Facial nerve palsy after reactivation of herpes simplex virus type 1 in diabetic mice.

PubMed

Esaki, Shinichi; Yamano, Koji; Katsumi, Sachiyo; Minakata, Toshiya; Murakami, Shingo

2015-04-01

Bell's palsy is highly associated with diabetes mellitus (DM). Either the reactivation of herpes simplex virus type 1 (HSV-1) or diabetic mononeuropathy has been proposed to cause the facial paralysis observed in DM patients. However, distinguishing whether the facial palsy is caused by herpetic neuritis or diabetic mononeuropathy is difficult. We previously reported that facial paralysis was aggravated in DM mice after HSV-1 inoculation of the murine auricle. In the current study, we induced HSV-1 reactivation by an auricular scratch following DM induction with streptozotocin (STZ). Controlled animal study. Diabetes mellitus was induced with streptozotocin injection in only mice that developed transient facial nerve paralysis with HSV-1. Recurrent facial palsy was induced after HSV-1 reactivation by auricular scratch. After DM induction, the number of cluster of differentiation 3 (CD3)(+) T cells decreased by 70% in the DM mice, and facial nerve palsy recurred in 13% of the DM mice. Herpes simplex virus type 1 deoxyribonucleic acid (DNA) was detected in the facial nerve of all of the DM mice with palsy, and HSV-1 capsids were found in the geniculate ganglion using electron microscopy. Herpes simplex virus type 1 DNA was also found in some of the DM mice without palsy, which suggested the subclinical reactivation of HSV-1. These results suggested that HSV-1 reactivation in the geniculate ganglion may be the main causative factor of the increased incidence of facial paralysis in DM patients. © 2014 The American Laryngological, Rhinological and Otological Society, Inc.

RNA interference inhibits herpes simplex virus type 1 isolated from saliva samples and mucocutaneous lesions.

PubMed

Silva, Amanda Perse da; Lopes, Juliana Freitas; Paula, Vanessa Salete de

2014-01-01

The aim of this study was to evaluate the use of RNA interference to inhibit herpes simplex virus type-1 replication in vitro. For herpes simplex virus type-1 gene silencing, three different small interfering RNAs (siRNAs) targeting the herpes simplex virus type-1 UL39 gene (sequence si-UL 39-1, si-UL 39-2, and si-UL 39-3) were used, which encode the large subunit of ribonucleotide reductase, an essential enzyme for DNA synthesis. Herpes simplex virus type-1 was isolated from saliva samples and mucocutaneous lesions from infected patients. All mucocutaneous lesions' samples were positive for herpes simplex virus type-1 by real-time PCR and by virus isolation; all herpes simplex virus type-1 from saliva samples were positive by real-time PCR and 50% were positive by virus isolation. The levels of herpes simplex virus type-1 DNA remaining after siRNA treatment were assessed by real-time PCR, whose results demonstrated that the effect of siRNAs on gene expression depends on siRNA concentration. The three siRNA sequences used were able to inhibit viral replication, assessed by real-time PCR and plaque assays and among them, the sequence si-UL 39-1 was the most effective. This sequence inhibited 99% of herpes simplex virus type-1 replication. The results demonstrate that silencing herpes simplex virus type-1 UL39 expression by siRNAs effectively inhibits herpes simplex virus type-1 replication, suggesting that siRNA based antiviral strategy may be a potential therapeutic alternative. Copyright © 2014. Published by Elsevier Editora Ltda.

Autophagy is involved in anti-viral activity of pentagalloylglucose (PGG) against Herpes simplex virus type 1 infection in vitro

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pei, Ying, E-mail: peiying-19802@163.com; Chen, Zhen-Ping, E-mail: 530670663@qq.com; Ju, Huai-Qiang, E-mail: 344464448@qq.com

2011-02-11

Research highlights: {yields} We showed PGG has anti-viral activity against Herpes simplex virus type 1 (HSV-1) and can induce autophgy. {yields} Autophagy may be a novel and important mechanism mediating PGG anti-viral activities. {yields} Inhibition of mTOR pathway is an important mechanism of induction of autophagy by PGG. -- Abstract: Pentagalloylglucose (PGG) is a natural polyphenolic compound with broad-spectrum anti-viral activity, however, the mechanisms underlying anti-viral activity remain undefined. In this study, we investigated the effects of PGG on anti-viral activity against Herpes simplex virus type 1 (HSV-1) associated with autophagy. We found that the PGG anti-HSV-1 activity was impairedmore » significantly in MEF-atg7{sup -/-} cells (autophagy-defective cells) derived from an atg7{sup -/-} knockout mouse. Transmission electron microscopy revealed that PGG-induced autophagosomes engulfed HSV-1 virions. The mTOR signaling pathway, an essential pathway for the regulation of autophagy, was found to be suppressed following PGG treatment. Data presented in this report demonstrated for the first time that autophagy induced following PGG treatment contributed to its anti-HSV activity in vitro.« less

The pathogenicity of thymidine kinase-deficient mutants of herpes simplex virus in mice.

