ inhibitor. Withaferin A was observed binding to the residues Gln 617, Gln 618, Asn 815 and Tyr 818, all of which are crucial to the proper functioning of the polymerase. A comparison of the conformation obtained from docking and the molecular dynamics simulations shows that substantial changes in the binding conformations have occurred. These results indicate that the initial receptor-ligand interaction observed after docking can be limited due to the receptor rigid docking algorithm and that the conformations and interactions observed after simulation runs are more energetically favoured. Conclusions We have performed docking and molecular dynamics simulation studies to elucidate the binding mechanism of prospective herbal drug withaferin A onto the structure of DNA polymerase of Herpes simplex virus. Our docking simulations results give high binding affinity of the ligand to the receptor. Long de novo MD simulations for 10 ns performed allowed us to evaluate the dynamic behaviour of the system studied and corroborate the docking results, as well as identify key residues in the enzyme-inhibitor interactions. The present MD simulations support the hypothesis that withaferin A is a potential ligand to target/inhibit DNA polymerase of the Herpes simplex

  2. The effect of adding tobramycin to Simplex P cement on femoral stem micromotion as measured by radiostereometric analysis

    PubMed Central

    2012-01-01

    Background Previous in vitro research on addition of antibiotics to bone cement has found no statistically significant deterioration in mechanical properties. However, no clinical studies have compared the performance of tobramycin-laden bone cement with that of standard bone cement (Simplex P). Patients and Methods 23 patients (25 hips) were randomized to receive an Exeter (Stryker Orthopaedics) femoral stem cemented with either Simplex P (standard) or Simplex T (tobramycin-laden) cement. There were 2 years of follow-up, with scheduled radiostereometric (RSA) examinations. Results All stems migrated distally and showed some degree of retroversion. No clinically significant differences in stem subsidence or retroversion were found between the Simplex T and Simplex P cement groups after 2 years. Overall subsidence was less than in previous studies, probably due to a postponed initial post-surgical examination. Rates of subsidence in both cement groups were consistent with those from previous studies of Exeter stems. Interpretation Subsidence of the femoral stem after 2 years was similar in the Simplex T (tobramycin-laden) and Simplex P (standard) groups. PMID:22248163

  3. Preventing herpes simplex virus transmission to the neonate.

    PubMed

    Brown, Zane

    2004-08-01

    Neonatal herpes simplex virus (HSV) infection can have severe consequences. Skin, eye and mouth infection is rarely fatal, but disseminated or central nervous system (CNS) disease has a mortality rate of 80% in the absence of therapy, and most surviving infants have neurological sequelae. Aciclovir therapy can improve the outcome of neonatal herpes, but is often delayed due to the early non-specific symptoms of the disease. Even with early therapy, some infants develop disseminated infection or CNS complications. The virus is usually vertically transmitted to the neonate from an infected mother during delivery. As such, the optimal strategy for reducing the morbidity of neonatal herpes is to prevent the neonate from acquiring HSV infection at delivery. The highest risk of neonatal infection occurs when the mother sheds HSV at labour, which happens more frequently in women who acquire genital herpes in the third trimester. Therefore, one approach for reducing maternal-fetal transmissions is to prevent HSV acquisition in late pregnancy. Definitive classification of genital HSV infection during pregnancy as either primary, non-primary first episode or recurrent can be accomplished only when clinical evaluation is accompanied by laboratory testing, including the use of gG-specific serological tests. The serological status of the mother's sexual partner should be considered when determining her risk of infection. The use of weekly viral cultures in pregnant women with confirmed genital herpes is not warranted, as they do not predict an infant's risk of acquisition of HSV at delivery and are not cost-effective. High-risk susceptible women should be counselled about abstinence and reducing oral-genital contact near term. Observational studies suggest that caesarean section can reduce transmission of neonatal herpes, and is warranted for women who shed HSV at delivery, although different countries vary in their approach to caesarean sections and so universal

  4. Efficacy Results of a Trial of a Herpes Simplex Vaccine

    PubMed Central

    Belshe, Robert B.; Leone, Peter A.; Bernstein, David I.; Wald, Anna; Levin, Myron J.; Stapleton, Jack T.; Gorfinkel, Iris; Morrow, Rhoda L. Ashley; Ewell, Marian G.; Stokes-Riner, Abbie; Dubin, Gary; Heineman, Thomas C.; Schulte, Joann M.; Deal, Carolyn D.

    2012-01-01

    Background Two previous studies of a herpes simplex virus type 2 (HSV-2) subunit vaccine containing glycoprotein D in HSV-discordant couples revealed 73% and 74% efficacy against genital disease in women who were negative for both HSV type 1 (HSV-1) and HSV-2 antibodies. Efficacy was not observed in men or HSV-1 seropositive women. Methods We conducted a randomized, double-blind efficacy field trial involving 8323 women 18 to 30 years of age who were negative for antibodies to HSV-1 and HSV-2. At months 0, 1, and 6, some subjects received the investigational vaccine, consisting of 20 μg of glycoprotein D from HSV-2 with alum and 3-O-deacylated monophosphoryl lipid A as an adjuvant; control subjects received the hepatitis A vaccine, at a dose of 720 enzyme-linked immunosorbent assay (ELISA) units. The primary end point was occurrence of genital herpes disease due to either HSV-1 or HSV-2 from month 2 (1 month after dose 2) through month 20. Results The HSV vaccine was associated with an increased risk of local reactions as compared with the control vaccine, and it elicited ELISA and neutralizing antibodies to HSV-2. Overall, the vaccine was not efficacious; vaccine efficacy was 20% (95% confidence interval [CI], −29 to 50) against genital herpes disease. However, efficacy against HSV-1 genital disease was 58% (95% CI, 12 to 80). Vaccine efficacy against HSV-1 infection (with or without disease) was 35% (95% CI, 13 to 52), but efficacy against HSV-2 infection was not observed (−8%; 95% CI, −59 to 26). Conclusions In a study population that was representative of the general population of HSV-1– and HSV-2–seronegative women, the investigational vaccine was effective in preventing HSV-1 genital disease and infection but not in preventing HSV-2 disease or infection. (Funded by the National Institute of Allergy and Infectious Diseases and GlaxoSmithKline; ClinicalTrials.gov number, NCT00057330.) PMID:22216840

  5. Herpes Simplex Virus 1 US3 Phosphorylates Cellular KIF3A To Downregulate CD1d Expression

    PubMed Central

    Xiong, Ran; Rao, Ping; Kim, Seil; Li, Michelle; Wen, Xiangshu

    2015-01-01

    ABSTRACT Herpes simplex virus 1 (HSV-1) causes one of the most prevalent herpesviral infections in humans and is the leading etiological agent of viral encephalitis and eye infections. Our understanding of how HSV-1 interacts with the host at the cellular and organismal levels is still limited. We and others previously reported that, upon infection, HSV-1 rapidly and efficiently downregulates CD1d cell surface expression and suppresses the function of NKT cells, a group of innate T cells with critical immunoregulatory function. The viral protein kinase US3 plays a major role in this immune evasion mechanism, and its kinase activity is required for this function. In this study, we investigated the cellular substrate(s) phosphorylated by US3 and how it mediates US3 suppression of CD1d recycling. We identified the type II kinesin motor protein KIF3A as a critical kinesin factor in the cell surface expression of CD1d. Interestingly, KIF3A is phosphorylated by US3 both in vitro and in infected cells. Mass spectrometry analysis of purified KIF3A showed that it is phosphorylated predominantly at serine 687 by US3. Ablation of this phosphorylation abolished US3-mediated downregulation of CD1d expression, suggesting that phosphorylation of KIF3A is the primary mechanism of HSV-1 suppression of CD1d expression by US3 protein. Understanding of the precise mechanism of viral modulation of CD1d expression will help to develop more efficient vaccines in the future to boost host NKT cell-mediated immune responses against herpesviruses. IMPORTANCE Herpes simplex virus 1 (HSV-1) is among the most common human pathogens. Little is known regarding the exact mechanism by which this virus evades the human immune system, particularly the innate immune system. We previously reported that HSV-1 employs its protein kinase US3 to modulate the expression of the key antigen-presenting molecule CD1d to evade the antiviral function of NKT cells. Here we identified the key cellular motor protein

  6. Optimization of Recombinant Adeno-Associated Virus-Mediated Expression for Large Transgenes, Using a Synthetic Promoter and Tandem Array Enhancers.

    PubMed

    Yan, Ziying; Sun, Xingshen; Feng, Zehua; Li, Guiying; Fisher, John T; Stewart, Zoe A; Engelhardt, John F

    2015-06-01

    The packaging capacity of recombinant adeno-associated viral (rAAV) vectors limits the size of the promoter that can be used to express the 4.43-kb cystic fibrosis transmembrane conductance regulator (CFTR) cDNA. To circumvent this limitation, we screened a set of 100-mer synthetic enhancer elements, composed of ten 10-bp repeats, for their ability to augment CFTR transgene expression from a short 83-bp synthetic promoter in the context of an rAAV vector designed for use in the cystic fibrosis (CF) ferret model. Our initial studies assessing transcriptional activity in monolayer (nonpolarized) cultures of human airway cell lines and primary ferret airway cells revealed that three of these synthetic enhancers (F1, F5, and F10) significantly promoted transcription of a luciferase transgene in the context of plasmid transfection. Further analysis in polarized cultures of human and ferret airway epithelia at an air-liquid interface (ALI), as well as in the ferret airway in vivo, demonstrated that the F5 enhancer produced the highest level of transgene expression in the context of an AAV vector. Furthermore, we demonstrated that increasing the size of the viral genome from 4.94 to 5.04 kb did not significantly affect particle yield of the vectors, but dramatically reduced the functionality of rAAV-CFTR vectors because of small terminal deletions that extended into the CFTR expression cassette of the 5.04-kb oversized genome. Because rAAV-CFTR vectors greater than 5 kb in size are dramatically impaired with respect to vector efficacy, we used a shortened ferret CFTR minigene with a 159-bp deletion in the R domain to construct an rAAV vector (AV2/2.F5tg83-fCFTRΔR). This vector yielded an ∼17-fold increase in expression of CFTR and significantly improved Cl(-) currents in CF ALI cultures. Our study has identified a small enhancer/promoter combination that may have broad usefulness for rAAV-mediated CF gene therapy to the airway. PMID:25763813

  7. Simultaneous Metabolite, Protein, Lipid Extraction (SIMPLEX): A Combinatorial Multimolecular Omics Approach for Systems Biology.

    PubMed

    Coman, Cristina; Solari, Fiorella Andrea; Hentschel, Andreas; Sickmann, Albert; Zahedi, René Peiman; Ahrends, Robert

    2016-04-01

    Interconnected molecular networks are at the heart of signaling pathways that mediate adaptive plasticity of eukaryotic cells. To gain deeper insights into the underlying molecular mechanisms, a comprehensive and representative analysis demands a deep and parallel coverage of a broad spectrum of molecular species. Therefore, we introduce a simultaneous metabolite, protein, lipid extraction (SIMPLEX) procedure, a novel strategy for the quantitative investigation of lipids, metabolites, and proteins. Compared with unimolecular workflows, SIMPLEX offers a fundamental turn in study design since multiple molecular classes can be accessed in parallel from one sample with equal efficiency and reproducibility. Application of this method in mass-spectrometry-based workflows allowed the simultaneous quantification of 360 lipids, 75 metabolites, and 3327 proteins from 10(6)cells. The versatility of this method is shown in a model system for adipogenesis- peroxisomal proliferator-activated receptor gamma (PPARG) signaling in mesenchymal stem cells-where we utilized SIMPLEX to explore cross-talk within and between all three molecular classes and identified novel potential molecular entry points for interventions, indicating that SIMPLEX provides a superior strategy compared with conventional workflows. PMID:26814187

  8. Ficus whitefly, Singhiella simplex, and its predation by a coccinellid beetle, Delphastus catalinae

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ficus whitefly, Singhiella simplex, is a pest of ficus plant such as Ficus benjamina, F. altissima, F. bengalensis and others. This invasive pest causes plants to exhibit leaf yellowing, wilting, and eventually, leaf drop. There is little information on the effectiveness of insect predators to contr...

  9. REPRODUCTION OF THE FICUS WHITEFLY, SINGHIELLA SIMPLEX (HEMIPTERA: ALEYRODIDAE): A NEW INVASIVE PEST IN THE USA

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ficus Whitefly (Singhiella simplex) was first reported in Miami-Dade County in August 2007. This invasive pest causes infested plants to exhibit leaf yellowing, followed by leaf drop. The pest has been recorded on multiple ficus hosts including Ficus benjamina, F. altissima, F. bengalensis, F. micro...

  10. Herpes Simplex Virus Infection in a University Health Population: Clinical Manifestations, Epidemiology, and Implications

    ERIC Educational Resources Information Center

    Horowitz, Robert; Aierstuck, Sara; Williams, Elizabeth A.; Melby, Bernette

    2010-01-01

    Objective: The authors described clinical presentations of oral and genital herpes simplex virus (HSV) infections in a university health population and implications of these findings. Participants and Methods: Using a standardized data collection tool, 215 records of patients with symptomatic culture-positive HSV infections were reviewed. Results:…

  11. 75 FR 59611 - Microbiology Devices; Reclassification of Herpes Simplex Virus Types 1 and 2 Serological Assays...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-28

    ... final rule that appeared in the Federal Register of August 25, 2009 (74 FR 42773). The direct final rule... INFORMATION: In the Federal Register of August 25, 2009 (74 FR 42773), FDA solicited comments concerning the... Herpes Simplex Virus Types 1 and 2 Serological Assays; Confirmation of Effective Date AGENCY: Food...

  12. Population- and Family-Based Studies Associate the "MTHFR" Gene with Idiopathic Autism in Simplex Families

    ERIC Educational Resources Information Center

    Liu, Xudong; Solehdin, Fatima; Cohen, Ira L.; Gonzalez, Maripaz G.; Jenkins, Edmund C.; Lewis, M. E. Suzanne; Holden, Jeanette J. A.

    2011-01-01

    Two methylenetetrahydrofolate reductase gene ("MTHFR") functional polymorphisms were studied in 205 North American simplex (SPX) and 307 multiplex (MPX) families having one or more children with an autism spectrum disorder. Case-control comparisons revealed a significantly higher frequency of the low-activity 677T allele, higher prevalence of the…

  13. Herpes simplex colitis in a child with combined liver and small bowel transplant.

    PubMed

    Delis, S; Kato, T; Ruiz, P; Mittal, N; Babinski, L; Tzakis, A

    2001-10-01

    Herpes simplex virus (HSV) has been a rare cause of gastrointestinal (GI) infection, especially in immunocompromised patients. A variety of GI sites may be involved; however, only three reported cases of HSV colitis have been documented in the literature. To our knowledge, this is the first report of HSV colitis in a small bowel transplant recipient. PMID:11560759

  14. Herpes simplex virus (HSV) colitis in a bone marrow transplant recipient.

    PubMed

    Naik, H R; Chandrasekar, P H

    1996-02-01

    Herpes simplex virus (HSV) infections are common in bone marrow transplantation patients. Unusual sites may be involved, however colonic disease with HSV is rare. We report a successfully treated case of colitis due to HSV, cytomegalovirus, Clostridium difficile and graft-versus-host disease in an allogeneic marrow recipient. PMID:8640181

  15. Does the Cognitive Architecture of Simplex and Multiplex ASD Families Differ?

    ERIC Educational Resources Information Center

    Oerlemans, Anoek M.; Hartman, Catharina A.; Franke, Barbara; Buitelaar, Jan K.; Rommelse, Nanda N. J.

    2016-01-01

    Children with an autism spectrum disorder (ASD) and their unaffected siblings from 54 simplex (SPX, one individual in the family affected) and 59 multiplex (MPX, two or more individuals affected) families, and 124 controls were assessed on intelligence, social cognition and executive functions. SPX and MPX ASD probands displayed similar cognitive…

  16. Herpes simplex virus lymphadenitis: case report and review of the literature.

    PubMed

    Witt, Mallory D; Torno, Mauro S; Sun, Nora; Stein, Tomiko

    2002-01-01

    Localized or regional necrotizing lymphadenitis is an extremely uncommon manifestation of herpes simplex virus (HSV) infection. We report a case of necrotizing HSV lymphadenitis in a patient with both common variable immunodeficiency and natural killer cell deficiency and review the literature on this unusual complication of HSV infection. PMID:11731938

  17. Intraoral herpes simplex virus infection in a patient with common variable immunodeficiency.

    PubMed

    Villa, Alessandro; Treister, Nathaniel S

    2013-10-01

    We report a challenging case of an atypical presentation of recrudescent herpes simplex virus infection in a patient with common variable immunodeficiency. Oral infections in immunosuppressed patients may present with unusual clinical features that can mimic non-infectious diseases. This report discusses the diagnostic steps necessary for definitive diagnosis and to guide appropriate and effective management. PMID:23933299

  18. Hepatoprotective constituents of Firmiana simplex stem bark against ethanol insult to primary rat hepatocytes

    PubMed Central

    Kim, Jung Wha; Yang, Heejung; Cho, Namki; Kim, Bitnarae; Kim, Young Choong; Sung, Sang Hyun

    2015-01-01

    Background: Ethanol causes hepatic cellular damage by alterations in biological functions. This study evaluated the hepatoprotective potential of the methanolic extract originating from Firmiana simplex (Sterculiaceae) stem bark against the ethanol-induced hepatotoxicity in rat primary hepatocytes. Materials and Methods: The extract of F. simplex stem bark was successively fractionated into n-hexane, chloroform, ethyl acetate (EtOAc), and n-butanol. Column chromatography with silica gel and sephadex LH-20 was used to isolate the EtOAc fraction. Rat primary hepatocytes were cultured to study the hepatoprotective activity of isolated substances against ethanol-induced toxicity. Intracellular reactive oxygen species (ROS) levels, the antioxidant activities of glutathione reductase (GR) and glutathione peroxidase (GSH-PX) enzymes, and the GSH content were measured to examine the antioxidative property of the isolated compounds. Results: Two flavonoid glycosides, quercitrin (1) and tamarixetin 3-O-rhamnopyranoside (2), were isolated from the active EtOAc fraction. Compound 1 significantly protected rat primary hepatocytes against ethanol-induced oxidative stress by reducing the intracellular ROS level and preserving antioxidative defense systems such as GR, GSH-PX, and total GSH. Conclusion: This is the first report on the hepatoprotective activities of the extract of F. simplex. The EtOAc fraction of F. simplex stem bark and its major constituent quercitrin (1) could function as hepatoprotective agents to attenuate the development of alcoholic liver disease. PMID:25709211

  19. Complete Genome Sequence of Steroid-Transforming Nocardioides simplex VKM Ac-2033D

    PubMed Central

    Shtratnikova, Victoriya Y.; Schelkunov, Mikhail I.; Pekov, Yury A.; Fokina, Victoria V.; Logacheva, Mariya D.; Sokolov, Sergey L.; Bragin, Eugeny Y.; Ashapkin, Vasily V.

    2015-01-01

    Nocardioides simplex VKM Ac-2033D is an effective microbial catalyst for 3-ketosteroid 1(2)-dehydrogenation, and it is capable of effective reduction of carbonyl groups at C-17 and C-20, hydrolysis of acetylated steroids, and utilization of natural sterols. Here, the complete genome sequence is reported. An array of genes related to steroid metabolic pathways have been identified. PMID:25573942

  20. Molluscum contagiosum and herpes simplex in Maasai pastoralists; refeeding activation of virus infection following famine?

    PubMed

    Murray, M J; Murray, A B; Murray, N J; Murray, M B; Murray, C J

    1980-01-01

    An epidemic of molluscum contagiosum and oro-genital herpes simplex was observed in Maasai pastoralists of the Rift Valley. It coincided with a period of refeeding following famine, when the relief diet was different from normal milk fare. We propose that refeeding may be an important mechanism for activation of certain viral infections previously suppressed by famine. PMID:7434431

  1. Predation of the ficus whitefly, Singhiella simplex by the coccinellid beetle, Delphastus catalinae

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ficus Whitefly (Singhiella simplex) was first reported in Miami-Dade County in August 2007. This invasive pest causes infested plants to exhibit leaf yellowing, followed by leaf drop. The pest has been recorded on multiple ficus hosts including Ficus benjamina, F. altissima, F. bengalensis, F. micro...

  2. Acute retinal necrosis secondary to herpes simplex virus type 2 with preexisting chorioretinal scarring.

    PubMed

    Moesen, Ingemarie; Khemka, Sneh; Ayliffe, William

    2008-01-01

    Acute retinal necrosis in children is a devastating disease that requires early diagnosis and treatment. The authors describe a rarely reported case of bilateral acute retinal necrosis in a child caused by neonatal herpes simplex virus type 2, where the presence of previous chorioretinal scarring made diagnosis challenging. PMID:18286969

  3. Quantitative autoradiographic mapping of focal herpes simplex virus encephalitis using a radiolabeled antiviral drug

    SciTech Connect

    Price, R.

    1984-12-18

    A method of mapping herpes simplex viral infection comprising administering a radiolabeled antiviral active 5-substituted 1-(2'-deoxy-2'-substituted-D-arabinofuranosyl) pyrimidine nucleoside to the infected subject, and scanning the area in which the infection is to be mapped for the radiolabel.

  4. Amino-terminal sequence of glycoprotein D of herpes simplex virus types 1 and 2

    SciTech Connect

    Eisenberg, R.J.; Long, D.; Hogue-Angeletti, R.; Cohen, G.H.

    1984-01-01

    Glycoprotein D (gD) of herpes simplex virus is a structural component of the virion envelope which stimulates production of high titers of herpes simplex virus type-common neutralizing antibody. The authors caried out automated N-terminal amino acid sequencing studies on radiolabeled preparations of gD-1 (gD of herpes simplex virus type 1) and gD-2 (gD of herpes simplex virus type 2). Although some differences were noted, particularly in the methionine and alanine profiles for gD-1 and gD-2, the amino acid sequence of a number of the first 30 residues of the amino terminus of gD-1 and gD-2 appears to be quite similar. For both proteins, the first residue is a lysine. When we compared out sequence data for gD-1 with those predicted by nucleic acid sequencing, the two sequences could be aligned (with one exception) starting at residue 26 (lysine) of the predicted sequence. Thus, the first 25 amino acids of the predicted sequence are absent from the polypeptides isolated from infected cells.

  5. Inhibition of topoisomerase II by ICRF-193 prevents efficient replication of herpes simplex virus type 1.

    PubMed Central

    Hammarsten, O; Yao, X; Elias, P

    1996-01-01

    Cellular topoisomerase II is specifically inactivated by the drug ICRF-193. This compound turns topoisomerase II into a closed clamp that is unable to cleave DNA. We have investigated the effects of this inhibitor on the replication of herpes simplex virus type 1. We show that ICRF-193 at low multiplicities of infection dramatically inhibits viral DNA synthesis and the production of infectious virus. The inhibition is less efficient at high multiplicities of infection. In addition, inhibition of viral DNA synthesis was observed only when ICRF-193 was present during the first 4 h of the infectious cycle. The transient replication of plasmids containing a herpes simplex virus type 1 origin of DNA replication, oriS, was affected by ICRF-193 in the same way. In contrast, neither cellular DNA synthesis nor replication of plasmids containing a simian virus 40 origin of DNA replication was inhibited. The observed effect on herpes simplex virus DNA replication was not caused by a decreased transcription of replication genes inasmuch as the levels of UL8, UL9, UL29, and UL30 rmRNAs were unaffected by the drug. These results suggest that topoisomerase II plays a vital role during the replication of herpes simplex virus type 1 DNA. We speculate that topoisomerase II is involved in the decatenation of newly synthesized daughter molecules. PMID:8676478

  6. Life history and biological control of the ficus whitefly, Singhiella simplex (Hemiptera)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ficus Whitefly (Singhiella simplex) was first reported in Miami-Dade County in August 2007. Since then, the whitefly has been found throughout southern Florida, as well as along both coasts of Florida up to central Florida. This invasive pest causes infested plants to exhibit leaf yellowing, followe...

  7. Life table analysis and development of Singhiella simplex (Hemiptera:Aleyrodidae) under different constant temperatures

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The ficus whitefly, Singhiella simplex (Singh) (Hemiptera: Aleyrodidae), is a newly-invasive pest of ficus plants in the United States. Very little is known about its biology and life history. Here, we studied development and reproduction at 15, 20, 25, 27, 30 and 35°C. No immatures survived the 35°...

  8. Long-range BOTDA sensor over 50 km distance employing pre-pumped Simplex coding

    NASA Astrophysics Data System (ADS)

    Sun, Qiao; Tu, Xiaobo; Sun, Shilin; Meng, Zhou

    2016-05-01

    We propose and demonstrate a long-range Brillouin optical time-domain analysis (BOTDA) sensor based on the pre-pumped Simplex coding technique. This approach combines Simplex coding with the pulse pre-pump technique, which takes full advantage of the signal-to-noise ratio enhancement provided by optical pulse coding and achieves meter-scale spatial resolution with an unbroadened Brillouin gain spectrum by the use of pre-pumped short pump pulse. Compared to the widely used differential pulse-width pair technique, a comparable performance can be realized while the measurement time is reduced by half. The theoretical analysis of pre-pumped Simplex coding applied to BOTDA systems is presented and a proof-of-concept experiment is carried out along a ∼51 km single-mode fiber composed of two fiber segments with slightly different Brillouin frequency shift values. With the proposed technique, Brillouin frequency shifts of the two different fiber sections at the end of the sensing fiber are clearly distinguished, and the obtained spatial resolution and temperature/strain accuracy along the sensing fiber are respectively 1 m and {0.4}\\circ {{C}}/8μ \\varepsilon . According to the experimental results, we believe that the BOTDA employing pre-pumped Simplex coding is able to realize extra-long distance sensing without Raman amplification, while keeping a high spatial resolution and measurement accuracy.

  9. FECUNDITY OF FICUS WHITEFLY, SINGHIELLA SIMPLEX (HEMIPTERA: ALEYRODIDAE), AND ITS PREDATION BY DELPHASTUS CATALINAE (COLEOPTERA: COCCINELLIDAE)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ficus Whitefly (Singhiella simplex) was first reported in Miami-Dade County in August 2007. This invasive pest causes infested plants to exhibit leaf yellowing, followed by leaf drop. The pest has been recorded on multiple ficus hosts including Ficus benjamina, F. altissima, F. bengalensis, F. micro...

  10. Serologic Screening for Herpes Simplex Virus among University Students: A Pilot Study

    ERIC Educational Resources Information Center

    Mark, Hayley; Nanda, Joy P.; Joffe, Alain; Roberts, Jessica; Rompalo, Anne; Melendez, Johan; Zenilman, Jonathan

    2008-01-01

    Objective: The authors examined the feasibility of conducting serologic testing for the herpes simplex virus 2 (HSV-2) among university students and assessed the psychosocial impact of an HSV-2 diagnosis. Methods: The authors recruited a convenience sample of 100 students (aged 18-39 years) without a history of genital herpes from 1 university…

  11. Molecular mimicry and myasthenia gravis. An autoantigenic site of the acetylcholine receptor alpha-subunit that has biologic activity and reacts immunochemically with herpes simplex virus.

    PubMed Central

    Schwimmbeck, P L; Dyrberg, T; Drachman, D B; Oldstone, M B

    1989-01-01

    The large majority of patients with the autoimmune disease myasthenia gravis characteristically have detectable antibodies against the acetylcholine receptor (AChR). We used synthetic peptides to identify antibodies in sera of myasthenia gravis patients reactive with the human acetylcholine receptor (HuAChR) alpha-subunit, residues 160-167. Affinity purification of these antibodies, using the HuAChR alpha-subunit 157-170 peptide immobilized on thiopropyl-Sepharose, yielded IgG antibodies that bound to the native AChR and inhibited the binding of alpha-bungarotoxin to the receptor. The HuAChR alpha-subunit 160-167 peptide demonstrated specific immunological cross-reactivity with a shared homologous domain on herpes simplex virus glycoprotein D, residues 286-293, by both binding and inhibition studies. Thus, HuAChR alpha-subunit, residues 160-167, elicits antibodies in myasthenic patients that binds to the native AChR protein and is capable of eliciting a biologic effect. Immunologic cross-reactivity of this "self" epitope with herpes simplex virus suggest that this virus may be associated with the initiation of some cases of myasthenia. Images PMID:2551924

  12. Brazilein from Caesalpinia sappan L. Antioxidant Inhibits Adipocyte Differentiation and Induces Apoptosis through Caspase-3 Activity and Anthelmintic Activities against Hymenolepis nana and Anisakis simplex

    PubMed Central

    Liang, Chia-Hua; Chan, Leong-Perng; Chou, Tzung-Han; Chiang, Feng-Yu; Yen, Chuan-Min; Chen, Pin-Ju; Ding, Hsiou-Yu

    2013-01-01

    Brazilein, a natural, biologically active compound from Caesalpinia sappan L., has been shown to exhibit anti-inflammatory and antioxidant properties and to inhibit the growth of several cancer cells. This study verifies the antioxidant and antitumor characteristics of brazilein in skin cancer cells and is the first time to elucidate the inhibition mechanism of adipocyte differentiation, cestocidal activities against Hymenolepis nana, and reduction of spontaneous movement in Anisakis simplex. Brazilein exhibits an antioxidant capacity as well as the ability to scavenge DPPH• and ABTS•+ free radicals and to inhibit lipid peroxidation. Brazilein inhibited intracellular lipid accumulation during adipocyte differentiation in 3T3-L1 cells and suppressed the induction of peroxisome proliferator-activated receptor γ (PPARγ), the master regulator of adipogenesis, suggesting that brazilein presents the antiobesity effects. The toxic effects of brazilein were evaluated in terms of cell viability, induction of apoptosis, and the activity of caspase-3 in BCC cells. The inhibition of the growth of skin cancer cells (A431, BCC, and SCC25) by brazilein is greater than that of human skin malignant melanoma (A375) cells, mouse leukemic monocyte macrophage (RAW 264.7 cells), and noncancerous cells (HaCaT and BNLCL2 cells). The anthelmintic activities of brazilein against Hymenolepis nana are better than those of Anisakis simplex. PMID:23554834

  13. Parasite diversity of Nyctiphanes simplex and Nematoscelis difficilis (Crustacea: Euphausiacea) along the northwestern coast of Mexico.

    PubMed

    Gómez-Gutiérrez, Jaime; Robinson, Carlos J; Kawaguchi, So; Nicol, Stephen

    2010-02-17

    The diversity of parasites found on Nyctiphanes simplex and Nematoscelis difficilis (Order Euphausiacea) was compared during 10 oceanographic cruises made off both coasts of the Baja California peninsula, Mexico. We tested the hypothesis that N. simplex has a more diverse parasitic assemblage than N. difficilis because it is a neritic species, has larger population abundance, and tends to form denser and more compact swarms than N. difficilis. These biological and behavioral features may enhance parasite transmission within swarms. We detected 6 types of ectoparasites: (1) epibiotic diatoms Licmophora sp.; (2) Ephelotidae suctorian ciliates; (3) Foettingeriidae exuviotrophic apostome ciliates; (4) an unidentified epicaridean cryptoniscus larvae (isopoda); and 2 castrators: (5) the ectoparasitic Dajidae isopod Notophryxus lateralis and (6) the ellobiopsid mesoparasite Thalassomyces fagei. We also detected 7 types of endoparasites: (1) an undescribed Collinia ciliate (Apostomatida); 3 types of Cestoda: (2) a Tetrarhynchobothruium sp. (Trypanorhyncha), (3) Echinobothrium sp. (Diphyllidea: Echinobothyriidae), and (4) unidentified metacestode; (5) a Trematoda Paronatrema-like metacercaria (Syncoeliidae); (6) the nematode Anisakis simplex (L3); and (7) Polymorphidae acantocephalan larvae (acanthor, acanthella, and cystacanth larval stages). N. simplex is affected by all types of parasites, except the isopod N. lateralis, having a considerably larger parasitic diversity and prevalence rates than N. difficilis, which is only infested with 3 types of ectoparasites and T. fagei. Euphausiid swarming is an adaptive behavior for reproduction, protection against predators, and increased efficiency in food searching, but has a negative effect due to parasitism. Although the advantages of aggregation must overcome the reduction of population and individual fitness induced by parasites, we demonstrated that all types of parasites can affect approximately 14% of N. simplex

  14. Mycosis Inhibits Cannibalism by Melanoplus sanguinipes, M. differentialis, Schistocerca americana, and Anabrus simplex

    PubMed Central

    Jaronski, Stefan T.

    2013-01-01

    Cannibalism is common among the Acrididae and the Mormon cricket, Anabrus simplex Haldeman (Orthoptera: Tettigoniidae). This behavior has been proposed as a mechanism for the horizontal transmission of Microsporida and entomopathogenic fungi. Aanecdotal observations suggested that the migratory grasshopper, Melanoplus sanguinipes Fabricius (Acrididae), and A. simplex did not eat cadavers that had been killed by insect pathogenic fungi. The hypothesis tested was that A. simplex or M. sanguinipes would not cannibalize individuals freshly killed by the entomopathogenic fungi, Beauveria bassiana Bals.-Criv. (Vuill.) (Hypocreales: Clavicipitaceae), or Metarhizium acridum (Driver and Milner) Bischoff, Rehner, and Humber. Cannibalism was examined in a series of no-choice tests with individual insects. Test insects included healthy adults of M. sanguinipes; the differential grasshopper, M. differentialis (Thomas); the American grasshopper, Schistocerca americana (Drury) (Acrididae); and A. simplex. Individual, starved Acrididae or A. simplex were confined in small cages with either a fungus-killed (but unsporulated) or uninfected cadaver. The insects were then observed periodically for the first 4 hr. After 24 hr, the cadavers were scored for the degree to which they had been consumed. Very few mycotic cadavers were fed upon by the healthy insects, and, at most only the tarsi were eaten. All four species generally refused to eat fungus-infected cadavers. In contrast, freeze-killed cadavers were partly or entirely consumed by most of the test insects, often within a few hours. Transmission of infection through contact in these tests was between 0–18.9%, depending upon the fungus and insect species, and was lower than the prevalence of cannibalism in all cases. PMID:24786183

  15. Activation of Checkpoint Kinase 2 Is Critical for Herpes Simplex Virus Type 1 Replication in Corneal Epithelium

    PubMed Central

    Alekseev, Oleg; Limonnik, Vladimir; Donovan, Kelly; Azizkhan-Clifford, Jane

    2015-01-01

    Background/Aims Herpes simplex virus (HSV) type I keratitis remains a leading cause of corneal morbidity, despite the availability of effective antiviral drugs. Improved understanding of virus-host interactions at the level of the host DNA damage response (DDR), a known factor in the development of HSV-1 keratitis, may shed light on potential new therapeutic targets. This report examines the role of checkpoint kinase 2 (Chk2), a DDR mediator protein, in corneal epithelial HSV-1 infection. Methods A small-molecule inhibitor of Chk2 (Chk2 inhibitor II) was applied to HSV-1-infected cultured human corneal epithelial cells (hTCEpi and HCE) as well as to explanted and organotypically cultured human and rabbit corneas. Infection levels were assessed by plaque assay and real-time PCR. RNAi-mediated depletion of Chk2 was performed to confirm the effect of the inhibitor. Results Inhibition of the Chk2 kinase activity greatly suppresses the cytopathic effect, genome replication and infectious progeny production in vitro and ex vivo. Conclusion This report demonstrates the critical role of Chk2 kinase in the establishment of HSV-1 corneal epithelial infection. These data contribute to our understanding of herpesvirus-host interactions and underscore the significance of DDR activation in HSV-1 keratitis. PMID:25531207

  16. Computational modeling and functional analysis of Herpes simplex virus type-1 thymidine kinase and Escherichia coli cytosine deaminase fusion protein

    SciTech Connect

    Zhang, Jufeng; Wang, Zhanli; Wei, Fang; Qiu, Wei; Zhang, Liangren; Huang, Qian . E-mail: qhuang@sjtu.edu.cn

    2007-08-17

    Herpes simplex virus type-1 thymidine kinase (HSV-1TK) and Escherichia coli cytosine deaminase (CD) fusion protein was designed using InsightII software. The structural rationality of the fusion proteins incorporating a series of flexible linker peptide was analyzed, and a suitable linker peptide was chosen for further investigated. The recombinant plasmid containing the coding regions of HSV-1TK and CD cDNA connected by this linker peptide coding sequence was generated and subsequently transfected into the human embryonic kidney 293 cells (HEK293). The Western blotting indicated that the recombinant fusion protein existed as a dimer with a molecular weight of approximately 90 kDa. The toxicity of the prodrug on the recombinant plasmid-transfected human lung cancer cell line NCIH460 was evaluated, which showed that TKglyCD-expressing cells conferred upon cells prodrug sensitivities equivalent to that observed for each enzyme independently. Most noteworthy, cytotoxicity could be enhanced by concurrently treating TKglyCD-expressing cells with prodrugs GCV and 5-FC. The results indicate that we have successfully constructed a HSV-1TKglyCD fusion gene which might have a potential application for cancer gene therapy.