PubMed Central

Field, H. J.; Wildy, P.

1978-01-01

The pathogenicity for mice of two mutants of herpes simplex virus (type 1 and type 2), which fail to induce thymidine kinase, were compared with their respective parent strains. The mutants were much less virulent than the parents following either intracerebral or peripheral inoculation. The replication of the virus at the site of inoculation and its progression into the nervous system were studied. Following a very large inoculum in the ear, the type 1 mutant was found to establish a latent infection in the cervical dorsal root ganglia. Mice inoculated intracerebrally with small doses of the mutant viruses were solidly immune to challenge with lethal doses of the parent strain. PMID:212476

The pathogenicity of thymidine kinase-deficient mutants of herpes simplex virus in mice.

PubMed

Field, H J; Wildy, P

1978-10-01

The pathogenicity for mice of two mutants of herpes simplex virus (type 1 and type 2), which fail to induce thymidine kinase, were compared with their respective parent strains. The mutants were much less virulent than the parents following either intracerebral or peripheral inoculation. The replication of the virus at the site of inoculation and its progression into the nervous system were studied. Following a very large inoculum in the ear, the type 1 mutant was found to establish a latent infection in the cervical dorsal root ganglia. Mice inoculated intracerebrally with small doses of the mutant viruses were solidly immune to challenge with lethal doses of the parent strain.

The effect of DNA priming-protein boosting on enhancing humoral immunity and protecting mice against lethal HSV infections.

PubMed

Soleimanjahi, Hoorieh; Roostaee, Mohammad Hassan; Rasaee, Mohammad Javad; Mahboudi, Fereidoon; Kazemnejad, Anooshirvan; Bamdad, Taravat; Zandi, Keivan

2006-02-01

Herpes simplex virus produces primary and latent infections with periodic recurrency. The prime-boost immunization strategies were studied using a DNA vaccine carrying the full-length glycoprotein D-1 gene and a baculovirus-derived recombinant glycoprotein D, both expressing herpes simplex virus glycoprotein D-1 protein. Immunization with recombinant DNAs encoding antigenic proteins could induce cellular and humoral responses by providing antigen expression in vivo. Higher immune response, however, occurred when the recombinant proteins followed DNA inoculation. While all groups of the immunized mice and positive control group could resist virus challenge, a higher virus neutralizing antibody level was detected in the animals receiving recombinant protein following DNA vaccination.

Herpes simplex virus following stab phlebectomy.

PubMed

Hicks, Caitlin W; Lum, Ying Wei; Heller, Jennifer A

2017-03-01

Herpes simplex virus infection following surgery is an unusual postoperative phenomenon. Many mechanisms have been suggested, with the most likely explanation related to latent virus reactivation due to a proinflammatory response in the setting of local trauma. Here, we present a case of herpes simplex virus reactivation in an immunocompetent female following a conventional right lower extremity stab phlebectomy. Salient clinical and physical examination findings are described, and management strategies for herpes simplex virus reactivation are outlined. This is the first known case report of herpes simplex virus reactivation following lower extremity phlebectomy.

Acute Morphine Administration Reduces Cell-Mediated Immunity and Induces Reactivation of Latent Herpes Simplex Virus Type 1 in BALB/c Mice

PubMed Central

Mojadadi, Shafi; Jamali, Abbas; Khansarinejad, Behzad; Soleimanjahi, Hoorieh; Bamdad, Taravat

2009-01-01

Acute morphine administration is known to alter the course of herpes simplex virus infection. In this study, the effect of acute morphine administration on the reactivation of latent herpes was investigated in a mouse model. Because of the important role of cytolytic T lymphocyte (CTL) activity in the inhibition of herpes simplex virus type 1 (HSV-1) reactivation, the effect of acute morphine administration on CTL responses was also evaluated. Furthermore, lymphocyte proliferation and IFN-γ production were evaluated for their roles in the induction of the CTL response. The findings showed that acute morphine administration significantly reduced CTL responses, lymphocyte proliferation, and IFN-γ production. Furthermore, acute morphine administration has been shown to reactivate latent HSV-1. Previous studies have shown that cellular immune responses have important roles in the inhibition of HSV reactivation. These findings suggest that suppression of a portion of the cellular immune response after acute morphine administration may constitute one part of the mechanism that induces HSV reactivation. PMID:19403060

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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 amore » 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.« less

Inactivation of Herpes Simplex Viruses by Nonionic Surfactants

PubMed Central

Asculai, Samuel S.; Weis, Margaret T.; Rancourt, Martha W.; Kupferberg, A. B.