  17. Inhibition of herpes simplex virus 1 gene expression and replication by RNase P-associated external guide sequences.

    PubMed

    Liu, Jin; Shao, Luyao; Trang, Phong; Yang, Zhu; Reeves, Michael; Sun, Xu; Vu, Gia-Phong; Wang, Yu; Li, Hongjian; Zheng, Congyi; Lu, Sangwei; Liu, Fenyong

    2016-01-01

    An external guide sequence (EGS) is a RNA sequence which can interact with a target mRNA to form a tertiary structure like a pre-tRNA and recruit intracellular ribonuclease P (RNase P), a tRNA processing enzyme, to degrade target mRNA. Previously, an in vitro selection procedure has been used by us to engineer new EGSs that are more robust in inducing human RNase P to cleave their targeted mRNAs. In this study, we constructed EGSs from a variant to target the mRNA encoding herpes simplex virus 1 (HSV-1) major transcription regulator ICP4, which is essential for the expression of viral early and late genes and viral growth. The EGS variant induced human RNase P cleavage of ICP4 mRNA sequence 60 times better than the EGS generated from a natural pre-tRNA. A decrease of about 97% and 75% in the level of ICP4 gene expression and an inhibition of about 7,000- and 500-fold in viral growth were observed in HSV infected cells expressing the variant and the pre-tRNA-derived EGS, respectively. This study shows that engineered EGSs can inhibit HSV-1 gene expression and viral growth. Furthermore, these results demonstrate the potential for engineered EGS RNAs to be developed and used as anti-HSV therapeutics. PMID:27279482

  18. Inhibition of herpes simplex virus 1 gene expression and replication by RNase P-associated external guide sequences

    PubMed Central

    Liu, Jin; Shao, Luyao; Trang, Phong; Yang, Zhu; Reeves, Michael; Sun, Xu; Vu, Gia-Phong; Wang, Yu; Li, Hongjian; Zheng, Congyi; Lu, Sangwei; Liu, Fenyong

    2016-01-01

    An external guide sequence (EGS) is a RNA sequence which can interact with a target mRNA to form a tertiary structure like a pre-tRNA and recruit intracellular ribonuclease P (RNase P), a tRNA processing enzyme, to degrade target mRNA. Previously, an in vitro selection procedure has been used by us to engineer new EGSs that are more robust in inducing human RNase P to cleave their targeted mRNAs. In this study, we constructed EGSs from a variant to target the mRNA encoding herpes simplex virus 1 (HSV-1) major transcription regulator ICP4, which is essential for the expression of viral early and late genes and viral growth. The EGS variant induced human RNase P cleavage of ICP4 mRNA sequence 60 times better than the EGS generated from a natural pre-tRNA. A decrease of about 97% and 75% in the level of ICP4 gene expression and an inhibition of about 7,000- and 500-fold in viral growth were observed in HSV infected cells expressing the variant and the pre-tRNA-derived EGS, respectively. This study shows that engineered EGSs can inhibit HSV-1 gene expression and viral growth. Furthermore, these results demonstrate the potential for engineered EGS RNAs to be developed and used as anti-HSV therapeutics. PMID:27279482

  19. Safety, formulation, and in vitro antiviral activity of the antimicrobial peptide subtilosin against herpes simplex virus type 1

    PubMed Central

    Torres, Nicolás I.; Noll, Katia Sutyak; Xu, Shiqi; Li, Ji; Huang, Qingrong; Sinko, Patrick J.; Wachsman, Mónica B.; Chikindas, Michael L.

    2013-01-01

    In the present study the antiviral properties of the bacteriocin subtilosin against Herpes simplex virus type 1 (HSV-1) and the safety and efficacy of a subtilosin-based nanofiber formulation were determined. High concentrations of subtilosin, the cyclical antimicrobial peptide produced by Bacillus amyloliquefaciens, were virucidal against HSV-1. Interestingly, at non-virucidal concentrations, subtilosin inhibited wild type HSV-1 and aciclovir-resistant mutants in a dose-dependent manner. Although the exact antiviral mechanism is not fully understood, time of addition experiments and western blot analysis suggest that subtilosin does not affect viral multiplication steps prior to protein synthesis. Poly(vinyl alcohol) (PVOH)-based subtilosin nanofibers with a width of 278 nm were produced by the electrospinning process. The retained antimicrobial activity of the subtilosin-based fibers was determined via an agar well diffusion assay. The loading capacity of the fibers was 2.4 mg subtilosin/g fiber, and loading efficiency was 31.6%. Furthermore, the nanofibers with and without incorporated subtilosin were shown to be nontoxic to human epidermal tissues using an in vitro human tissue model. Taking together these results subtilosin-based nanofibers should be further studied as a novel alternative method for treatment and/or control of HSV-1 infection. PMID:23637711

  20. Replication-Competent Herpes Simplex Virus Vector G207 and Cisplatin Combination Therapy for Head and Neck Squamous Cell Carcinoma

    PubMed Central

    Chahlavi, Ali; Todo, Tomoki; Martuza, Robert L; Rabkin, Samuel D

    1999-01-01

    Abstract Replication-competent virus vectors are attractive therapeutic agents for cancer. G207, a second-generation, multimutated herpes simplex virus type 1 (HSV-1), is one such vector that is safe in primates and efficacious against human tumors in athymic mice. Squamous cell carcinoma is the most frequently encountered malignancy of the head and neck, and the chemotherapeutic agent cisplatin is a standard treatment for recurrent head and neck cancer. In this study we examine the therapeutic potential of G207, alone and in combination with cisplatin, against squamous cell carcinoma. Human squamous cell carcinoma cell lines are sensitive to G207 replication and cytotoxicity in vitro at a multiplicity of infection of 0.01, including cisplatin sensitive (UMSCC-22A), moderately sensitive (UMSCC-38), and weakly sensitive (SQ20B) cell lines. Cisplatin did not inhibit the cytopathic effect of G207. G207 inhibited the growth of established subcutaneous head and neck tumors in athymic mice. The therapeutic effects of cisplatin and G207 in vivo were independent. However, in cisplatin-sensitive tumors (UMSCC-38), combination therapy resulted in 100% cures in contrast to 42% with G207 or 14% with cisplatin alone. We conclude that G207 should be considered for the treatment of head and neck cancer and that combination with chemotherapeutic agents may improve efficacy. PMID:10933051

  1. Extended Release of an Anti–Heparan Sulfate Peptide From a Contact Lens Suppresses Corneal Herpes Simplex Virus-1 Infection

    PubMed Central

    Jaishankar, Dinesh; Buhrman, Jason S.; Valyi-Nagy, Tibor; Gemeinhart, Richard A.; Shukla, Deepak

    2016-01-01

    Purpose To prolong the release of a heparan sulfate binding peptide, G2-C, using a commercially available contact lens as a delivery vehicle and to demonstrate the ability of the released peptide to block herpes simplex virus-1 (HSV-1) infection using in vitro, ex vivo, and in vivo models of corneal HSV-1 infection. Methods Commercially available contact lenses were immersed in peptide solution for 5 days prior to determining the release of the peptide at various time points. Cytotoxicity of the released samples was determined by MTT and cell cycle analysis, and the functional activity of the released samples were assessed by viral entry, and viral spread assay using human corneal epithelial cells (HCE). The ability to suppress infection in human and pig cornea ex vivo and mouse in vivo models were also assessed. Results Peptide G2-C was released through the contact lens. Following release for 3 days, the peptide showed significant activity by inhibiting HSV-1 viral entry and spread in HCE cells. Significant suppression of infection was also observed in the ex vivo and in vivo experiments involving corneas. Conclusions Extended release of an anti–HS peptide through a commercially available contact lens can generate significant anti–HSV-1 activity and provides a new and effective way to control corneal herpes. PMID:26780322

  2. The alpha sequence of the cytomegalovirus genome functions as a cleavage/packaging signal for herpes simplex virus defective genomes.

    PubMed Central

    Spaete, R R; Mocarski, E S

    1985-01-01

    Although herpes simplex virus (HSV) 1 and human cytomegalovirus (CMV) differ remarkably in their biological characteristics and do not share nucleotide sequence homology, they have in common a genome structure that undergoes sequence isomerization of the long (L) and short (S) components. We have demonstrated that the similarity in their genome structures extends to the existence of an alpha sequence in the CMV genome as previously defined for the HSV genome. As such, the alpha sequence is predicted to participate as a cis-replication signal in four viral functions: (i) inversion, (ii) circularization, (iii) amplification, and (iv) cleavage and packaging of progeny viral DNA. We have constructed a chimeric HSV-CMV amplicon (herpesvirus cis replication functions carried on an Escherichia coli plasmid vector) substituting CMV DNA sequences for the HSV cleavage/packaging signal in a test of the ability of this CMV L-S junction sequence to provide the cis signal for cleavage/packaging in HSV 1-infected cells. We demonstrate that the alpha sequence of CMV DNA functions as a cleavage/packaging signal for HSV defective genomes. We show the structure of this sequence and provide a functional demonstration of cross complementation in replication signals which have been preserved over evolutionary time in these two widely divergent human herpesviruses. Images PMID:2987533

  3. Safety, formulation, and in vitro antiviral activity of the antimicrobial peptide subtilosin against herpes simplex virus type 1.

    PubMed

    Torres, Nicolás I; Noll, Katia Sutyak; Xu, Shiqi; Li, Ji; Huang, Qingrong; Sinko, Patrick J; Wachsman, Mónica B; Chikindas, Michael L

    2013-03-01

    In the present study the antiviral properties of the bacteriocin subtilosin against Herpes simplex virus type 1 (HSV-1) and the safety and efficacy of a subtilosin-based nanofiber formulation were determined. High concentrations of subtilosin, the cyclical antimicrobial peptide produced by Bacillus amyloliquefaciens, were virucidal against HSV-1. Interestingly, at non-virucidal concentrations, subtilosin inhibited wild type HSV-1 and aciclovir-resistant mutants in a dose-dependent manner. Although the exact antiviral mechanism is not fully understood, time of addition experiments and western blot analysis suggest that subtilosin does not affect viral multiplication steps prior to protein synthesis. Poly(vinyl alcohol) (PVOH)-based subtilosin nanofibers with a width of 278 nm were produced by the electrospinning process. The retained antimicrobial activity of the subtilosin-based fibers was determined via an agar well diffusion assay. The loading capacity of the fibers was 2.4 mg subtilosin/g fiber, and loading efficiency was 31.6%. Furthermore, the nanofibers with and without incorporated subtilosin were shown to be nontoxic to human epidermal tissues using an in vitro human tissue model. Taking together these results subtilosin-based nanofibers should be further studied as a novel alternative method for treatment and/or control of HSV-1 infection. PMID:23637711

  4. Schizophrenia Susceptibility Genes Directly Implicated in the Life Cycles of Pathogens: Cytomegalovirus, Influenza, Herpes simplex, Rubella, and Toxoplasma gondii

    PubMed Central

    Carter, C.J.

    2009-01-01

    Many genes implicated in schizophrenia can be related to glutamatergic transmission and neuroplasticity, oligodendrocyte function, and other families clearly related to neurobiology and schizophrenia phenotypes. Others appear rather to be involved in the life cycles of the pathogens implicated in the disease. For example, aspartylglucosaminidase (AGA), PLA2, SIAT8B, GALNT7, or B3GAT1 metabolize chemical ligands to which the influenza virus, herpes simplex, cytomegalovirus (CMV), rubella, or Toxoplasma gondii bind. The epidermal growth factor receptor (EGR/EGFR) is used by the CMV to gain entry to cells, and a CMV gene codes for an interleukin (IL-10) mimic that binds the host cognate receptor, IL10R. The fibroblast growth factor receptor (FGFR1) is used by herpes simplex. KPNA3 and RANBP5 control the nuclear import of the influenza virus. Disrupted in schizophrenia 1 (DISC1) controls the microtubule network that is used by viruses as a route to the nucleus, while DTNBP1, MUTED, and BLOC1S3 regulate endosomal to lysosomal routing that is also important in viral traffic. Neuregulin 1 activates ERBB receptors releasing a factor, EBP1, known to inhibit the influenza virus transcriptase. Other viral or bacterial components bind to genes or proteins encoded by CALR, FEZ1, FYN, HSPA1B, IL2, HTR2A, KPNA3, MED12, MED15, MICB, NQO2, PAX6, PIK3C3, RANBP5, or TP53, while the cerebral infectivity of the herpes simplex virus is modified by Apolipoprotein E (APOE). Genes encoding for proteins related to the innate immune response, including cytokine related (CCR5, CSF2RA, CSF2RB, IL1B, IL1RN, IL2, IL3, IL3RA, IL4, IL10, IL10RA, IL18RAP, lymphotoxin-alpha, tumor necrosis factor alpha [TNF]), human leukocyte antigen (HLA) antigens (HLA-A10, HLA-B, HLA-DRB1), and genes involved in antigen processing (angiotensin-converting enzyme and tripeptidyl peptidase 2) are all concerned with defense against invading pathogens. Human microRNAs (Hsa-mir-198 and Hsa-mir-206) are predicted to bind

  5. Molecular epidemiology and risk factors for Anisakis simplex s.l. infection in blue whiting (Micromesistius poutassou) in a confluence zone of the Atlantic and Mediterranean: Differences between A. simplex s.s. and A. pegreffii.

    PubMed

    Gómez-Mateos, Magdalena; Valero, Adela; Morales-Yuste, Manuel; Martín-Sánchez, Joaquina

    2016-09-01

    Our study determined parameters of parasitization of Anisakis simplex s.l. in Micromesistius poutassou in a confluence zone of the Atlantic and Mediterranean, with a total prevalence of 82%. Also, in the three seasons analyzed, high prevalence's values were found, reaching 100% in spring; however mean intensity and abundance values were higher in winter. The use of molecular techniques to differentiate between Anisakis genotypes of the larvae characterized allowed obtaining values of 99.7% Anisakis simplex s.l. (50.1% A. simplex s.s., 42.9% A. pegreffii, 7.0% A. simplex s.s. - A. pegreffii hybrids) and 0.3% A. typica. The infections found in the fish were of both single and mixed species, in all the different possible combinations. The presence of A. simplex s.l. in the viscera varied according to genotype and season. Likewise, factors associated with the presence of the parasite in the ventral or dorsal musculature were different, where A. simplex s.s. proportion was double than that of A. pegreffii. The ecology of the two sibling species with regard to their location in fish and the influence of the season were different. PMID:27289194

  6. Effect of Prior Immunization on Induction of Cervical Cancer in Mice by Herpes Simplex Virus Type 2

    NASA Astrophysics Data System (ADS)

    Budd Wentz, W.; Heggie, Alfred D.; Anthony, Donald D.; Reagan, James W.

    1983-12-01

    Previous studies at this laboratory showed that repeated application of inactivated herpes simplex virus type 2 to the mouse cervix produces premalignant and malignant lesions. In the present study mice were inoculated with inactivated herpes simplex virus type 2 or control solution and Freund's adjuvant by intraperitoneal and subcutaneous routes before exposure of the cervix to inactivated virus. It appears that immunization with inactivated virus conferred a protection against the induction of cervical carcinoma.

  7. Equation-of-State Based Tie-Simplex Parameterization for Multiphase Thermal-Compositional Simulation

    NASA Astrophysics Data System (ADS)

    Iranshahr, A.; Voskov, D.; Tchelepi, H. A.

    2011-12-01

    Enhanced Oil Recovery (EOR) processes usually involve complex phase behaviors between the injected fluid (e.g., steam, hydrocarbon, CO2, sour) and the in-situ rock-fluid system. Several fundamental questions remain regarding equation-of-state computations for mixtures than can form three, or more, phases at equilibrium. In addition, numerical and computational issues related to proper coupling of the thermodynamic phase-behavior with multiphase flow multi-component transport must be resolved in order to model the behaviors of large-scale EOR processes accurately and efficiently. We describe a general negative-flash method for multi-component, thermal systems that can form three, or more, fluid phases. We prove that the new method is convergent to the unique solution. Based on our multiphase negative-flash technique, we have developed an adaptive tie-simplex parameterization framework for thermal-compositional simulation. We also prove that the tie-simplexes change continuously as a function of pressure, temperature, and composition. The continuity of the parameterized compositional space allows for interpolation in pressure and temperature using a limited number of tie-simplexes. We show that the tie-simplex framework constrains thermodynamic computations, and converges to the global minimum of the Gibbs free energy. The extended negative-flash approach accounts rigorously for tie-simplex degeneration (critical behavior) across phase boundaries. We study the behaviors of thermal-compositional reservoir displacement processes across a wide range of fluid mixtures, pressures, and temperatures. The focus is on the complex behaviors of the tie-triangles and tie-lines associated with three-phase, thermal steam-injection problems in heterogeneous formations. The algorithms that capture the complex combinations of the appearance and disappearance of multiple phases are described in detail. This tie-simplex based parameterization framework is integrated with a general

  8. Chronic urticaria associated with recurrent genital herpes simplex infection and success of antiviral therapy--a report of two cases.

    PubMed

    Zawar, Vijay; Godse, Kiran; Sankalecha, Sudhir

    2010-06-01

    The role of infectious agents as a cause of chronic idiopathic urticaria (CIU) is uncertain. The objective of this study was to investigate whether genital herpes simplex infection is causally related to CIU. We identified two patients with recurrent genital herpes simplex infections associated with CIU. Episodes of genital herpes were especially associated with acute exacerbation of urticaria. Anti-herpes simplex 2 antibodies and Tzanck smears were done in both patients, along with other relevant investigations for CIU. Acyclovir was added to antihistamine therapy. Both patients were apparently in good health and appeared clinically immunologically stable, though one of them was found to be diabetic. Clinical and laboratory investigations for genital lesions supported a diagnosis of herpes simplex. Anti-herpes simplex 2 antibodies were markedly raised in both patients. The Tzanck smear was positive in one case and negative in the other, despite a definitive clinical diagnosis of herpes progenitalis. CIU, which was inadequately controlled with antihistamines alone, responded dramatically to the addition of acyclovir therapy. Our results may not be applicable to other patients with CIU, especially when there is inadequate evidence of an association with genital herpes. CIU may be associated with recurrent genital herpes simplex infection. In such situations, the addition of acyclovir to therapy may be beneficial. PMID:19699670

  9. Expression of Herpes Simplex Virus 1 Glycoprotein B by a Recombinant Vaccinia Virus and Protection of Mice against Lethal Herpes Simplex Virus 1 Infection

    NASA Astrophysics Data System (ADS)

    Cantin, Edouard M.; Eberle, Richard; Baldick, Joseph L.; Moss, Bernard; Willey, Dru E.; Notkins, Abner L.; Openshaw, Harry

    1987-08-01

    The herpes simplex virus 1 (HSV-1) strain F gene encoding glycoprotein gB was isolated and modified at the 5' end by in vitro oligonucleotide-directed mutagenesis. The modified gB gene was inserted into the vaccinia virus genome and expressed under the control of a vaccinia virus promoter. The mature gB glycoprotein produced by the vaccinia virus recombinant was glycosylated, was expressed at the cell surface, and was indistinguishable from authentic HSV-1 gB in terms of electrophoretic mobility. Mice immunized intradermally with the recombinant vaccinia virus produced gB-specific neutralizing antibodies and were resistant to a lethal HSV-1 challenge.

  10. Herpes simplex virus glycoprotein C: molecular mimicry of complement regulatory proteins by a viral protein.

    PubMed

    Huemer, H P; Wang, Y; Garred, P; Koistinen, V; Oppermann, S

    1993-08-01

    Herpes simplex virus (HSV) encodes a protein, glycoprotein C (gC), which binds to the third complement component, the central mediator of complement activation. In this study the structural and functional relationships of gC from HSV type 1 (HSV-1) and known human complement regulatory proteins factor H, properdin, factor B, complement receptor 1 (CR1) and 2 (CR2) were investigated. The interaction of gC with C3b was studied using purified complement components, synthetic peptides, antisera against different C3 fragments and anti-C3 monoclonal antibodies (mAb) with known inhibitory effects on C3-ligand interactions. All the mAb that inhibited gC/C3b interactions, in a differential manner, also prevented binding of C3 fragments to factors H, B, CR1 or CR2. No blocking was observed with synthetic peptides representing different C3 regions or with factor B and C3d, whereas C3b, C3c and factor H were inhibitory, as well as purified gC. There was no binding of gC to cobra venom factor (CVF), a C3c-like fragment derived from cobra gland. Purified gC bound to iC3, iC3b and C3c, but failed to bind to C3d. Glycoprotein C bound only weakly to iC3 derived from bovine and porcine plasma, thus indicating a preference of the viral protein for the appropriate host. Binding of gC was also observed to proteolytic C3 fragments, especially to the beta-chain, thus suggesting the importance of the C3 region as a binding site. Purified gC from HSV-1, but not HSV-2, inhibited the binding of factor H and properdin but not of CR1 to C3b. The binding of iC3b to CR2, a molecule involved in B-cell activation and binding of the Epstein-Barr virus, was also inhibited by the HSV-1 protein. As factor H and properdin, the binding of which was inhibited by gC, are important regulators of the alternative complement pathway, these data further support a role of gC in the evasion of HSV from a major first-line host defence mechanism, i.e. the complement system. In addition, the inhibition of the C3/CR

  11. Cross-linking of glycoprotein oligomers during herpes simplex virus type 1 entry.

    PubMed

    Handler, C G; Cohen, G H; Eisenberg, R J

    1996-09-01

    Herpes simplex virus (HSV) has 10 glycoproteins in its envelope. Glycoprotein B (gB), gC, gD, gH, and gL have been implicated in virus entry. We previously used chemical cross-linking to show that these five glycoproteins were close enough to each other to be cross-linked into homodimeric and hetero-oligomeric forms; hetero-oligomers of gB-gC, gC-gD, gD-gB, gH-gL, gC-gL and gD-gL were found in purified virions. To better understand the roles of these glycoproteins in viral entry, we have modified a standard HSV penetration assay to include cross-linkers. This allowed us to examine changes in associations of viral glycoproteins during the entry process. HSV-1(KOS) was adsorbed at 4 degrees C to human neuroblastoma cells (SY5Y). The temperature was raised to 37 degrees C and cells were treated with cross-linker at various times after the temperature shift. Cytoplasmic extracts were examined by Western blotting (immunoblotting) for viral glycoproteins. We found that (i) as in virus alone, the length and concentration of the cross-linking agent affected the number of specific complexes isolated; (ii) the same glycoprotein patterns found in purified virions were also present after attachment of virions to cells; and (iii) the ability to cross-link HSV glycoproteins changed as virus penetration proceeded, e.g., gB and gD complexes which were present during attachment disappeared with increasing time, and their disappearance paralleled the kinetics of penetration. However, this phenomenon appeared to be selective since it was not observed with gC oligomers. In addition, we examined the cross-linking patterns of gB and gD in null viruses K082 and KOSgD beta. Neither of these mutants, which attach but cannot penetrate, showed changes in glycoprotein cross-linking over time. We speculate that these changes are due to conformational changes which preclude cross-linking or spatial alterations which dissociate the glycoprotein interactions during the penetration events. PMID

  12. The Autism Simplex Collection: an international, expertly phenotyped autism sample for genetic and phenotypic analyses

    PubMed Central

    2014-01-01

    Background There is an urgent need for expanding and enhancing autism spectrum disorder (ASD) samples, in order to better understand causes of ASD. Methods In a unique public-private partnership, 13 sites with extensive experience in both the assessment and diagnosis of ASD embarked on an ambitious, 2-year program to collect samples for genetic and phenotypic research and begin analyses on these samples. The program was called The Autism Simplex Collection (TASC). TASC sample collection began in 2008 and was completed in 2010, and included nine sites from North America and four sites from Western Europe, as well as a centralized Data Coordinating Center. Results Over 1,700 trios are part of this collection, with DNA from transformed cells now available through the National Institute of Mental Health (NIMH). Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule-Generic (ADOS-G) measures are available for all probands, as are standardized IQ measures, Vineland Adaptive Behavioral Scales (VABS), the Social Responsiveness Scale (SRS), Peabody Picture Vocabulary Test (PPVT), and physical measures (height, weight, and head circumference). At almost every site, additional phenotypic measures were collected, including the Broad Autism Phenotype Questionnaire (BAPQ) and Repetitive Behavior Scale-Revised (RBS-R), as well as the non-word repetition scale, Communication Checklist (Children’s or Adult), and Aberrant Behavior Checklist (ABC). Moreover, for nearly 1,000 trios, the Autism Genome Project Consortium (AGP) has carried out Illumina 1 M SNP genotyping and called copy number variation (CNV) in the samples, with data being made available through the National Institutes of Health (NIH). Whole exome sequencing (WES) has been carried out in over 500 probands, together with ancestry matched controls, and this data is also available through the NIH. Additional WES is being carried out by the Autism Sequencing Consortium (ASC), where the

  13. Seroprevalence of Herpes Simplex Virus Type 1 and 2 in Taiwan and Risk Factor Analysis, 2007

    PubMed Central

    Chao-Yu, Chen; Chen, Chih-Jung; Lin, Tzou-Yien; Huang, Yhu-Chering

    2015-01-01

    Background Herpes simplex virus type 1 (HSV-1) and 2 (HSV-2) are common human pathogens and might cause severe illness. Following primary infection, the viruses establish lifelong latent infection and are transmitted by close contact, both sexual and nonsexual. However, the information about the seroprevalence of HSV-1 and HSV-2 across all age groups is limited. Methods Residual sera collected during the nationwide serosurvey in 2007 in Taiwan were selected for the study. The enzyme-linked immunosorbent assay was used to detect anti-HSV-1 and anti-HSV-2 type-specific glycoprotein IgG. Demographics and personal health data were used for risk analysis. Results A total of 1411 and 1072 serum samples were included for anti-HSV-1 and anti-HSV-2 seroprevalence analysis, respectively. The weighted overall seroprevalence was 63.2% for HSV-1, and 7.7% for HSV-2, respectively. The HSV-1 seropositive rate was 19.2% for those less than 5 years old, increased to 46.4% for those aged 5–13 years, 60.9% for those aged 14–29 years, and reached as much as 95.0% for those aged over 30 years. In contrast, the HSV-2 seropositve rate was 1.6% for those less than 30 years old, rose to 10.1% for those age 30–39 years, and was up to 31.2% for those aged over 60 years. A significantly higher HSV-2 seropositive rate was noted in females than males aged over 40 years (26.3% v.s. 16.8%), and the overall HSV-2 seropositive rate was almost twice higher in females than males. Smoking history, drinking habit, and educational level were associated with the HSV-1 seropositivity. Female gender and rural residence were independent factors for the HSV-2 seropositivity. Conclusions An obvious increase of primary HSV-1 infection occurred in late adolescents and young adults, joined by the rise of HSV-2 infection in middle-aged adults, especially females. The acquistion and transmission of HSV warrant further studies in the susceptible population. PMID:26252011

  14. Dynamic Response of IFI16 and Promyelocytic Leukemia Nuclear Body Components to Herpes Simplex Virus 1 Infection

    PubMed Central

    2015-01-01

    ABSTRACT Intrinsic immunity is an aspect of antiviral defense that operates through diverse mechanisms at the intracellular level through a wide range of constitutively expressed cellular proteins. In the case of herpesviruses, intrinsic resistance involves the repression of viral gene expression during the very early stages of infection, a process that is normally overcome by viral tegument and/or immediate-early proteins. Thus, the balance between cellular repressors and virus-counteracting proteins determines whether or not a cell becomes productively infected. One aspect of intrinsic resistance to herpes simplex virus 1 (HSV-1) is conferred by components of promyelocytic leukemia nuclear bodies (PML NBs), which respond to infection by accumulating at sites that are closely associated with the incoming parental HSV-1 genomes. Other cellular proteins, including IFI16, which has been implicated in sensing pathogen DNA and initiating signaling pathways that lead to an interferon response, also respond to viral genomes in this manner. Here, studies of the dynamics of the response of PML NB components and IFI16 to invading HSV-1 genomes demonstrated that this response is extremely rapid, occurring within the first hour after addition of the virus, and that human Daxx (hDaxx) and IFI16 respond more rapidly than PML. In the absence of HSV-1 regulatory protein ICP0, which counteracts the recruitment process, the newly formed, viral-genome-induced PML NB-like foci can fuse with existing PML NBs. These data are consistent with a model involving viral genome sequestration into such structures, thereby contributing to the low probability of initiation of lytic infection in the absence of ICP0. IMPORTANCE Herpesviruses have intimate interactions with their hosts, with infection leading either to the productive lytic cycle or to a quiescent infection in which viral gene expression is suppressed while the viral genome is maintained in the host cell nucleus. Whether a cell

  15. Herpes Simplex Virus 1 Reactivates from Autonomic Ciliary Ganglia Independently from Sensory Trigeminal Ganglia To Cause Recurrent Ocular Disease

    PubMed Central

    Lee, Sungseok; Ives, Angela M.

    2015-01-01

    ABSTRACT Herpes simplex virus 1 (HSV-1) and HSV-2 establish latency in sensory and autonomic neurons after ocular or genital infection, but their recurrence patterns differ. HSV-1 reactivates from latency to cause recurrent orofacial disease, and while HSV-1 also causes genital lesions, HSV-2 recurs more efficiently in the genital region and rarely causes ocular disease. The mechanisms regulating these anatomical preferences are unclear. To determine whether differences in latent infection and reactivation in autonomic ganglia contribute to differences in HSV-1 and HSV-2 anatomical preferences for recurrent disease, we compared HSV-1 and HSV-2 clinical disease, acute and latent viral loads, and viral gene expression in sensory trigeminal and autonomic superior cervical and ciliary ganglia in a guinea pig ocular infection model. HSV-2 produced more severe acute disease, correlating with higher viral DNA loads in sensory and autonomic ganglia, as well as higher levels of thymidine kinase expression, a marker of productive infection, in autonomic ganglia. HSV-1 reactivated in ciliary ganglia, independently from trigeminal ganglia, to cause more frequent recurrent symptoms, while HSV-2 replicated simultaneously in autonomic and sensory ganglia to cause more persistent disease. While both HSV-1 and HSV-2 expressed the latency-associated transcript (LAT) in the trigeminal and superior cervical ganglia, only HSV-1 expressed LAT in ciliary ganglia, suggesting that HSV-2 is not reactivation competent or does not fully establish latency in ciliary ganglia. Thus, differences in replication and viral gene expression in autonomic ganglia may contribute to differences in HSV-1 and HSV-2 acute and recurrent clinical disease. IMPORTANCE Herpes simplex virus 1 (HSV-1) and HSV-2 establish latent infections, from which the viruses reactivate to cause recurrent disease throughout the life of the host. However, the viruses exhibit different manifestations and frequencies of recurrent

  16. Intrinsic Innate Immunity Fails To Control Herpes Simplex Virus and Vesicular Stomatitis Virus Replication in Sensory Neurons and Fibroblasts

    PubMed Central

    Rosato, Pamela C.

    2014-01-01

    ABSTRACT Herpes simplex virus 1 (HSV-1) establishes lifelong latent infections in the sensory neurons of the trigeminal ganglia (TG), wherein it retains the capacity to reactivate. The interferon (IFN)-driven antiviral response is critical for the control of HSV-1 acute replication. We therefore sought to further investigate this response in TG neurons cultured from adult mice deficient in a variety of IFN signaling components. Parallel experiments were also performed in fibroblasts isolated concurrently. We showed that HSV-1 replication was comparable in wild-type (WT) and IFN signaling-deficient neurons and fibroblasts. Unexpectedly, a similar pattern was observed for the IFN-sensitive vesicular stomatitis virus (VSV). Despite these findings, TG neurons responded to IFN-β pretreatment with STAT1 nuclear localization and restricted replication of both VSV and an HSV-1 strain deficient in γ34.5, while wild-type HSV-1 replication was unaffected. This was in contrast to fibroblasts in which all viruses were restricted by the addition of IFN-β. Taken together, these data show that adult TG neurons can mount an effective antiviral response only if provided with an exogenous source of IFN-β, and HSV-1 combats this response through γ34.5. These results further our understanding of the antiviral response of neurons and highlight the importance of paracrine IFN-β signaling in establishing an antiviral state. IMPORTANCE Herpes simplex virus 1 (HSV-1) is a ubiquitous virus that establishes a lifelong latent infection in neurons. Reactivation from latency can cause cold sores, blindness, and death from encephalitis. Humans with deficiencies in innate immunity have significant problems controlling HSV infections. In this study, we therefore sought to elucidate the role of neuronal innate immunity in the control of viral infection. Using neurons isolated from mice, we found that the intrinsic capacity of neurons to restrict virus replication was unaffected by the presence

  17. Genetic and morphological approaches distinguish the three sibling species of the Anisakis simplex species complex, with a species designation as Anisakis berlandi n. sp. for A. simplex sp. C (Nematoda: Anisakidae).

    PubMed

    Mattiucci, Simonetta; Cipriani, Paolo; Webb, Stephen C; Paoletti, Michela; Marcer, Federica; Bellisario, Bruno; Gibson, David I; Nascetti, Giuseppe

    2014-04-01

    Numerous specimens of the 3 sibling species of the Anisakis simplex species complex (A. pegreffii, A. simplex (senso stricto)), and A. simplex sp. C) recovered from cetacean species stranded within the known geographical ranges of these nematodes were studied morphologically and genetically. The genetic characterization was performed on diagnostic allozymes and sequences analysis of nuclear (internal transcribed spacer [ITS] of ribosomal [r]DNA) and mitochondrial (mitochondrial [mt]DNA cox2 and rrnS) genes. These markers showed (1) the occurrence of sympatry of the 2 sibling species A. pegreffii and A. simplex sp. C in the same individual host, the pilot whale, Globicephala melas Traill, from New Zealand waters; (2) the identification of specimens of A. pegreffii in the striped dolphin, Stenella coeruleoalba (Meyen), from the Mediterranean Sea; and (3) the presence of A. simplex (s.s.) in the pilot whale and the minke whale, Balaenoptera acutorostrata Lacépède, from the northeastern Atlantic waters. No F1 hybrids were detected among the 3 species using the nuclear markers. The phylogenetic inference, obtained by maximum parsimony (MP) analysis of separate nuclear (ITS rDNA region), combined mitochondrial (mtDNA cox2 and rrnS) sequences datasets, and by concatenated analysis obtained at both MP and Bayesian inference (BI) of the sequences datasets at the 3 studied genes, resulted in a similar topology. They were congruent in depicting the existence of the 3 species as distinct phylogenetic lineages, and the tree topologies support the finding that A. simplex (s.s.), A. pegreffii, and A. berlandi n. sp. (= A. simplex sp. C) represent a monophyletic group. The morphological and morphometric analyses revealed the presence of morphological features that differed among the 3 biological species. Morphological analysis using principal component analysis, and Procrustes analysis, combining morphological and genetic datasets, showed the specimens clustering into 3 well

  18. Functional Characterization of Glycoprotein H Chimeras Composed of Conserved Domains of the Pseudorabies Virus and Herpes Simplex Virus 1 Homologs

    PubMed Central

    Böhm, Sebastian W.; Backovic, Marija; Klupp, Barbara G.; Rey, Felix A.; Fuchs, Walter

    2015-01-01

    herpesviruses can serve as tools to elucidate the molecular basis of gH function. The present study shows that the C-terminal part of human herpesvirus 1 (herpes simplex virus 1) gH can functionally substitute for the corresponding part of suid herpesvirus 1 (pseudorabies virus) gH, whereas other tested combinations proved to be nonfunctional. Interestingly, the exchangeable fragment included the membrane-proximal end of the gH ectodomain (domain IV), which is most conserved in sequence and structure and might be capable of transient membrane interaction during fusion. PMID:26491153

  19. Draft Genome Sequence of Bacillus simplex DSM 1321 for Setting Up Phylogenomics in Genomic Taxonomy of the Bacillus-Like Bacteria

    PubMed Central

    Liu, Guo-hong; Wang, Jie-ping; Che, Jian-mei; Chen, Qian-qian; Chen, Zheng

    2016-01-01

    Bacillus simplex DSM 1321 is a Gram-positive, spore-forming, and aerobic bacterium. Here, we report the draft genome sequence of B. simplex DSM 1321, with 6,494,937 bp, which will provide useful information for setting up phylogenomics in genomic taxonomy of the Bacillus-like bacteria as well as for the functional gene mining and application of B. simplex DSM 1321. PMID:27340061

  20. A Cationic Peptide, TAT-Cd0, Inhibits Herpes Simplex Virus Type 1 Ocular Infection In Vivo

    PubMed Central

    Jose, Gilbert G.; Larsen, Inna V.; Gauger, Joshua; Carballo, Erica; Stern, Rebecca; Brummel, Rachel; Brandt, Curtis R.