1978-01-01

Nonionic surface-active agents possessing ether or amide linkages between the hydrophillic and hydrophobic portions of the molecule rapidly inactivated the infectivity of herpes simplex viruses. The activity stemmed from the ability of nonionic surfactants to dissolve lipid-containing membranes. This was confirmed by observing surfactant destruction of mammalian cell plasma membranes and herpes simplex virus envelopes. Proprietary vaginal contraceptive formulations containing nonionic surfactants also inactivated herpes simplex virus infectivity. This observation suggests that nonionic surfactants in appropriate formulation could effectively prevent herpes simplex virus transmission. Images PMID:208460

Mimicking herpes simplex virus 1 and herpes simplex virus 2 mucosal behavior in a well-characterized human genital organ culture.

PubMed

Steukers, Lennert; Weyers, Steven; Yang, Xiaoyun; Vandekerckhove, Annelies P; Glorieux, Sarah; Cornelissen, Maria; Van den Broeck, Wim; Temmerman, Marleen; Nauwynck, Hans J

2014-07-15

We developed and morphologically characterized a human genital mucosa explant model (endocervix and ectocervix/vagina) to mimic genital herpes infections caused by herpes simplex virus types 1 (HSV-1) and 2 (HSV-2). Subsequent analysis of HSV entry receptor expression throughout the menstrual cycle in genital tissues was performed, and the evolution of HSV-1/-2 mucosal spread over time was assessed. Nectin-1 and -2 were expressed in all tissues during the entire menstrual cycle. Herpesvirus entry mediator expression was limited mainly to some connective tissue cells. Both HSV-1 and HSV-2 exhibited a plaque-wise mucosal spread across the basement membrane and induced prominent epithelial syncytia. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

The "Knife-Cut Sign" Revisited: A Distinctive Presentation of Linear Erosive Herpes Simplex Virus Infection in Immunocompromised Patients.

PubMed

Cohen, Philip R

2015-10-01

The "knife-cut sign" is a distinctive presentation of linear erosive herpes simplex virus infection in immunocompromised patients. To describe a man whose herpes simplex virus infection-related skin lesions demonstrated the "knife-cut sign" and to review the characteristics of reported immunosuppressed individuals with "knife-cut" cutaneous herpes simplex virus lesions. A man with multiple myeloma and post-stem cell transplant cutaneous graft-versus-host disease managed with systemic prednisone and sirolimus developed disseminated cutaneous herpes simplex virus infection with virus-associated linear ulcers of the inguinal folds and the area between his ear and scalp; the lesions at both sites had a distinctive "knife-cut" appearance. Using the PubMed database, an extensive literature search was performed on herpes simplex virus, immunocompromised patient, and "knife-cut sign". Herpes simplex virus infection-associated skin lesions that demonstrate the "knife-cut sign" present in patients who are immunosuppressed secondary to either an underlying medical condition or a systemic therapy or both. The distinctive virus-related cutaneous lesions appear as linear ulcers and fissures in intertriginous areas, such as the folds in the inguinal area, the vulva, and the abdomen; in addition, other sites include beneath the breast, within the gluteal cleft, and the area between the ear and the scalp. Not only herpes simplex virus-2, but also herpes simplex virus-1 has been observed as the causative viral serotype; indeed, herpes simplex virus-1 has been associated with genital and inframammary lesions in addition to those above the neck. Direct fluorescent antibody testing is a rapid method for confirming the clinically suspected viral infection; however, since false-negative direct fluorescent antibody testing occurred in some of the patients, it may be prudent to also perform viral cultures and possibly lesional skin biopsies to establish the diagnosis. The herpes simplex virus infection-related skin lesions clinically improve once systemic antiviral therapy is initiated. In immunosuppressed individuals, the "knife-cut sign" is a distinctive presentation of cutaneous linear erosive herpes simplex virus infection. Recognition of the linear ulcers in intertriginous areas and body folds should prompt the clinician to consider herpes simplex virus infection-associated skin lesions in an immunocompromised patient and to initiate systemic antiviral treatment while awaiting the results of laboratory evaluation to confirm the suspected diagnosis.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vafai, A.; Wellish, M.; Devlin, M.

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 proteinsmore » in human sensory ganglia.« less

Glutamine Deprivation Causes Enhanced Plating Efficiency of a Herpes Simplex Virus Type 1 ICP0-Null Mutant ▿

PubMed Central

Bringhurst, Ryan M.; Dominguez, Antonia A.; Schaffer, Priscilla A.

2008-01-01

Isoleucine deprivation of cellular monolayers prior to infection has been reported to result in partial complementation of a herpes simplex virus type 1 (HSV-1) ICP0 null (ICP0−) mutant. We now report that glutamine deprivation alone is able to enhance the plating efficiency of an ICP0− virus and that isoleucine deprivation has little or no effect. Because a low glutamine level is associated with stress and because stress is known to induce reactivation, low levels of glutamine may be relevant to the reactivation of HSV-1 from latency. Additionally, we demonstrate that arginine and methionine deprivation result in partial complementation of the ICP0− virus. PMID:18768961

Protease-deficient herpes simplex virus protects mice from lethal herpesvirus infection.

PubMed Central

Hippenmeyer, P J; Rankin, A M; Luckow, V A; Neises, G R

1997-01-01

Null mutants and attenuated mutants of herpes simplex virus (HSV) have been shown to induce immunity against challenge from wild-type virus. Null viruses with a defect in late gene products would be expected to express more viral genes than viruses with defects in essential early gene products and thus induce a better immune response. Herpesviruses encode a late gene product (serine protease) that is autocatalytic and cleaves the capsid assembly protein during viral replication. To determine whether a virus with a mutation in this gene could induce immunity, we constructed a recombinant virus containing the gusA reporter gene in the protease domain of the HSV type 1 UL26 open reading frame (ORF). Consistent with previous results (M. Gao, L. Matusick-Kumar, W. Hurlburt, S. F. DiTusa, W. W. Newcomb, J. C. Brown, P. J. McCann, I. Deckman, and R. J. Colonno, J. Virol. 68:3702-3712, 1994), recombinant virus could be isolated only from helper cell lines expressing the product of the UL26 ORF. Mice inoculated with the recombinant virus were unaffected by doses of virus that were lethal to mice infected with wild-type virus. Mice which were previously inoculated with the recombinant virus were also protected by a subsequent challenge with wild-type virus in a dose-dependent manner. These results indicate that recombinant viruses lacking the protease gene are avirulent but render protection from subsequent challenge. PMID:8995617

A Herpes Simplex Virus Type 2 Deleted for Glycoprotein D Enables Dendritic Cells to Activate CD4+ and CD8+ T Cells

PubMed Central

Retamal-Díaz, Angello R.; Kalergis, Alexis M.; Bueno, Susan M.; González, Pablo A.

2017-01-01

Herpes simplex virus type 2 (HSV-2) is highly prevalent in the human population producing significant morbidity, mainly because of the generation of genital ulcers and neonatal encephalitis. Additionally, HSV-2 infection significantly increases the susceptibility of the host to acquire HIV and promotes the shedding of the latter in the coinfected. Despite numerous efforts to create a vaccine against HSV-2, no licensed vaccines are currently available. A long-standing strategy, based on few viral glycoproteins combined with adjuvants, recently displayed poor results in a Phase III clinical study fueling exploration on the development of mutant HSV viruses that are attenuated in vivo and elicit protective adaptive immune components, such as antiviral antibodies and T cells. Importantly, such specialized antiviral immune components are likely induced and modulated by dendritic cells, professional antigen presenting cells that process viral antigens and present them to T cells. However, HSV interferes with several functions of DCs and ultimately induces their death. Here, we propose that for an attenuated mutant virus to confer protective immunity against HSV in vivo based on adaptive immune components, such virus should also be attenuated in dendritic cells to promote a robust and effective antiviral response. We provide a background framework for this idea, considerations, as well as the means to assess this hypothesis. Addressing this hypothesis may provide valuable insights for the development of novel, safe, and effective vaccines against herpes simplex viruses. PMID:28848543

Concomitant herpes simplex virus colitis and hepatitis in a man with ulcerative colitis: Case report and review of the literature.

PubMed

Phadke, Varun K; Friedman-Moraco, Rachel J; Quigley, Brian C; Farris, Alton B; Norvell, J P

2016-10-01

Herpesvirus infections often complicate the clinical course of patients with inflammatory bowel disease; however, invasive disease due to herpes simplex virus is distinctly uncommon. We present a case of herpes simplex virus colitis and hepatitis, review all the previously published cases of herpes simplex virus colitis, and discuss common clinical features and outcomes. We also discuss the epidemiology, clinical manifestations, diagnosis, and management of herpes simplex virus infections, focusing specifically on patients with inflammatory bowel disease. A 43-year-old man with ulcerative colitis, previously controlled with an oral 5-aminosalicylic agent, developed symptoms of a colitis flare that did not respond to treatment with systemic corticosteroid therapy. One week later he developed orolabial ulcers and progressive hepatic dysfunction, with markedly elevated transaminases and coagulopathy. He underwent emergent total colectomy when imaging suggested bowel micro-perforation. Pathology from both the colon and liver was consistent with herpes simplex virus infection, and a viral culture of his orolabial lesions and a serum polymerase chain reaction assay also identified herpes simplex virus. He was treated with systemic antiviral therapy and made a complete recovery. Disseminated herpes simplex virus infection with concomitant involvement of the colon and liver has been reported only 3 times in the published literature, and to our knowledge this is the first such case in a patient with inflammatory bowel disease. The risk of invasive herpes simplex virus infections increases with some, but not all immunomodulatory therapies. Optimal management of herpes simplex virus in patients with inflammatory bowel disease includes targeted prophylactic therapy for patients with evidence of latent infection, and timely initiation of antiviral therapy for those patients suspected to have invasive disease.