    2013-01-01

    Purpose. To test the in vivo activity of a peptide derived from the protein transducing domain of the human immunodeficiency virus (HIV) Tat protein, TAT-Cd0, in a murine herpes simplex type 1 (HSV-1) keratitis model. Methods. The efficacy of TAT-Cd0 was assessed in a postinfection treatment model with different concentrations (1 mg/mL, 0.1 mg/mL, 0.01 mg/mL) of the peptide in one of four delivery vehicles: artificial tears, PBS, methylcellulose, and aquaphor cream. Treatment began within 4 or 24 hours postinfection. Viral titers in the tear film were determined by plaque assay. Results. TAT-Cd0 reduced the severity of keratitis in all of the delivery vehicles tested when treatment started, 4 hours postinfection. Peptide in the tears or PBS delivery vehicle had the most significant reduction in disease severity and delayed the onset of vascularization and stromal keratitis. The percentage of mice presenting with disease was also significantly reduced and viral titers were reduced by 1 log at 24 hours postinfection in mice treated with 1 mg/mL TAT-Cd0, suggesting that inhibiting replication early is sufficient to achieve clinical effects. Lower concentrations were not effective and delaying treatment by 24 hours was also not effective. Conclusions. This study shows that TAT-Cd0 is an effective antiviral against HSV-1 strain KOS when applied shortly postinfection and that aqueous-based formulations are more suitable. PMID:23341013

  1. Antibiotic-free production of a herpes simplex virus 2 DNA vaccine in a high yield cGMP process

    PubMed Central

    Nelson, Jared; Rodriguez, Stephen; Finlayson, Neil; Williams, Jim; Carnes, Aaron

    2013-01-01

    Two DNA vaccine plasmids encoding Herpes simplex virus type 2 (HSV-2) glycoprotein D, NTC8485-O2-gD2 and NTC8485-O2-UgD2tr, were produced at large scale under current good manufacturing practice (cGMP) for use in a Phase I human clinical trial. These DNA vaccines incorporate the regulatory agency compliant, minimal, antibiotic-free (AF) NTC8485 mammalian expression vector. Plasmid yields of > 1 g/L were achieved using the HyperGRO™ fed-batch fermentation process, with successful scale up from 10 L process development scale to 320 L culture volume for cGMP production. The DNA vaccines were purified using a low residence time, high shear lysis process and AIRMIXTM technology, followed by chromatographic purification. This combination of optimized plasmid vector, high yield upstream production, and efficient downstream purification resulted in purified HSV-2 DNA vaccines with > 99% total supercoiled plasmid, ≤ 0.2% RNA, ≤ 0.1% host cell genomic DNA, and ≤ 0.1 endotoxin units per mg. PMID:23899469

  2. Interleukin-2 protects neonatal mice from lethal herpes simplex virus infection: a macrophage-mediated, gamma interferon-induced mechanism.

    PubMed

    Kohl, S; Loo, L S; Drath, D B; Cox, P

    1989-02-01

    Administration of human recombinant interleukin-2 (IL-2) protected neonatal mice from a lethal herpes simplex virus (HSV) infection. Protection was not associated with viral antibody production, enhanced natural killer cell cytotoxicity, or intrinsic resistance of macrophages to viral infection. Protection was associated with increased macrophage-mediated antiviral antibody-dependent cellular cytotoxicity (ADCC). Spleen cells from IL-2-treated neonatal mice and from neonatal mice that were treated in vitro with IL-2 transferred protection to neonatal mice. These cells, by adherence, silica, and asialo GM 1 antibody treatment, were shown to be macrophages. IL-2 treatment in vitro enhanced the neonatal macrophages' ADCC function and superoxide release. Similar protection was induced by gamma interferon (IFN-gamma)-treated spleen cells. Antibody to IFN-gamma ablated both IFN-gamma- and IL-2-induced protection by adherent spleen cells. Thus, IL-2-mediated protection against murine neonatal HSV infection was affected by stimulated macrophage activity, via helper T cell-produced IFN-gamma. PMID:2492588

  3. A role for heparan sulfate 3-O-sulfotransferase isoform 2 in herpes simplex virus type 1 entry and spread

    SciTech Connect

    O'Donnell, Christopher D.; Tiwari, Vaibhav; Oh, Myung-Jin; Shukla, Deepak . E-mail: dshukla@uic.edu

    2006-03-15

    Heparan sulfate (HS) 3-O-sulfotransferase isoform-2 (3-OST-2), which belongs to a family of enzymes capable of generating herpes simplex virus type-1 (HSV-1) entry and spread receptors, is predominantly expressed in human brain. Despite its unique expression pattern, the ability of 3-OST-2 to mediate HSV-1 entry and cell-to-cell fusion is not known. Our results demonstrate that expression of 3-OST-2 can render Chinese hamster ovary K1 (CHO-K1) cells susceptible to entry of wild-type and mutant strains of HSV-1. Evidence for generation of gD receptors by 3-OST-2 were suggested by gD-mediated interference assay and the ability of 3-OST-2-expressing CHO-K1 cells to preferentially bind HSV-1 gD, which could be reversed by prior treatment of cells with HS lyases (heparinases II/III). In addition, 3-OST-2-expressing CHO-K1 cells acquired the ability to fuse with cells-expressing HSV-1 glycoproteins, a phenomenon that mimics a way of viral spread in vivo. Demonstrating specificity, the cell fusion was inhibited by soluble 3-O-sulfated forms of HS, but not unmodified HS. Taken together, our results raise the possibility of a role of 3-OST-2 in the spread of HSV-1 infection in the brain.

  4. Genital herpes simplex virus type 1 in women: detection in cervicovaginal specimens from gynecological practices in the United States.

    PubMed

    Peña, Kristen C; Adelson, Martin E; Mordechai, Eli; Blaho, John A

    2010-01-01

    Herpes simplex virus types 1 and 2 (HSV-1 and -2) are significant human pathogens causing clinically indistinguishable facial and genital lesions. Recently, the number of reported genital herpes cases caused by type 1 virus has increased. Identifying the HSV type is of clinical importance to determine proper treatment, as there is no licensed vaccine or cure. We assessed, by PCR, the frequency of HSV-1 and HSV-2 present in more than 60,000 clinical cervicovaginal specimens derived from samples originating from 43 continental U.S. states. Fourteen percent were positive for HSV-1 and/or HSV-2. This likely represents subclinal shedding. It was not a measurement of the prevalence of HSV infection. While the majority were HSV-2, 32% were HSV-1. The distribution of HSV types varied between the states with the largest number of specimens, New Jersey, Florida, and Texas. Specimens from women under the age of 24 had an HSV-1 positivity rate of 47 percent. Importantly, in New Jersey, an observed age effect was the disproportionately high prevalence of genital HSV-1 in young women. This represents the largest analysis of HSV types reported and has important public health implications, particularly for younger women. PMID:19923487

  5. Herpes simplex virus type 2 and other genital ulcerative infections as a risk factor for HIV-1 acquisition.

    PubMed Central

    Keet, I P; Lee, F K; van Griensven, G J; Lange, J M; Nahmias, A; Coutinho, R A

    1990-01-01

    We studied the role of genital ulcerative infections for acquisition of human immunodeficiency virus type 1 (HIV-1) infection in a cohort of 989 homosexual men in Amsterdam between October 1984 and December 1988. Among 53 HIV-1 seroconverters serological and anamnestic data were gathered regarding herpes simplex virus type 2 (HSV-2) and syphilis in the 6 months before seroconversion. For statistical analysis a control who remained seronegative during the same interval was selected at random for each HIV-1 seroconverter. A significant difference between the prevalence of HSV-2 antibodies among HIV-1 seroconverters and controls was found (72% vs 38%). HSV-2 seroconversions among men initially seronegative for HSV-2 were found among three of 18 HIV-1 seroconverters and among three of 36 controls. (O.R. = 2.2, 95% C.I. 0.4-12.1). Self-reported cases of anogenital herpes were found more frequently among HIV-1 seroconverters (8) than among controls (4). One case of syphilis was diagnosed among HIV-1 seroconverters, and one among controls. Summing up these cases we assessed the total number of genital ulcerative infections: 12 among HIV-1 seroconverters and eight among controls (23 vs 15%, O.R. 1.7, C.I. 0.6-4.62). These data suggest little evidence for genital ulcerative infections being an important independent risk factor for HIV-1 acquisition among homosexual men in Amsterdam during the time period studied. PMID:2245979

  6. Production of immunogenic West Nile virus-like particles using a herpes simplex virus 1 recombinant vector.

    PubMed

    Taylor, Travis J; Diaz, Fernando; Colgrove, Robert C; Bernard, Kristen A; DeLuca, Neal A; Whelan, Sean P J; Knipe, David M

    2016-09-01

    West Nile virus (WNV) is a flavivirus that swept rapidly across North America in 1999, declined in prevalence, and then resurged in 2012. To date, no vaccine is available to prevent infection in the human population. Herpes simplex virus (HSV) replication-defective vaccine vectors induce a durable immunity characterized by strong antibody and CD8(+) T cell responses even in HSV-immune animals. In this study, a WNV protein expression cassette was optimized for virus-like particle (VLP) production in transfection studies, and the cassette was recombined into an HSV-1 d106-WNV virus vector, which produced extracellular VLPs, as confirmed by immunoelectron microscopy. Immunization of mice with the d106-WNV recombinant vector elicited a specific anti-WNV IgG response. This study highlights the flavivirus coding sequences needed for efficient assembly of virus-like particles. This information will facilitate generation of additional vaccine vectors against other flaviviruses including the recently emerged Zika virus. PMID:27336950

  7. Disruption of Adherens Junctions Liberates Nectin-1 To Serve as Receptor for Herpes Simplex Virus and Pseudorabies Virus Entry

    PubMed Central

    Yoon, Miri; Spear, Patricia G.

    2002-01-01

    Nectin-1, a cell adhesion molecule belonging to the immunoglobulin superfamily, can bind to virion glycoprotein D (gD) to mediate entry of herpes simplex viruses (HSV) and pseudorabies virus (PRV). Nectin-1 colocalizes with E-cadherin at adherens junctions in epithelial cells. The disruption of cell junctions can result in the redistribution of nectin-1. To determine whether disruption of junctions by calcium depletion influenced the susceptibility of epithelial cells to viral entry, Madin-Darby canine kidney cells expressing endogenous nectin-1 or transfected human nectin-1 were tested for the ability to bind soluble forms of viral gD and to be infected by HSV and PRV, before and after calcium depletion. Confocal microscopy revealed that binding of HSV and PRV gD was localized to adherens junctions in cells maintained in normal medium but was distributed, along with nectin-1, over the entire cell surface after calcium depletion. Both the binding of gD and the fraction of cells that could be infected by HSV-1 and PRV were enhanced by calcium depletion. Taken together, these results provide evidence that nectin-1 confined to adherens junctions in epithelial cells is not very accessible to virus, whereas dissociation of cell junctions releases nectin-1 to serve more efficiently as an entry receptor. PMID:12072519

  8. A Strategy for O-Glycoproteomics of Enveloped Viruses—the O-Glycoproteome of Herpes Simplex Virus Type 1

    PubMed Central

    Bagdonaite, Ieva; Nordén, Rickard; Joshi, Hiren J.; Dabelsteen, Sally; Nyström, Kristina; Vakhrushev, Sergey Y.; Olofsson, Sigvard; Wandall, Hans H.

    2015-01-01

    Glycosylation of viral envelope proteins is important for infectivity and interaction with host immunity, however, our current knowledge of the functions of glycosylation is largely limited to N-glycosylation because it is difficult to predict and identify site-specific O-glycosylation. Here, we present a novel proteome-wide discovery strategy for O-glycosylation sites on viral envelope proteins using herpes simplex virus type 1 (HSV-1) as a model. We identified 74 O-linked glycosylation sites on 8 out of the 12 HSV-1 envelope proteins. Two of the identified glycosites found in glycoprotein B were previously implicated in virus attachment to immune cells. We show that HSV-1 infection distorts the secretory pathway and that infected cells accumulate glycoproteins with truncated O-glycans, nonetheless retaining the ability to elongate most of the surface glycans. With the use of precise gene editing, we further demonstrate that elongated O-glycans are essential for HSV-1 in human HaCaT keratinocytes, where HSV-1 produced markedly lower viral titers in HaCaT with abrogated O-glycans compared to the isogenic counterpart with normal O-glycans. The roles of O-linked glycosylation for viral entry, formation, secretion, and immune recognition are poorly understood, and the O-glycoproteomics strategy presented here now opens for unbiased discovery on all enveloped viruses. PMID:25830354

  9. Absence of induction of enhanced reactivation of herpes simplex virus in cells from xeroderma pigmentosum patients without skin cancer

    SciTech Connect

    Abrahams, P.J.; van der Kleij, A.A.; Schouten, R.; van der Eb, A.J.

    1988-11-01

    The time course of appearance of enhanced reactivation (ER) and enhanced mutagenesis (EM) of herpes simplex virus type 1 were studied in UV-irradiated stationary cultures of xeroderma pigmentosum (XP) fibroblasts. In some of the XP cells EM followed similar kinetics of appearance as ER. Maximal activities occurred when infection was delayed 1 or 2 days after cell treatment. However, in certain XP cells only induction of the EM response was observed, whereas ER was absent. Interestingly, the latter XP cells had been obtained from patients who had not yet developed skin cancer at the time they were described in the literature, whereas the former XP patients had already developed skin tumors. This suggests that the ER response may somehow be involved in the process of oncogenic transformation. Dose-response studies of ER in XP cells from tumor-bearing patients showed that ER is maximally induced with a UV dose of 40 Jm-2 given to the virus. Normal levels of ER were observed in 14 different normal human skin fibroblasts, indicating that the ER- phenotype does not occur in normal cells or at least more rarely than in XP cells.

  10. Axonal transport of herpes simplex virions to epidermal cells: evidence for a specialized mode of virus transport and assembly.

    PubMed Central

    Penfold, M E; Armati, P; Cunningham, A L

    1994-01-01

    To examine the transmission of herpes simplex virus (HSV) from axon to epidermal cell, an in vitro model was constructed consisting of human fetal dorsal root ganglia cultured in the central chamber of a dual-chamber tissue culture system separated from autologous skin explants in an exterior chamber by concentric steel cylinders adhering to the substratum through silicon grease and agarose. Axons grew through the agarose viral diffusion barrier and terminated on epidermal cells in the exterior chamber. After inoculation of HSV onto dorsal root ganglia, anterograde axonal transport of glycoprotein and nucleocapsid antigen was observed by confocal microscopy to appear in exterior chamber axons within 12 h and in epidermal cells within 16 h, moving at 2-3 mm/h. Although both enveloped and unenveloped nucleocapsids were observed in the neuronal soma by transmission electron microscopy, only nucleocapsids were observed in the axons, closely associated with microtubules. Nodule formation at the surface of HSV-infected axons, becoming more dense at the axon terminus on epidermal cells, and patches of axolemmal HSV glycoprotein D expression were observed by scanning (immuno)electron microscopy, probably representing virus emerging from the axolemma. These findings strongly suggest a specialized mode of viral transport, assembly, and egress in sensory neurons: microtubule-associated intermediate-fast anterograde axonal transport of unenveloped nucleocapsids with separate transport of glycoproteins to the distal regions of the axon and assembly prior to virus emergence at the axon terminus. Images PMID:7517552

  11. Transforming low-discrepancy sequences from a cube to a simplex

    NASA Astrophysics Data System (ADS)

    Pillards, Tim; Cools, Ronald

    2005-02-01

    Sequences of points with a low discrepancy are the basic building blocks for quasi-Monte Carlo methods. Traditionally these points are generated in a unit cube.To develop point sets on a simplex we will transform the low-discrepancy points from the unit cube to a simplex. An advantage of this approach is that most of the known results on low-discrepancy sequences can be re-used. After introducing several transformations, their efficiency as well as their quality will be evaluated. We present a Koksma-Hlawka inequality which says that under certain conditions the order of convergence using the new point set is the same as that of the original set.

  12. Which plant for which skin disease? Part 1: Atopic dermatitis, psoriasis, acne, condyloma and herpes simplex.

    PubMed

    Reuter, Juliane; Wölfle, Ute; Weckesser, Steffi; Schempp, Christoph

    2010-10-01

    Plant extracts and isolated compounds are increasingly used in cosmetics and food supplements to improve skin conditions. We first introduce the positive plant monographs with dermatological relevance of the former German Commission E. Subsequently clinical studies with botanicals for atopic dermatitis, psoriasis, acne, condylomata acuminata and herpes simplex are discussed. The best studies have been conducted with atopic dermatitis and psoriasis patients. Mahonia aquifolium, Hypericum perforatum, Glycyrrhiza glabra and certain traditional Chinese therapies have been shown to be effective in the treatment of atopic dermatitis. Mahonia aquifolium, Indigo naturalis and Capsicum frutescens are effective treatments for psoriasis. Green tea extract and tea tree oil have been investigated in the treatment of acne. Podophyllin and green tea extract are effective treatments for condylomata acuminata. Balm mint and a combination of sage and rhubarb have been shown to be effective in the treatment of herpes simplex in proof of concept studies. PMID:20707875

  13. Fatal herpes simplex infection in a pygmy African hedgehog (Atelerix albiventris).

    PubMed

    Allison, N; Chang, T C; Steele, K E; Hilliard, J K

    2002-01-01

    An adult pygmy African hedgehog developed acute posterior paresis attributed to a prolapsed intervertebral disc diagnosed by C-T scan. Corticosteroid therapy resulted in prompt resolution of the ataxia, but 2 weeks later the animal became anorexic and died. Macroscopically, the liver was stippled with punctate off-white foci which were confirmed microscopically to be foci of necrosis. Numerous hepatocytes contained intranuclear inclusions and syncytial cell formation was also present. A herpes virus was isolated and identified by fluorescent antibody and polymerase chain reaction studies as herpesvirus simplex type 1. To our knowledge, this is the first report of herpes infection in the African hedgehog and the first time herpes simplex has been identified as a cause of disease in insectivores. PMID:11814325

  14. Pathogenesis of herpes simplex labialis: correlation of vesicle fluid interferon with lesion age and virus titer.

    PubMed Central

    Spruance, S L; Green, J A; Chiu, G; Yeh, T J; Wenerstrom, G; Overall, J C

    1982-01-01

    Of 51 patients with herpes simplex labialis, 50 had detectable interferon (IFN) in samples of lesion vesicle fluid. The median titer of vesicle fluid IFN was 8,200 U. and the range of values was 400 to 63,600 U. The amount of vesicle fluid IFN was correlated with lesion age (r = 0.32, P = 0.024) and vesicle fluid virus titer (r = 0.59, P = 0.00004), but not with the clinical severity of the disease. The presence of vesicle fluid IFN (1,500 to 28,600 U) in 15 lesions less than 12 h old emphasizes the need for early treatment in studies of antiviral agents for herpes simplex labialis. PMID:6178690

  15. Psoralen inactivation of influenza and herpes simplex viruses and of virus-infected cells

    SciTech Connect

    Redfield, D.C.; Richman, D.D.; Oxman, M.N.; Kronenberg, L.H.