Concomitant herpes simplex virus colitis and hepatitis in a man with ulcerative colitis

PubMed Central

Phadke, Varun K.; Friedman-Moraco, Rachel J.; Quigley, Brian C.; Farris, Alton B.; Norvell, J. P.

2016-01-01

Abstract Background: Herpesvirus infections often complicate the clinical course of patients with inflammatory bowel disease; however, invasive disease due to herpes simplex virus is distinctly uncommon. Methods: We present a case of herpes simplex virus colitis and hepatitis, review all the previously published cases of herpes simplex virus colitis, and discuss common clinical features and outcomes. We also discuss the epidemiology, clinical manifestations, diagnosis, and management of herpes simplex virus infections, focusing specifically on patients with inflammatory bowel disease. Results: A 43-year-old man with ulcerative colitis, previously controlled with an oral 5-aminosalicylic agent, developed symptoms of a colitis flare that did not respond to treatment with systemic corticosteroid therapy. One week later he developed orolabial ulcers and progressive hepatic dysfunction, with markedly elevated transaminases and coagulopathy. He underwent emergent total colectomy when imaging suggested bowel micro-perforation. Pathology from both the colon and liver was consistent with herpes simplex virus infection, and a viral culture of his orolabial lesions and a serum polymerase chain reaction assay also identified herpes simplex virus. He was treated with systemic antiviral therapy and made a complete recovery. Conclusions: Disseminated herpes simplex virus infection with concomitant involvement of the colon and liver has been reported only 3 times in the published literature, and to our knowledge this is the first such case in a patient with inflammatory bowel disease. The risk of invasive herpes simplex virus infections increases with some, but not all immunomodulatory therapies. Optimal management of herpes simplex virus in patients with inflammatory bowel disease includes targeted prophylactic therapy for patients with evidence of latent infection, and timely initiation of antiviral therapy for those patients suspected to have invasive disease. PMID:27759636

Combined oncolytic virotherapy with herpes simplex virus for oral squamous cell carcinoma.

PubMed

Ogawa, Fumi; Takaoka, Hiroo; Iwai, Soichi; Aota, Keiko; Yura, Yoshiaki

2008-01-01

The effect of dual infection with herpes simplex virus type 1 (HSV-1) mutants on human oral squamous cell carcinoma (SCC) cells was examined. Human oral SCC cells were infected with gamma1(34.5) gene-deficient HSV-1 R849 and HSV-1 HF that has multiple mutations and induces cell fusion. Cell viability was measured by LDH release assay. Athymic mice were injected with oral SCC cells into the buccal region to induce subcutaneous tumors. Oral SCC cells were infected with R849, followed by infection with R849 or HF. Virus production was elevated by both strains of HSV-1. Although the release of LDH from R849-infected cells was increased by secondary infection with R849 or HF, the effect of HF was more remarkable. When nude mouse tumors were treated with R849, HF, R849+R849, or R849+HF, treatment with R849+HF was the most effective. These results suggest that fusion-inducing virus HF enhances the oncolytic ability of gamma1(34.5) gene-deficient HSV-1 and provides a rationale for using fusogenic viruses as enhancing agents

Involvement of UL24 in herpes-simplex-virus-1-induced dispersal of nucleolin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lymberopoulos, Maria H.; Pearson, Angela

2007-07-05

UL24 of herpes simplex virus 1 is important for efficient viral replication, but its function is unknown. We generated a recombinant virus, vHA-UL24, encoding UL24 with an N-terminal hemagglutinin tag. By indirect immunofluorescence at 9 h post-infection (hpi), we detected HA-UL24 in nuclear foci and in cytoplasmic speckles. HA-UL24 partially co-localized with nucleolin, but not with ICP8 or coilin, markers for nucleoli, viral replication compartments, and Cajal bodies respectively. HA-UL24 staining was often juxtaposed to that of another nucleolar protein, fibrillarin. Analysis of HSV-1-induced nucleolar modifications revealed that by 18 hpi, nucleolin staining had dispersed, and fibrillarin staining went frommore » clusters of small spots to a few separate but prominent spots. Fibrillarin redistribution appeared to be independent of UL24. In contrast, cells infected with a UL24-deficient virus retained foci of nucleolin staining. Our results demonstrate involvement of UL24 in dispersal of nucleolin during infection.« less

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

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…

Pathogenicity in mice of strains of herpes simplex virus which are resistant to acyclovir in vitro and in vivo.