    1981-06-01

    Psoralen compounds covalently bind to nucleic acids when irradiated with long-wavelength ultraviolet light. This treatment can destroy the infectivity of deoxyribonucleic acid and ribonucleic acid viruses. Two psoralen compounds, 4'-hydroxymethyltrioxsalen and 4'-aminomethyltrioxsalen, were used with long-wavelength ultraviolet light to inactivate cell-free herpes simplex and influenza viruses and to render virus-infected cells noninfectious. This method of inactivation was compared with germicidal (short-wavelength) ultraviolet light irradiation. The antigenicity of the treated, virus-infected, antigen-bearing cells was examined by immunofluorescence and radioimmunoassay and by measuring the capacity of the herpes simplex virus-infected cells to stimulate virus-specific lymphocyte proliferation. The infectivity of the virus-infected cells could be totally eliminated without altering their viral antigenicity. The use of psoralen plus long-wavelength ultraviolet light is well suited to the preparation of noninfectious virus antigens and virus antigen-bearing cells for immunological assays.

  16. Optimization of soy isoflavone extraction with different solvents using the simplex-centroid mixture design.

    PubMed

    Yoshiara, Luciane Yuri; Madeira, Tiago Bervelieri; Delaroza, Fernanda; da Silva, Josemeyre Bonifácio; Ida, Elza Iouko

    2012-12-01

    The objective of this study was to optimize the extraction of different isoflavone forms (glycosidic, malonyl-glycosidic, aglycone and total) from defatted cotyledon soy flour using the simplex-centroid experimental design with four solvents of varying polarity (water, acetone, ethanol and acetonitrile). The obtained extracts were then analysed by high-performance liquid chromatography. The profile of the different soy isoflavones forms varied with different extractions solvents. Varying the solvent or mixture used, the extraction of different isoflavones was optimized using the centroid-simplex mixture design. The special cubic model best fitted to the four solvents and its combination for soy isoflavones extraction. For glycosidic isoflavones extraction, the polar ternary mixture (water, acetone and acetonitrile) achieved the best extraction; malonyl-glycosidic forms were better extracted with mixtures of water, acetone and ethanol. Aglycone isoflavones, water and acetone mixture were best extracted and total isoflavones, the best solvents were ternary mixture of water, acetone and ethanol. PMID:22621769

  17. Targeted Entry of Enveloped Viruses: Measles and Herpes Simplex Virus I

    PubMed Central

    Navaratnarajah, Chanakha K.; Miest, Tanner S.; Carfi, Andrea; Cattaneo, Roberto

    2011-01-01

    We compare the receptor-based mechanisms that a small RNA virus and a larger DNA virus have evolved to drive the fusion of viral and cellular membranes. Both systems rely on tight control over triggering the concerted refolding of a trimeric fusion protein. While measles virus entry depends on a receptor-binding protein and a fusion protein only, the herpes simplex virus is more complex and requires four viral proteins. Nevertheless, in both viruses a receptor-binding protein is required for triggering the membrane fusion process. Moreover, specificity domains can be appended to these receptor-binding proteins to target virus entry to cells expressing a designated receptor. We discuss how principles established with measles and herpes simplex virus can be applied to targeting other enveloped viruses, and alternatively how retargeted envelopes can be fitted on foreign capsids. PMID:22440965

  18. Herpes simplex virus type 1 entry into epithelial MDCKII cells: role of VASP activities.

    PubMed

    Jaeger, Verena; Hoppe, Sven; Petermann, Philipp; Liebig, Timo; Jansen, Matthias K; Renné, Thomas; Knebel-Mörsdorf, Dagmar

    2010-09-01

    VASP is an actin-regulatory protein that links signalling to remodelling of the cytoskeleton. We investigated the role of VASP during entry of herpes simplex viruses into epithelial MDCKII cells. As VASP functions are regulated by phosphorylations, the phosphorylation pattern was determined upon infection. Phosphorylated VASP decreased temporarily at 15 and 30 min after infection. The impact of phosphorylated VASP was addressed by overexpression of phosphomimetic VASP mutants. Our results revealed that phosphorylated VASP slightly reduced the number of infected cells. Expression studies with deletion mutants further indicated minor effects of VASP on infection efficiency, whereas RNA interference studies demonstrated that reduced VASP expression did not suppress infection. We conclude that VASP activities alone may contribute to herpes simplex virus infection to only a minor extent. PMID:20463151

  19. Application of low-intensity laser in the treatment of Herpes simplex recidivans

    NASA Astrophysics Data System (ADS)

    Uzunov, Tzonko T.; Uzunov, T.; Grozdanova, R.

    2004-06-01

    We made our aim to investigate the effect of the low intensive laser with λ=630 nm in the visible red spectrum of light at Herpes simplex treatment. For this purpose we carried out a clinical research upon 62 persons with Herpes simplex lesions which have been divided into two groups of 31 persons. At the first group the effect of laser with power density 100 mW/cm2 +/- 5 mW/cm2 and time of exposure 3 min. on field was traced out. At the second group the low intensive laser with the same characteristics has been used but in combination with the patent medicine Granofurin H as a photosensibilizer. The clinical approbations of this method showed high therapeutical effectiveness. The obtained results showed that at both groups there is an expressed anaesthetic, anti-inflammatory and regeneration stimulating effect and at the second group with the use of Granofurin H the reconvalescent period is shorter.

  20. Herpes Simplex Virus: Genome Size and Redundancy Studied by Renaturation Kinetics

    PubMed Central

    Frenkel, Niza; Roizman, Bernard

    1971-01-01

    Herpes simplex virus subtype 1 deoxyribonucleic acid (DNA) was sheared in a French press to uniform fragments, denatured by heating, then allowed to reassociate. The renaturation reaction followed second-order kinetics with a single rate constant indicating that at least 95% of the genome was unique and that repetitive sequences, if present, were not detectable by this technique. The kinetic complexity of the herpes simplex genome was determined by DNA renaturation kinetics to be (95 ± 1) × 106 daltons. Since this value is in excellent agreement with the molecular weight of viral DNA [(99 ± 5) × 106 daltons] obtained from velocity sedimentation studies, it is concluded that virions contain only one species of double-stranded DNA molecules 95 × 106 to 99 × 106 daltons in molecular weight. PMID:4331657

  1. Transmission of herpes simplex virus type 1 infection in rugby players.

    PubMed

    White, W B; Grant-Kels, J M

    1984-07-27

    Skin infections, both bacterial and viral, are endemic in contact sports such as wrestling and rugby football. In this report, we describe four cases of extensive cutaneous herpes simplex virus in players on a rugby team. All players had a prodrome of fever, malaise, and anorexia with a weight loss of 3.6 to 9.0 kg. Two players experienced ocular lesions associated with cutaneous vesicular lesions of the face. A third player, who had herpetic lesions on his lower extremity, experienced paresthesias, weakness, and intermittent urinary retention and constipation. All infected players on the team were forwards or members of the "scrum," which suggests a field-acquired infection analogous to the herpetic infections seen in wrestlers (herpes gladiatorum). Considering the serious sequelae of recurrent herpes simplex keratitis, the traumatic skin lesions in rugby football players should be cultured for herpes virus, and infected individuals should be restricted from playing until crusted lesions have disappeared. PMID:6737650

  2. Rapid isolation of herpes simplex virus by using mink lung and rhabdomyosarcoma cell cultures.

    PubMed Central

    Johnston, S L; Wellens, K; Siegel, C S

    1990-01-01

    Highly sensitive and rapid results can be obtained by isolating herpes simplex virus from clinical specimens in simple cell culture with rhabdomyosarcoma (RD) cells. In this study, 3,186 clinical specimens were inoculated into locally produced, equivalent-age RD and mink lung (ML) cells. Of 727 positive isolates, all (100%) were isolated from RD cells and only 691 (95%) were isolated from ML cells. Furthermore, 162 of the positive isolates (22%) were isolated in RD cells earlier than in ML cells. RD cells are continuous and can be cultivated in house without decreasing sensitivity as the passage number increases. They produce a highly distinguishable cytopathic effect in response to herpes simplex virus and maintain intense confirmatory staining patterns. PMID:2177754

  3. Connecting the dots : analysis, development and applications of the SimpleX algorithm

    NASA Astrophysics Data System (ADS)

    Kruip, Chael

    2011-11-01

    The SimpleX radiative transfer method is based on the interpretation of photons as particles interacting on a natural scale: the local mean free path. In our method, light is transported along the lines of an unstructured Delaunay mesh that encodes this natural distance and represents the physical medium. The SimpleX method is fast, highly adaptive and its computational cost does not scale with the number of sources. It is therefore well-suited for cosmological applications where it is essential to cover many orders of magnitude in resolution and where millions of sources can exist within a single simulation. We describe the code, its recent developments and apply it to several relevant astrophysical problems. In particular, we perform radiative transfer calculations of cosmological reionization and of the wind-wind interaction region of the Eta Carinae binary system.

  4. Herpes simplex virus type 1 infection in two pet marmosets in Japan.

    PubMed

    Imura, Kei; Chambers, James Kenn; Uchida, Kazuyuki; Nomura, Shunsuke; Suzuki, Satoshi; Nakayama, Hiroyuki; Miwa, Yasutsugu

    2014-12-01

    An 8-month-old common marmoset (Callithrix jacchus) was presented with tic-like symptoms, and a 2-year-old pigmy marmoset (Callithrix pygmaea) was presented with dyspnea and hypersalivation. Both monkeys died within a few days, and necropsies were performed. Histopathological examinations revealed ulcerative stomatitis with epithelial cell swelling and eosinophilic intranuclear inclusion bodies in the oral epithelium of both cases. In the central and peripheral nervous systems, neuronal cell degeneration with intranuclear inclusion bodies was observed. Immunohistochemical examination using anti-herpes simplex virus type 1 antibody revealed virus antigens in both cases. Both animals had been kept as pets with limited exposure to the ambient environment except via their owners. Therefore, herpes simplex virus type-1 was probably acquired from close contact with their owners. PMID:25649955

  5. Herpes Simplex Virus Type 1 Infection in Two Pet Marmosets in Japan

    PubMed Central

    IMURA, Kei; CHAMBERS, James Kenn; UCHIDA, Kazuyuki; NOMURA, Shunsuke; SUZUKI, Satoshi; NAKAYAMA, Hiroyuki; MIWA, Yasutsugu

    2014-01-01

    An 8-month-old common marmoset (Callithrix jacchus) was presented with tic-like symptoms, and a 2-year-old pigmy marmoset (Callithrix pygmaea) was presented with dyspnea and hypersalivation. Both monkeys died within a few days, and necropsies were performed. Histopathological examinations revealed ulcerative stomatitis with epithelial cell swelling and eosinophilic intranuclear inclusion bodies in the oral epithelium of both cases. In the central and peripheral nervous systems, neuronal cell degeneration with intranuclear inclusion bodies was observed. Immunohistochemical examination using anti-herpes simplex virus type 1 antibody revealed virus antigens in both cases. Both animals had been kept as pets with limited exposure to the ambient environment except via their owners. Therefore, herpes simplex virus type-1 was probably acquired from close contact with their owners. PMID:25649955

  6. The Use of Cultured Allogenic Keratinocyte Grafting in a Patient with Epidermolysis Bullosa Simplex

    PubMed Central

    Shin, Kee Cheol; Park, Bo Young; Kim, Woo Seob; Bae, Tae Hui

    2011-01-01

    Epidermolysis bullosa (EB) is a rare genetic disease that is known for continuous skin blistering caused by minor trauma. The skin blisters and bullae that develop often cause skin defects. There is no definitive treatment for EB, only symptomatic relief. We report our experience with cultured allogenic keratinocyte grafting in a newborn patient with EB simplex who had unhealed raw surfaces and was not a skin grafting candidate. The skin lesions of the patient were covered with cultured allogenic keratinocyte grafts and re-epithelialized quickly with no scarring. Allogenic keratinocyte grafting reduced pain and produced noticeable improvements in the unhealed wounds. We think that allogenic keratinocyte grafting can play an important role in the management of patients with EB simplex. PMID:22346287

  7. The treatment of herpes simplex virus epithelial keratitis.

    PubMed Central

    Wilhelmus, K R

    2000-01-01

    PURPOSE: Epithelial keratitis is the most common presentation of ocular infection by herpes simplex virus (HSV). Quantitative assessment of available therapy is needed to guide evidence-based ophthalmology. This study aimed to compare the efficacy of various treatments for dendritic or geographic HSV epithelial keratitis and to evaluate the role of various clinical characteristics on epithelial healing. METHODS: Following a systematic review of the literature, information from clinical trials of HSV dendritic or geographic epithelial keratitis was extracted, and the methodological quality of each study was scored. Methods of epithelial cauterization and curettage were grouped as relatively equivalent physicochemical therapy, and solution and ointment formulations of a given topical antiviral agent were combined. The proportion healed with 1 week of therapy, a scheduled follow-up day that approximated the average time of resolution with antiviral therapy, was selected as the primary outcome based on a masked evaluation of maximum treatment differences in published healing curves. The proportion healed at 14 days was recorded as supplemental information. Fixed-effects and random-effects meta-analysis models were used to obtain summary estimates by pooling results from comparative treatment trials. Hypotheses about which prognostic factors might affect epithelial healing during antiviral therapy were developed by multivariate analysis of the Herpetic Eye Disease Study dataset. RESULTS: After excluding 48 duplicate reports, 14 nonrandomized studies, 15 studies with outdated or similar treatments, and 29 trials lacking sufficient data on healing or accessibility, 76 primary reports were identified. These reports involved 4,251 patients allocated to 93 treatment comparisons of dendritic epithelial keratitis in 28 categories and 9 comparisons of geographic epithelial keratitis in 6 categories. For dendritic keratitis, idoxuridine was better than placebo at 7 days

  8. Simplex s={plus_minus}i excitations in {sup 141}Xe.

    SciTech Connect

    Urban, W.; Schulz, N.; Bentaleb, M.; Lubkiewicz, E.; Durell, J. L.; Leddy, M. J.; Jones, M. A.; Phillips, W. R.; Smith, A. G.; Varley, B. J.; Ahmad, I.; Morss, L. R.; Warsaw Univ.; Univ. Louis Pasteur; Univ. of Manchester

    2000-05-01

    Excited levels of {sup 141}Xe, populated in spontaneous fission of {sup 248}Cm, were studied by means of prompt {gamma}-ray spectroscopy, using the EUROGAMM2 array. Level scheme of {sup 141}Xe obtained in this work shows patterns characteristic of simplex symmetry with s = +i and s = -i bands present but low value of D{sub 0} moment indicates that octupole correlations in Xe isotopes are systematically lower than in Ba nuclei.

  9. Vessel wall enhancement in herpes simplex virus central nervous system vasculitis.

    PubMed

    Guerrero, Waldo R; Dababneh, Haitham; Hedna, Shushrutha; Johnson, James A; Peters, Keith; Waters, Michael F

    2013-09-01

    Infection is a well-known cause of cerebral vasculopathy and vasculitis. We report a 36-year-old woman with cerebral vasculitis and ischemic stroke secondary to herpes simplex virus (HSV). MRI studies revealed a pontine stroke with basilar artery stenosis and vessel wall gadolinium enhancement. This case demonstrates the ability of HSV to cause a focal brainstem vasculitis and the utility of enhanced MRI in the diagnosis of stroke related to HSV central nervous system vasculitis. PMID:23517674

  10. Multiple strokes associated with herpes simplex virus type-2 infection: case report.

    PubMed

    Joshi, Prajwol

    2016-04-01

    Herpes simplex virus (HSV) type-2 is known to cause meningitis and usually runs a benign course. Association of such infection with vasculitis of the central nervous system is not well known. Presented here is a case initially diagnosed as aseptic meningitis that subsequently evolved as stroke and exhibited angiographic evidence of widespread vasculitis of the intracranial vessels in association with a positive polymerase chain reaction (PCR) for HSV-2 in the cerebrospinal fluid (CSF). PMID:26443565

  11. Georges-Paul Dieulafoy (1839-1911) and the first description of "exulceratio simplex"

    PubMed

    Karamanou, Marianna; Fiska, Aliki; Demetriou, Thespis; Androutsos, George

    2011-01-01

    Professor Georges Dieulafoy is considered to be an outstanding clinician who played a leading role in medicine during the 19th century. He invented the well-known Dieulafoy aspirator, he described a triad for the diagnosis of acute appendicitis and he tried to bridge the gap between internal medicine and surgery. This article presents in details the first description of "exulceratio simplex" that bears his name. PMID:24713721

  12. The Intelligence of Dual Simplex Method to Solve Linear Fractional Fuzzy Transportation Problem

    PubMed Central

    Narayanamoorthy, S.; Kalyani, S.

    2015-01-01

    An approach is presented to solve a fuzzy transportation problem with linear fractional fuzzy objective function. In this proposed approach the fractional fuzzy transportation problem is decomposed into two linear fuzzy transportation problems. The optimal solution of the two linear fuzzy transportations is solved by dual simplex method and the optimal solution of the fractional fuzzy transportation problem is obtained. The proposed method is explained in detail with an example. PMID:25810713

  13. Contributions of herpes simplex virus type 1 envelope proteins to entry by endocytosis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Herpes simplex virus (HSV) proteins specifically required for endocytic entry but not direct penetration have not been identified. HSVs deleted of gE, gG, gI, gJ, gM, UL45, or Us9 entered cells via either pH-dependent or pH-independent endocytosis and were inactivated by mildly acidic pH. Thus, the ...

  14. Topical and systemic therapies for oral and perioral herpes simplex virus infections.

    PubMed

    Stoopler, Eric T; Balasubramaniam, Ramesh

    2013-04-01

    Oral and perioral herpes simplex virus (HSV) infections in healthy individuals often present with signs and symptoms that are clearly recognized by oral health care providers (OHCPs). Management of these infections is dependent upon a variety of factors and several agents may be used for treatment to accelerate healing and decrease symptoms associated with lesions. This article will review the pertinent aspects of topical and systemic therapies of HSV infections for the OHCP. PMID:23705241

  15. Proton MR spectroscopy in herpes simplex encephalitis: Assessment of neuronal loss

    SciTech Connect

    Menon, D.K.; Sargentoni, J.; Peden, C.J.; Bell, J.D.; Cox, I.J.; Coutts, G.A.; Baudouin, C.; Newman, C.G. )

    1990-05-01

    We present here the case of an 11-year-old boy with herpes simplex encephalitis diagnosed on the basis of clinical features, serology, and response to acyclovir, who relapsed after 3 weeks of therapy. In vivo proton magnetic resonance spectroscopy (1H MRS) of the brain, at 8 and 16 weeks after the onset of symptoms, showed abnormalities, most prominently a reduction in the N-acetylaspartate/choline ratio. The role of 1H MRS in assessing disease activity is discussed.