PubMed Central

Field, H J; Darby, G

1980-01-01

Mice infected with three different isolates of herpes simplex virus (HSV) and treated with acyclovir (acycloguanosine; ACV) showed low levels of virus replication during the acute phase of infection. However, virus isolated from such treated mice did not show increased resistance to ACV. In contrast, resistant virus was readily isolated in vitro by passaging HSV in the presence of the drug. The degree of resistance was determined, in part, by the nature of the cells used to test the virus. The majority of ACV-resistant strains induced low or undetectable levels of HSV-specified thymidine kinase (TK), the enzyme responsible for phosphorylating ACV in infected cells. The TK-resistant strains were attenuated when injected into mice as indicated by reductions in virus replication, inflammation, and establishment of latent infections in sensory ganglia. The reduced virulence of the TK- strains was most marked after intracerebral inoculation, where the lethal dose was increased more than 100-fold compared with the parental isolates. However, one mutant is described which induced high levels of TK but was highly resistant to ACV and retained virulence for mice. PMID:6247969

Granulomatous herpes simplex encephalitis in an infant with multicystic encephalopathy: a distinct clinicopathologic entity?

PubMed

Schutz, Peter W; Fauth, Clarissa T; Al-Rawahi, Ghada N; Pugash, Denise; White, Valerie A; Stockler, Sylvia; Dunham, Christopher P

2014-04-01

Herpes simplex virus encephalitis can manifest as a range of clinical presentations including classic adult, neonatal, and biphasic chronic-granulomatous herpes encephalitis. We report an infant with granulomatous herpes simplex virus type 2 encephalitis with a subacute course and multicystic encephalopathy. A 2-month-old girl presented with lethargy and hypothermia. Computed tomography scan of the head showed multicystic encephalopathy and calcifications. Cerebrospinal fluid analysis by polymerase chain reaction testing for herpes simplex virus 1 and 2, enterovirus, and cytomegalovirus was negative. Normal cerebrospinal fluid interferon-α levels argued against Aicardi-Goutières syndrome. The patient died 2 weeks after presentation. At autopsy, multicystic encephalopathy was confirmed with bilateral gliosis, granulomatous inflammation with multinucleated giant cells, and calcifications. Bilateral healing necrotizing retinitis suggested a viral etiology, but retina and brain were free of viral inclusions and immunohistochemically negative for herpes simplex virus-2 and cytomegalovirus. However, polymerase chain reaction analysis showed herpes simplex virus-2 DNA in four cerebral paraffin blocks. Subsequent repeat testing of the initial cerebrospinal fluid sample using a different polymerase chain reaction assay was weakly positive for herpes simplex virus-2 DNA. Granulomatous herpes simplex virus encephalitis in infants can present with subacute course and result in multicystic encephalopathy with mineralization and minimal cerebrospinal fluid herpes simplex virus DNA load. Infectious etiologies should be carefully investigated in the differential diagnosis of multicystic encephalopathy with mineralization, in particular if multinucleated giant cells are present. Copyright © 2014 Elsevier Inc. All rights reserved.

2,3-Dihydroxy-quinoxaline induces ATPase activity of Herpes Simplex Virus thymidine kinase.

PubMed

Zeifman, Alexey A; Novikov, Fedor N; Stroylov, Victor S; Stroganov, Oleg V; Chilov, Ghermes G; Skoblov, Alexander Y; Miroshnikov, Anatoly I; Skoblov, Yuri S

2014-01-31

2,3-Dihydroxy-quinoxaline, a small molecule that promotes ATPase catalytic activity of Herpes Simplex Virus thymidine kinase (HSV-TK), was identified by virtual screening. This compound competitively inhibited HSV-TK catalyzed phosphorylation of acyclovir with Ki=250 μM (95% CI: 106-405 μM) and dose-dependently increased the rate of the ATP hydrolysis with KM=112 μM (95% CI: 28-195 μM). The kinetic scheme consistent with this experimental data is proposed. Copyright © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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 themore » neurons.« less

Prevalence of herpes simplex, Epstein Barr and human papilloma viruses in oral lichen planus.