  16. Successful treatment of hypertrophic herpes simplex genitalis in HIV-infected patient with topical imiquimod.

    PubMed

    Deza, Gustavo; Martin-Ezquerra, Gemma; Curto-Barredo, Laia; Villar García, Judit; Pujol, Ramon M

    2015-12-01

    Hypertrophic herpes simplex genitalis is an atypical presentation of genital herpes described in the context of immunosuppression, particularly HIV-positive patients. This situation can become a diagnostic and therapeutic challenge. For this reason, alternative therapies are currently being discussed in the literature. We report a case of hypertrophic genital herpes in a HIV-positive patient who was successfully treated with topical 5% imiquimod after treatment failures with oral and i.v. antivirals. PMID:26074211

  17. Antiviral activity of sandalwood oil against herpes simplex viruses-1 and -2.

    PubMed

    Benencia, F; Courrèges, M C

    1999-05-01

    Sandalwood oil, the essential oil of Santalum album L., was tested for in vitro antiviral activity against Herpes simplex viruses-1 and -2. It was found that the replication of these viruses was inhibited in the presence of the oil. This effect was dose-dependent and more pronounced against HSV-1. A slight diminution of the effect was observed at higher multiplicity of infections. The oil was not virucidal and showed no cytotoxicity at the concentrations tested. PMID:10374251

  18. Ascending in utero herpes simplex virus infection in an initially healthy-appearing premature infant.

    PubMed

    Edwards, Morven S; Popek, Edwina J; Wise, Brittany; Hatzenbuehler, Lindsay; Arunachalam, Athis R; Hair, Amy B

    2015-01-01

    The usual route of acquisition for intrauterine herpes simplex virus (HSV) infection is transplacental. We evaluated a premature infant with in utero acquisition of HSV resulting from ascending infection. Histopathologic evidence of chronic chorioamnionitis and positive staining with immunohistochemistry for HSV in the placenta and umbilical cord established the diagnosis. The clinical presentation was also of interest in that the infant was initially healthy appearing. PMID:25535792

  19. Slipping and Sliding: frameshift mutations in herpes simplex virus thymidine kinase and drug-resistance

    PubMed Central

    Griffiths, Anthony

    2011-01-01

    Some of the most successful antiviral agents currently available are effective against herpes simplex virus. However, resistance to these drugs is frequently associated with significant morbidity, particularly in immunocompromised patients. In addition to the clinical implications of drug resistance, the range of biological processes exploited by the virus to attain resistance while maintaining pathogenicity is proving to be surprising. These mechanisms, which include ribosomal frameshifting, induced infidelity of the DNA polymerase, and internal ribosome entry, are discussed. PMID:21940196

  20. The Us3 Protein of Herpes Simplex Virus 1 Inhibits T Cell Signaling by Confining Linker for Activation of T Cells (LAT) Activation via TRAF6 Protein*

    PubMed Central

    Yang, Yin; Wu, Songfang; Wang, Yu; Pan, Shuang; Lan, Bei; Liu, Yaohui; Zhang, Liming; Leng, Qianli; Chen, Da; Zhang, Cuizhu; He, Bin; Cao, Youjia

    2015-01-01

    Herpes simplex virus 1 (HSV-1) is the most prevalent human virus and causes global morbidity because the virus is able to infect multiple cell types. Remarkably, HSV infection switches between lytic and latent cycles, where T cells play a critical role. However, the precise way of virus-host interactions is incompletely understood. Here we report that HSV-1 productively infected Jurkat T-cells and inhibited antigen-induced T cell receptor activation. We discovered that HSV-1-encoded Us3 protein interrupted TCR signaling and interleukin-2 production by inactivation of the linker for activation of T cells. This study unveils a mechanism by which HSV-1 intrudes into early events of TCR-mediated cell signaling and may provide novel insights into HSV infection, during which the virus escapes from host immune surveillance. PMID:25907557

  1. Inhibitory activity of Melissa officinalis L. extract on Herpes simplex virus type 2 replication.

    PubMed

    Mazzanti, G; Battinelli, L; Pompeo, C; Serrilli, A M; Rossi, R; Sauzullo, I; Mengoni, F; Vullo, V

    2008-01-01

    Melissa officinalis L. (Lamiaceae) (lemon balm) is used in folk medicine for nervous complaints, lower abdominal disorders and, more recently, for treating Herpes simplex lesions. In this work the antiviral activity of a hydroalcoholic extract of lemon balm leaves against the Herpes simplex virus type 2 (HSV-2) was assessed by the cytopathic effect inhibition assay on Vero cells (ATCC CCL-81), in comparison with acyclovir. The cytotoxicity of the extract on Vero cells was previously tested by evaluating the cellular death and was confirmed by the Trypan blue test. Lemon balm showed to reduce the cytopathic effect of HSV-2 on Vero cells, in the range of non-toxic concentrations of 0.025-1 mg mL(-1) (with reference to the starting crude herbal material). The maximum inhibiting effect (60%) was obtained with 0.5 mg mL(-1). The viral binding assay showed that the extract does not prevent the entry of HSV-2 in the cells, thus suggesting a mechanism of action subsequent to the penetration of the virus in the cell. The extract was also chemically characterised by NMR and HPLC analysis; it showed to contain cinnamic acid-like compounds, mainly rosmarinic acid (4.1% w/w). Our experiments support the use of lemon balm for treating Herpes simplex lesions and encourage clinical trials on this medicinal plant. PMID:19023806

  2. Viability and antigenicity of anisakis simplex after conventional and microwave heating at fixed temperatures.

    PubMed

    Vidaček, Sanja; De Las Heras, Cristina; Solas, Maria Teresa; García, Maria Luisa; Mendizábal, Angel; Tejada, Margarita

    2011-12-01

    Inactivation of parasites in food by microwave treatment may vary due to differences in the characteristics of microwave ovens and food properties. Microwave treatment in standard domestic ovens results in hot and cold spots, and the microwaves do not penetrate all areas of the samples depending on the thickness, which makes it difficult to compare microwave with conventional heat treatments. The viability of Anisakis simplex (isolated larvae and infected fish muscle) heated in a microwave oven with precise temperature control was compared with that of larvae heated in a water bath to investigate any additional effect of the microwaves. At a given temperature, less time was required to kill the larvae by microwaves than by heated water. Microwave treatment killed A. simplex larvae faster than did conventional cooking when the microwaves fully penetrated the samples and resulted in fewer changes in the fish muscle. However, the heat-stable allergen Ani s 4 was detected by immunohistochemistry in the fish muscle after both heat treatments, even at 70°C, suggesting that Ani s 4 allergens were released from the larvae into the surrounding tissue and that the tissues retained their allergenicity even after the larvae were killed by both heat treatments. Thus, microwave cooking will not render fish safe for individuals already sensitized to A. simplex heat-resistant allergens. PMID:22186053

  3. Herpes Simplex Virus Hepatitis in an Immunocompetent Adult: A Fatal Outcome due to Liver Failure

    PubMed Central

    Poley, Rachel A.; Snowdon, Jaime F.; Howes, Daniel W.

    2011-01-01

    Objective. To present a case of a healthy 41-year-old female who developed fulminant hepatic failure leading to death. The cause of hepatic failure identified on postmortem exam was herpes simplex virus hepatitis. Design. Observation of a single patient. Setting. Intensive care unit of a tertiary care university teaching hospital in Canada. Patient. 41-year-old previously healthy female presenting with a nonspecific viral illness and systemic inflammatory response syndrome. Intervention. The patient was treated with intravenous fluids and broad-spectrum antibiotics. On the second day of admission, she was found to have elevated transaminases, and, over 48 hours, she progressed to fulminant liver failure with disseminated intravascular coagulopathy, refractory lactic acidosis, and shock. She progressed to respiratory failure requiring intubation and mechanical ventilation. She was started on N-acetylcysteine, a bicarbonate infusion, hemodialysis, and multiple vasopressors and inotropes. Measurements and Main Results. Despite treatment, the patient died roughly 70 hours after her initial presentation to hospital. Her postmortem liver biopsy revealed herpes simplex virus hepatitis as her cause of death. Conclusions. Herpes simplex virus must be considered in all patients presenting with liver failure of unknown cause. If suspected, prompt treatment with acyclovir should be initiated. PMID:24826316

  4. Parallel Implementations Of The Nelder-Mead Simplex Algorithm For Unconstrained Optimization

    NASA Astrophysics Data System (ADS)

    Dennis, J. E.; Torczon, Virginia

    1988-04-01

    We are interested in implementing direct search methods on parallel computers to solve the unconstrained minimization problem: Given a function f : IRn --? IR find an x E En that minimizes 1 (x). Our preliminary work has focused on the Nelder-Mead simplex algorithm. The origin of the algorithm can be found in a 1962 paper by Spendley, Hext and Himsworth;1 Nelder and Meade proposed an adaptive version which proved to be much more robust in practice. Dennis and Woods3 give a clear presentation of the standard Nelder-Mead simplex algorithm; Woods4 includes a more complete discussion of implementation details as well as some preliminary convergence results. Since descriptions of the standard Nelder-Mead simplex algorithm appear in Nelder and Mead,2 Dennis and Woods,3 and Woods,4 we will limit our introductory discussion to the advantages and disadvantages of the algorithm, as well as some of the features which make it so popular. We then outline the approaches we have taken and discuss our preliminary results. We conclude with a discussion of future research and some observations about our findings.

  5. Valaciclovir versus aciclovir for the treatment of primary genital herpes simplex: a cost analysis.

    PubMed

    Pinder, Melissa; Wright, Alison

    2015-11-01

    The current guidelines for the treatment of primary herpes simplex in the Genito-urinary department in Sheffield Teaching Hospitals NHS Foundation Trust, recommend valaciclovir as a first-line medication. This is a prodrug of aciclovir, which has been used for many years as a treatment for primary herpes simplex virus. The basis of the recommendation largely relates to valaciclovir being more bioavailable than aciclovir. However, there is no evidence to suggest this has an effect on overall outcome with regard to symptom control and viral shedding. The purpose of the service evaluation was to discover if significant cost savings could be made by changing the prescribing policy to make aciclovir the drug of choice for primary herpes simplex virus. Based on 160 patients receiving valaciclovir (500 mg BD) during April 2013 and March 2014, if they had been treated with aciclovir (400 mg TDS) instead, a saving of £828.80 (66% reduction) could have been made. PMID:25505043

  6. Development of New Lipid-Based Paclitaxel Nanoparticles Using Sequential Simplex Optimization

    PubMed Central

    Dong, Xiaowei; Mattingly, Cynthia A.; Tseng, Michael; Cho, Moo; Adams, Val R.; Mumper, Russell J.

    2008-01-01

    The objective of these studies was to develop Cremophor-free lipid-based paclitaxel (PX) nanoparticle formulations prepared from warm microemulsion precursors. To identify and optimize new nanoparticles, experimental design was performed combining Taguchi array and sequential simplex optimization. The combination of Taguchi array and sequential simplex optimization efficiently directed the design of paclitaxel nanoparticles. Two optimized paclitaxel nanoparticles (NPs) were obtained: G78 NPs composed of glyceryl tridodecanoate (GT) and polyoxyethylene 20-stearyl ether (Brij 78), and BTM NPs composed of Miglyol 812, Brij 78 and D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS). Both nanoparticles successfully entrapped paclitaxel at a final concentration of 150 μg/ml (over 6% drug loading) with particle sizes less than 200 nm and over 85% of entrapment efficiency. These novel paclitaxel nanoparticles were stable at 4°C over three months and in PBS at 37°C over 102 hours as measured by physical stability. Release of paclitaxel was slow and sustained without initial burst release. Cytotoxicity studies in MDA-MB-231 cancer cells showed that both nanoparticles have similar anticancer activities compared to Taxol®. Interestingly, PX BTM nanocapsules could be lyophilized without cryoprotectants. The lyophilized powder comprised only of PX BTM NPs in water could be rapidly rehydrated with complete retention of original physicochemical properties, in-vitro release properties, and cytotoxicity profile. Sequential Simplex Optimization has been utilized to identify promising new lipid-based paclitaxel nanoparticles having useful attributes. PMID:19111929

  7. Antiviral activity of 1-docosanol, an inhibitor of lipid-enveloped viruses including herpes simplex.

    PubMed Central

    Katz, D H; Marcelletti, J F; Khalil, M H; Pope, L E; Katz, L R

    1991-01-01

    This article reports that 1-docosanol, a 22-carbon-long saturated alcohol, exerts a substantial inhibitory effect on replication of certain viruses (e.g., herpes simplex virus and respiratory syncytial virus) within primary target cells in vitro. To study the basis for its viral inhibitory activity, a suspension of 1-docosanol was formulated in an inert and nontoxic surfactant, Pluronic F-68; this suspension exerted potent inhibitory activity on the ability of susceptible viruses to infect cultured target cells. Susceptible viruses included wild-type herpes simplex viruses 1 and 2 as well as acyclovir-resistant herpes simplex virus 2 and also respiratory syncytial virus--all of which are lipid-enveloped. In contrast, nonenveloped poliovirus was not susceptible to the inhibitory action of 1-docosanol. Although the precise mechanism has yet to be defined, current evidence suggests that 1-docosanol inhibits viral replication by interfering with the early intracellular events surrounding viral entry into target cells. It is possible that interaction between the highly lipophilic compound and components of target cell membranes renders such target cells less susceptible to viral fusion and/or entry. If this mechanism proves to be correct, 1-docosanol may provide a broad spectrum activity against many different viruses, especially those with lipid-containing envelopes. Images PMID:1660151

  8. Developmental stages and fecundity of Lepeophtheirus simplex (Copepoda: Caligidae) parasitic on bullseye puffer fish (Sphoeroides annulatus).

    PubMed

    Neptali Morales-Serna, Francisco; Rivas-Salas, Ana Ines; Gomez, Samuel; Fajer-Avila, Emma Josefina

    2015-01-01

    Lepeophtheirus simplex Ho, Gómez et Fajer-Avila, 2001 is a parasite of Sphoeroides annulatus (Jenyns), an economically important fish species, with potential for aquaculture, in northwestern Mexico. The goal of this study was to describe the developmental stages under experimental conditions and seasonal fecundity of this parasite on wild fish. There are two naupliar, one copepodid, two chalimus and two pre-adult stages preceding the adult of L. simplex. The results support previous findings, which point out that the life cycle of the caligid copepods includes only six post-naupliar stages. The generation time from egg extrusion to adult for L. simplex was approximately 10 days at 22 °C. The body length of the ovigerous females ranged between 2.2 and 4.1 mm, and its fecundity between 12 and 36 eggs per string. Fecundity was negatively correlated with the egg size and positively correlated with the egg string length. Our data did not reveal significant differences in fecundity among sampling months, but ovigerous females were significantly larger in March (when water temperature was 22 °C) than in June and July (when water temperature was 30 °C). To some extent, our fecundity results contrast with those found in species of sea lice from higher latitudes. Undoubtedly, biological information on different species of sea lice from different environmental conditions will enhance our understanding of their infection strategies and will be valuable, given the increasing interest in marine fish farming in Mexico. PMID:25960548

  9. Herpes simplex encephalitis is linked with selective mitochondrial damage; a post-mortem and in vitro study.

    PubMed

    Wnęk, Małgorzata; Ressel, Lorenzo; Ricci, Emanuele; Rodriguez-Martinez, Carmen; Guerrero, Julio Cesar Villalvazo; Ismail, Zarini; Smith, Colin; Kipar, Anja; Sodeik, Beate; Chinnery, Patrick F; Solomon, Tom; Griffiths, Michael J

    2016-09-01

    Herpes simplex virus type-1 (HSV-1) encephalitis (HSE) is the most commonly diagnosed cause of viral encephalitis in western countries. Despite antiviral treatment, HSE remains a devastating disease with high morbidity and mortality. Improved understanding of pathogenesis may lead to more effective therapies. Mitochondrial damage has been reported during HSV infection in vitro. However, whether it occurs in the human brain and whether this contributes to the pathogenesis has not been fully explored. Minocycline, an antibiotic, has been reported to protect mitochondria and limit brain damage. Minocycline has not been studied in HSV infection. In the first genome-wide transcriptomic study of post-mortem human HSE brain tissue, we demonstrated a highly preferential reduction in mitochondrial genome (MtDNA) encoded transcripts in HSE cases (n = 3) compared to controls (n = 5). Brain tissue exhibited a significant inverse correlation for immunostaining between cytochrome c oxidase subunit 1 (CO1), a MtDNA encoded enzyme subunit, and HSV-1; with lower abundance for mitochondrial protein in regions where HSV-1 was abundant. Preferential loss of mitochondrial function, among MtDNA encoded components, was confirmed using an in vitro primary human astrocyte HSV-1 infection model. Dysfunction of cytochrome c oxidase (CO), a mitochondrial enzyme composed predominantly of MtDNA encoded subunits, preceded that of succinate dehydrogenase (composed entirely of nuclear encoded subunits). Minocycline treated astrocytes exhibited higher CO1 transcript abundance, sustained CO activity and cell viability compared to non-treated astrocytes. Based on observations from HSE patient tissue, this study highlights mitochondrial damage as a critical and early event during HSV-1 infection. We demonstrate minocycline preserves mitochondrial function and cell viability during HSV-1 infection. Minocycline, and mitochondrial protection, offers a novel adjunctive therapeutic approach for

  10. Nonthermal Dielectric Barrier Discharge (DBD) Plasma Suppresses Herpes Simplex Virus Type 1 (HSV-1) Replication in Corneal Epithelium

    PubMed Central

    Alekseev, Oleg; Donovan, Kelly; Limonnik, Vladimir; Azizkhan-Clifford, Jane

    2014-01-01

    Purpose Herpes keratitis (HK) is the leading cause of cornea-derived and infection-associated blindness in the developed world. Despite the availability of effective antivirals, some patients develop refractory disease, drug-resistant infection, and topical toxicity. A nonpharmaceutical treatment modality may offer a unique advantage in the management of such cases. This study investigated the antiviral effect of nonthermal dielectric barrier discharge (DBD) plasma, a partially ionized gas that can be applied to organic substances to produce various biological effects. Methods Human corneal epithelial cells and explanted corneas were infected with herpes simplex virus type 1 (HSV-1) and exposed to culture medium treated with nonthermal DBD plasma. The extent of infection was measured by plaque assay, quantitative PCR, and Western blot. Corneal toxicity assessment was performed with fluorescein staining, histologic examination, and 8-OHdG detection. Results Application of DBD plasma–treated medium to human corneal epithelial cells and explanted corneas produced a dose-dependent reduction of the cytopathic effect, viral genome replication, and the overall production of infectious viral progeny. Toxicity studies showed lack of detrimental effects in explanted human corneas. Conclusions Nonthermal DBD plasma substantially suppresses corneal HSV-1 infection in vitro and ex vivo without causing pronounced toxicity. Translational Relevance Nonthermal plasma is a versatile tool that holds great biomedical potential for ophthalmology, where it is being investigated for wound healing and sterilization and is already in use for ocular microsurgery. The anti-HSV-1 activity of DBD plasma demonstrated here could be directly translated to the clinic for use against drug-resistant herpes keratitis. PMID:24757592

  11. Varicella-Zoster Virus and Herpes Simplex Virus 1 Can Infect and Replicate in the Same Neurons whether Co- or Superinfected

    PubMed Central

    Sloutskin, Anna; Yee, Michael B.; Kinchington, Paul R.