PubMed

Yildirim, Benay; Sengüven, Burcu; Demir, Cem

2011-03-01

The aim of the present study was to assess the prevalence of Herpes Simplex virus, Epstein Barr virus and Human Papilloma virus -16 in oral lichen planus cases and to evaluate whether any clinical variant, histopathological or demographic feature correlates with these viruses. The study was conducted on 65 cases. Viruses were detected immunohistochemically. We evaluated the histopathological and demographic features and statistically analysed correlation of these features with Herpes Simplex virus, Epstein Barr virus and Human Papilloma virus-16 positivity. Herpes Simplex virus was positive in six (9%) cases and this was not statistically significant. The number of Epstein Barr virus positive cases was 23 (35%) and it was statistically significant. Human Papilloma virus positivity in 14 cases (21%) was statistically significant. Except basal cell degeneration in Herpes Simplex virus positive cases, we did not observe any significant correlation between virus positivity and demographic or histopathological features. However an increased risk of Epstein Barr virus and Human Papilloma virus infection was noted in oral lichen planus cases. Taking into account the oncogenic potential of both viruses, oral lichen planus cases should be detected for the presence of these viruses.

Decreased reactivation of a herpes simplex virus type 1 (HSV-1) latency associated transcript (LAT) mutant using the in vivo mouse UV-B model of induced reactivation

PubMed Central

BenMohamed, Lbachir; Osorio, Nelson; Srivastava, Ruchi; Khan, Arif A.; Simpson, Jennifer L.; Wechsler, Steven L.

2015-01-01

Blinding ocular herpetic disease in humans is due to herpes simplex virus type 1 (HSV-1) reactivations from latency, rather than to primary acute infection. The cellular and molecular mechanisms that control the HSV-1 latency-reactivation cycle remain to be fully elucidated. The aim of this study was to determine if reactivation of the HSV-1 latency associated transcript (LAT) deletion mutant (dLAT2903) was impaired in this model, as it is in the rabbit model of induced and spontaneous reactivation and in the explant TG induced reactivation model in mice. The eyes of mice latently infected with wild type HSV-1 strain McKrae (LAT(+) virus) or dLAT2903 (LAT(−) virus) were irradiated with UV-B and reactivation was determined. We found that compared to LAT(−) virus, LAT(+) virus reactivated at a higher rate as determined by shedding of virus in tears on days 3 to 7 after UV-B treatment. Thus, the UV-B induced reactivation model of HSV-1 appears to be a useful small animal model for studying the mechanisms involved in how LAT enhances the HSV-1 reactivation phenotype. The utility of the model for investigating the immune evasion mechanisms regulating the HSV-1 latency/reactivation cycle and for testing the protective efficacy of candidate therapeutic vaccines and drugs are discussed. PMID:26002839

Neurological Consequences of Cytomegalovirus Infection

MedlinePlus

... viruses that causes cold sores (herpes simplex virus), infectious mononucleosis (Epstein-Barr virus), and chickenpox/shingles (varicella zoster ... viruses that causes cold sores (herpes simplex virus), infectious mononucleosis (Epstein-Barr virus), and chickenpox/shingles (varicella zoster ...

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

Isolation and characterization of acyclovir-resistant mutants of herpes simplex virus.

PubMed

Field, H J; Darby, G; Wildy, P

1980-07-01

Mutants of HSV which are resistant to acyclovir (acycloguanosine) have been isolated following serial passages of several herpes simplex virus (HSV) strains in the presence of the drug. The majority of the mutants isolated are defective in induction of thymidine kinase (TK) and this is consistent with the observation that independently isolated TK- viruses are naturally resistant to ACV. One mutant is described (SC16 R9C2) which is resistant in biochemically transformed cells which express HSV TK. This suggests that its resistance resides at a level other than TK. It is also resistant to phosphonoacetic acid, suggesting that the DNA polymerase locus may be involved. A further mutant is described [Cl (101) P2C5] which induces normal levels of TK, although the nature of resistance of this virus is not yet elucidated.

Disparities in herpes simplex virus type 2 infection between black and white men who have sex with men in Atlanta, GA.

PubMed

Okafor, Netochukwu; Rosenberg, Eli S; Luisi, Nicole; Sanchez, Travis; del Rio, Carlos; Sullivan, Patrick S; Kelley, Colleen F

2015-09-01

HIV disproportionately affects black men who have sex with men, and herpes simplex virus type 2 is known to increase acquisition of HIV. However, data on racial disparities in herpes simplex virus type 2 prevalence and risk factors are limited among men who have sex with men in the United States. InvolveMENt was a cohort study of black and white HIV-negative men who have sex with men in Atlanta, GA. Univariate and multivariate cross-sectional associations with herpes simplex virus type 2 seroprevalence were assessed among 455 HIV-negative men who have sex with men for demographic, behavioural and social determinant risk factors using logistic regression. Seroprevalence of herpes simplex virus type 2 was 23% (48/211) for black and 16% (38/244) for white men who have sex with men (p = 0.05). Education, poverty, drug/alcohol use, incarceration, circumcision, unprotected anal intercourse, and condom use were not associated with herpes simplex virus type 2. In multivariate analyses, black race for those ≤25 years, but not >25 years, and number of sexual partners were significantly associated. Young black men who have sex with men are disproportionately affected by herpes simplex virus type 2, which may contribute to disparities in HIV acquisition. An extensive assessment of risk factors did not explain this disparity in herpes simplex virus type 2 infection suggesting differences in susceptibility or partner characteristics. © The Author(s) 2014.