    2014-01-01

    ABSTRACT The two human neurotropic alphaherpesviruses varicella-zoster virus (VZV) and herpes simplex virus type 1 (HSV1) both establish latency in sensory ganglia. Human trigeminal ganglia are known to frequently harbor both viruses, and there is evidence to suggest the presence of both VZV and HSV1 DNA in the same neuron. We ask here whether VZV and HSV1 can exclude themselves and each other and whether they can productively infect the same cells in human neurons and human foreskin fibroblasts (HFF). Simultaneous infection (coinfection) or consecutive infection (superinfection) was assessed using cell-free HSV1 and VZV expressing fluorescent reporter proteins. Automated analysis was carried out to detect singly and dually infected cells. We demonstrate that VZV and HSV1 both display efficient superinfection exclusion (SE) in HFF, with each virus excluding either itself or the other virus. While SE also occurred in neurons, it was with much lower efficiency. Both alphaherpesviruses productively infected the same neurons, whether applied simultaneously or even consecutively, albeit at lower frequencies. IMPORTANCE Superinfection exclusion by VZV for itself or the related neurotropic alphaherpesvirus HSV1 has been studied here for the first time. We find that while these viruses display classic SE in fibroblasts, SE is less efficient for both HSV1 and VZV in human neurons. The ability of multiple VZV strains to productively infect the same neurons has important implications in terms of recombination of both wild-type and vaccine strains in patients. PMID:24574392

  12. Anti-(herpes simplex virus) activity of 4'-thio-2'-deoxyuridines: a biochemical investigation for viral and cellular target enzymes.

    PubMed Central

    Verri, A; Focher, F; Duncombe, R J; Basnak, I; Walker, R T; Coe, P L; de Clercq, E; Andrei, G; Snoeck, R; Balzarini, J; Spadari, S

    2000-01-01

    The antiviral activity of several nucleoside analogues is often limited by their rapid degradation by pyrimidine nucleoside phosphorylases. In an attempt to avoid this degradation, several modified nucleosides have been synthesized. A series of 4'-thio-2'-deoxyuridines exhibits an anti-[herpes simplex virus (HSV)] activity significantly higher (20-600 times) than that shown by the corresponding 4'-oxy counterpart. We investigated the mode of action of these compounds and we found that: (i) several 4'-thio-2'-deoxyuridines are phosphorylated to the mono- and di-phosphates by HSV-1 thymidine kinase (TK) more efficiently than their corresponding 4'-oxy counterpart; (ii) both are inhibitors of cellular thymidylate synthase; (iii) 4'-thio-2'-deoxyuridines are resistant to phosphorolysis by human thymidine phosphorylase; (iv) both 4'-oxy- and 4'-thio-2'-deoxyuridines are phosphorylated to deoxyribonucleotide triphosphate in HSV-1-infected cells and are incorporated into viral DNA; (v) 4'-thio-2'-deoxyuridines are better inhibitors than their 4'-oxy counterparts of [(3)H]thymidine incorporation in HSV-1-infected cells; (vi) 4'-thio-2'-deoxyuridines are not recognized by HSV-1 and human uracil-DNA glycosylases. Our data suggest that 4'-thio-2'-deoxyuridines, resistant to pyrimidine phosphorylase, can be preferentially or selectively phosphorylated by viral TK in HSV-infected cells, where they are further converted into triphosphate by cellular nucleotide kinases. Once incorporated into viral DNA, they are better inhibitors of viral DNA synthesis than their corresponding 4'-oxy counterpart, either because they are not recognized, and thus not removed, by viral uracil-DNA glycosylase, or because they preferentially interfere with viral DNA polymerase. PMID:11023816

  13. Chlamydial Pre-Infection Protects from Subsequent Herpes Simplex Virus-2 Challenge in a Murine Vaginal Super-Infection Model.

    PubMed

    Slade, Jessica; Hall, Jennifer V; Kintner, Jennifer; Schoborg, Robert V

    2016-01-01

    Chlamydia trachomatis and Herpes Simplex Virus-2 (HSV-2) genital tract co-infections have been reported in humans and studied in vitro but the clinical consequences are unknown. Limited epidemiologic evidence suggests that these co-infections could be more severe than single infections of either pathogen, but the host-pathogen interactions during co-infection remain uncharacterized. To determine whether disease progression and/or pathogen shedding differs between singly-infected and super-infected animals, we developed an in vivo super-infection model in which female BALB/c mice were vaginally infected with Chlamydia muridarum (Cm) followed later by HSV-2. Pre-infection with Chlamydia 3 or 9 days prior to HSV-2 super-infection conferred significant protection from HSV-2-induced neurologic disease and significantly reduced viral recovery compared to HSV-2 singly-infected controls. Neither protection from mortality nor reduced viral recovery were observed when mice were i) super-infected with HSV-2 on day 27 post Cm; ii) infected with UV-irradiated Cm and super-infected with HSV-2; or iii) azithromycin-treated prior to HSV-2 super-infection. Therefore, protection from HSV-2-induced disease requires active infection with viable chlamydiae and is not observed after chlamydial shedding ceases, either naturally or due to antibiotic treatment. Thus, Chlamydia-induced protection is transient and requires the continued presence of chlamydiae or their components. These data demonstrate that chlamydial pre-infection can alter progression of subsequent HSV-2 infection, with implications for HSV-2 transmission from co-infected humans. PMID:26726882

  14. Chlamydial Pre-Infection Protects from Subsequent Herpes Simplex Virus-2 Challenge in a Murine Vaginal Super-Infection Model

    PubMed Central

    Slade, Jessica; Hall, Jennifer V.; Kintner, Jennifer; Schoborg, Robert V.

    2016-01-01

    Chlamydia trachomatis and Herpes Simplex Virus-2 (HSV-2) genital tract co-infections have been reported in humans and studied in vitro but the clinical consequences are unknown. Limited epidemiologic evidence suggests that these co-infections could be more severe than single infections of either pathogen, but the host-pathogen interactions during co-infection remain uncharacterized. To determine whether disease progression and/or pathogen shedding differs between singly-infected and super-infected animals, we developed an in vivo super-infection model in which female BALB/c mice were vaginally infected with Chlamydia muridarum (Cm) followed later by HSV-2. Pre-infection with Chlamydia 3 or 9 days prior to HSV-2 super-infection conferred significant protection from HSV-2-induced neurologic disease and significantly reduced viral recovery compared to HSV-2 singly-infected controls. Neither protection from mortality nor reduced viral recovery were observed when mice were i) super-infected with HSV-2 on day 27 post Cm; ii) infected with UV-irradiated Cm and super-infected with HSV-2; or iii) azithromycin-treated prior to HSV-2 super-infection. Therefore, protection from HSV-2-induced disease requires active infection with viable chlamydiae and is not observed after chlamydial shedding ceases, either naturally or due to antibiotic treatment. Thus, Chlamydia-induced protection is transient and requires the continued presence of chlamydiae or their components. These data demonstrate that chlamydial pre-infection can alter progression of subsequent HSV-2 infection, with implications for HSV-2 transmission from co-infected humans. PMID:26726882

  15. Infection of vascular endothelial cells with herpes simplex virus enhances tissue factor activity and reduces thrombomodulin expression.

    PubMed Central

    Key, N S; Vercellotti, G M; Winkelmann, J C; Moldow, C F; Goodman, J L; Esmon, N L; Esmon, C T; Jacob, H S

    1990-01-01

    Latent infection of vascular cells with herpes-viruses may play a pathogenic role in the development of human atherosclerosis. In a previous study, we found that cultured human umbilical vein endothelial cells (HUVECs) infected with herpes simplex virus 1 (HSV-1) became procoagulant, exemplified both by their enhanced assembly of the prothrombinase complex and by their inability to reduce adhesion of platelets. We now report two further procoagulant consequences of endothelial HSV infection: loss of surface thrombomodulin (TM) activity and induction of synthesis of tissue factor. Within 4 hr of infection of HUVECs, TM activity measured by thrombin-dependent protein C activation declined 21 +/- 3% (P less than 0.05) and by 18 hr, 48 +/- 5% (P less than 0.001). Similar significant TM decrements accompanied infection of bovine aortic endothelial cells. Identical TM loss was induced with HSV-2 infection but not with adenovirus infection. Decreased surface expression of TM antigen (measured by the specific binding of a polyclonal antibody to bovine TM) closely paralleled the loss of TM activity. As examined by Northern blotting, these losses apparently reflected rapid onset (within 4 hr of HSV infection) loss of mRNA for TM. In contrast, HSV infection induced a viral-dose-dependent increase in synthesis of tissue factor protein, adding to the procoagulant state. The results indicate that loss of endothelial protein-synthetic capacity is not a universal effect of HSV infection. We suggest that the procoagulant state induced by reduction in TM activity and amplified tissue factor activity accompanying HSV infection of endothelium could contribute to deposition of thrombi on atherosclerotic plaques and to the "coagulant-necrosis" state that characterizes HSV-infected mucocutaneous lesions. Images PMID:2169619

  16. Use of Immunostimulatory Sequence-Containing Oligonucleotides as Topical Therapy for Genital Herpes Simplex Virus Type 2 Infection

    PubMed Central

    Pyles, Richard B.; Higgins, Debbie; Chalk, Claudia; Zalar, Anthony; Eiden, Joseph; Brown, Carrie; Van Nest, Gary; Stanberry, Lawrence R.

    2002-01-01

    Synthetic oligonucleotides containing CpG motifs in specific sequence contexts have been shown to induce potent immune responses. We have evaluated mucosal administration of two immunostimulatory sequence (ISS)-containing phosphorothioate-stabilized oligonucleotides for antiherpetic efficacy in animal models. The ISS oligonucleotides, suspended in phosphate-buffered saline, were tested in mouse and guinea pig vaginal models of herpes simplex virus type 2 (HSV-2) infection. For comparison, groups of untreated, non-ISS oligonucleotide-treated, and acyclovir-treated animals also were monitored. The results indicated that vaginal epithelial application of ISS (up to 6 h after viral inoculation) with mice lethally challenged with HSV-2 delayed disease onset and reduced the number of animals that developed signs of disease (P = 0.003). ISS application significantly increased survival rates over those of controls (P = 0.0014). The ISS also impacted an established infection in the guinea pig model of HSV-2 disease. A single administration of ISS (21 days after viral inoculation) significantly reduced the frequency and severity of HSV-2 lesions compared to results with non-ISS oligonucleotide-treated and untreated guinea pigs (P < 0.01). HSV-2 is shed from the vaginal cavity of the guinea pig in the absence of lesions, similar to the case with humans. As an additional indication of ISS efficacy, the magnitude of viral shedding also was significantly reduced in ISS-treated animals (P < 0.001). These effects appeared to be immunologically mediated, since ISS had no direct effect on HSV-2 replication in vitro using standard plaque assays. These data suggest that ISS may be useful in the treatment and control of genital herpes in humans. PMID:12388699

  17. Experimental challenge of Anisakis simplex sensu stricto and Anisakis pegreffii (Nematoda: Anisakidae) in rainbow trout and olive flounder.

    PubMed

    Quiazon, Karl Marx A; Yoshinaga, Tomoyoshi; Ogawa, Kazuo

    2011-06-01

    The third-stage larvae of Anisakis simplex sensu lato (s.l.) are found in many marine fishes. To ensure food safety, it is important to determine whether these larvae are present in the body muscle of commercial fish species. However, there is little information regarding the tissue specificity of Anisakis and two of its sibling species, A. simplex sensu stricto (s.s.) and Anisakis pegreffii, that are common in marine fish in Japanese waters. We orally challenged rainbow trout (Oncorhynchus mykiss (Walbaum)), and olive flounder (Paralichthys olivaceus (Temminck and Schlegel)) with L3 larvae of these two sibling species and monitored infection for 5weeks. In rainbow trout, A. simplex s.s., but not A. pegreffii larvae, migrated into the body muscle. A small number of freely moving A. pegreffii larvae were recovered within the body cavity. In olive flounder, A. simplex s.s. larvae were found in both the body cavity and body muscle. A. pegreffii larvae were found only in the body cavity and primarily encapsulated in lumps. Our results indicate that there are differences in the sites of infection and host specificity between the two sibling species of A. simplex s.l. PMID:21122822

  18. Herpes Simplex Virus 1 (HSV-1) and HSV-2 Mediate Species-Specific Modulations of Programmed Necrosis through the Viral Ribonucleotide Reductase Large Subunit R1

    PubMed Central

    Yu, Xiaoliang; Li, Yun; Chen, Qin; Su, Chenhe; Zhang, Zili; Yang, Chengkui; Hu, Zhilin; Hou, Jue; Zhou, Jinying; Gong, Ling; Jiang, Xuejun

    2015-01-01

    ABSTRACT Receptor-interacting protein kinase 3 (RIP3) and its substrate mixed-lineage kinase domain-like protein (MLKL) are core regulators of programmed necrosis. The elimination of pathogen-infected cells by programmed necrosis acts as an important host defense mechanism. Here, we report that human herpes simplex virus 1 (HSV-1) and HSV-2 had opposite impacts on programmed necrosis in human cells versus their impacts in mouse cells. Similar to HSV-1, HSV-2 infection triggered programmed necrosis in mouse cells. However, neither HSV-1 nor HSV-2 infection was able to induce programmed necrosis in human cells. Moreover, HSV-1 or HSV-2 infection in human cells blocked tumor necrosis factor (TNF)-induced necrosis by preventing the induction of an RIP1/RIP3 necrosome. The HSV ribonucleotide reductase large subunit R1 was sufficient to suppress TNF-induced necrosis, and its RIP homotypic interaction motif (RHIM) domain was required to disrupt the RIP1/RIP3 complex in human cells. Therefore, this study provides evidence that HSV has likely evolved strategies to evade the host defense mechanism of programmed necrosis in human cells. IMPORTANCE This study demonstrated that infection with HSV-1 and HSV-2 blocked TNF-induced necrosis in human cells while these viruses directly activated programmed necrosis in mouse cells. Expression of HSV R1 suppressed TNF-induced necrosis of human cells. The RHIM domain of R1 was essential for its association with human RIP3 and RIP1, leading to disruption of the RIP1/RIP3 complex. This study provides new insights into the species-specific modulation of programmed necrosis by HSV. PMID:26559832

  19. Immunity to herpes simplex virus type 2. Suppression of virus-induced immune responses in ultraviolet B-irradiated mice

    SciTech Connect

    Yasumoto, S.; Hayashi, Y.; Aurelian, L.

    1987-10-15

    Ultraviolet B irradiation (280 to 320 nm) of mice at the site of intradermal infection with herpes simplex virus type 2 increased the severity of the herpes simplex virus type 2 disease and decreased delayed-type hypersensitivity (DTH) responses to viral antigen. Decrease in DTH resulted from the induction of suppressor T cells, as evidenced by the ability of spleen cells from UV-irradiated mice to inhibit DTH and proliferative responses after adoptive transfer. Lymph node cells from UV-irradiated animals did not transfer suppression. DTH was suppressed at the induction but not the expression phase. Suppressor T cells were Lyt-1+, L3T4+, and their activity was antigen-specific. However, after in vitro culture of spleen cells from UV-irradiated mice with herpes simplex virus type 2 antigen, suppressor activity was mediated by Lyt-2+ cells. Culture supernatants contained soluble nonantigen-specific suppressive factors.

  20. Histophagous ciliate Pseudocollinia brintoni and bacterial assemblage interaction with krill Nyctiphanes simplex. I. Transmission process.

    PubMed

    Gómez-Gutiérrez, Jaime; López-Cortés, Alejandro; Aguilar-Méndez, Mario J; Del Angel-Rodríguez, Jorge A; Tremblay, Nelly; Zenteno-Savín, Tania; Robinson, Carlos J

    2015-10-27

    Histophagous ciliates of the genus Pseudocollinia cause epizootic events that kill adult female krill (Euphausiacea), but their mode of transmission is unknown. We compared 16S rRNA sequences of bacterial strains isolated from stomachs of healthy krill Nyctiphanes simplex specimens with sequences of bacterial isolates and sequences of natural bacterial communities from the hemocoel of N. simplex specimens infected with P. brintoni to determine possible transmission pathways. All P. brintoni endoparasitic life stages and the transmission tomite stage (outside the host) were associated with bacterial assemblages. 16S rRNA sequences from isolated bacterial strains showed that Photobacterium spp. and Pseudoalteromonas spp. were dominant members of the bacterial assemblages during all life phases of P. brintoni and potential pathobionts. They were apparently unaffected by the krill's immune system or the histophagous activity of P. brintoni. However, other bacterial strains were found only in certain P. brintoni life phases, indicating that as the infection progressed, microhabitat conditions and microbial interactions may have become unfavorable for some strains of bacteria. Trophic infection is the most parsimonious explanation for how P. brintoni infects krill. We estimated N. simplex vulnerability to P. brintoni infection during more than three-fourths of their life span, infecting mostly adult females. The ciliates have relatively high prevalence levels (albeit at <10% of sampled stations) and a short life cycle (estimated <7 d). Histophagous ciliate-krill interactions may occur in other krill species, particularly those that form dense swarms and attain high population densities that potentially enhance trophic transmission and allow completion of the Pseudocollinia spp. life cycle. PMID:26503776