A Fusogenic Oncolytic Herpes Simplex Virus for Therapy of Advanced Ovarian Cancer

DTIC Science & Technology

2006-06-01

killer and NKT cells play a critical role in innate protection against genital herpes simplex virus type 2 infection. J Virol 2003;77:10168-71. 8...AD_________________ Award Number: DAMD17-03-1-0434 TITLE: A Fusogenic Oncolytic Herpes Simplex...CONTRACT NUMBER A Fusogenic Oncolytic Herpes Simplex Virus for Therapy of Advanced Ovarian Cancer 5b. GRANT NUMBER DAMD17-03-1-0434 5c

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Perna, J.J.; Mannix, M.L.; Rooney, J.F.

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 herpesmore » simplex virus under experimentally defined conditions. This model in humans should prove useful in evaluating the pathophysiology and prevention of viral reactivation.« less

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

PubMed

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.

Surgical excision for recurrent herpes simplex virus 2 (HSV-2) anogenital infection in a patient with human immunodeficiency virus (HIV).

PubMed

Arinze, Folasade; Shaver, Aaron; Raffanti, Stephen

2017-10-01

Recurrent anogenital herpes simplex virus infections are common in patients with human immunodeficiency virus (HIV), of whom approximately 5% develop resistance to acyclovir. We present a case of a 49-year-old man with HIV who had an 8-year history of recurrent left inguinal herpes simplex virus type 2 ulcerations. He initially responded to oral acyclovir, but developed resistance to acyclovir and eventually foscarnet. The lesion progressed to a large hypertrophic mass that required surgical excision, which led to resolution without recurrences. Our case highlights the importance of surgical excision as a treatment option in refractory herpes simplex virus anogenital infections.

Infection of endothelial cells by common human viruses.

PubMed

Friedman, H M

1989-01-01

Common human viruses were evaluated for their ability to replicate in the endothelial cells of human umbilical vein and bovine thoracic aorta in vitro. Infection occurred with most viruses. The susceptibilities of endothelial cells derived from bovine aorta, pulmonary artery, and vena cava were compared. Among the viruses studied, no differences were noted in the ability to grow in endothelial cells from these three large vessels. One virus, herpes simplex virus type 1, was evaluated for its ability to produce persistent infection of endothelial cells. Infection developed and persisted for up to 3 months. After the first week, productive infection was found in less than 1% of cells. Nevertheless, the infection markedly affected the growth and morphology of the endothelial monolayer. Infection with any of several different viruses was noted to alter endothelial cell functions, including adherence of granulocytes, production of colony-stimulating factor, and synthesis of matrix protein. In addition, herpes simplex virus type 1 induced receptors for the Fc portion of IgG and for complement component C3b. These findings indicate that common human viruses can profoundly affect the biology of the endothelium.

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

PubMed

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

1986-02-01

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.

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

Properties of a herpes simplex virus multiple immediate-early gene-deleted recombinant as a vaccine vector

DOE Office of Scientific and Technical Information (OSTI.GOV)

Watanabe, Daisuke; Brockman, Mark A.; Ndung'u, Thumbi

2007-01-20

Herpes simplex virus (HSV) recombinants induce durable immune responses in rhesus macaques and mice and have induced partial protection in rhesus macaques against mucosal challenge with virulent simian immunodeficiency virus (SIV). In this study, we evaluated the properties of a new generation HSV vaccine vector, an HSV-1 multiple immediate-early (IE) gene deletion mutant virus, d106, which contains deletions in the ICP4, ICP27, ICP22, and ICP47 genes. Because several of the HSV IE genes have been implicated in immune evasion, inactivation of the genes encoding these proteins was expected to result in enhanced immunogenicity. The d106 virus expresses few HSV genemore » products and shows minimal cytopathic effect in cultured cells. When d106 was inoculated into mice, viral DNA accumulated at high levels in draining lymph nodes, consistent with an ability to transduce dendritic cells and activate their maturation and movement to lymph nodes. A d106 recombinant expressing Escherichia coli {beta}-galactosidase induced durable {beta}-gal-specific IgG and CD8{sup +} T cell responses in naive and HSV-immune mice. Finally, d106-based recombinants have been constructed that express simian immunodeficiency virus (SIV) gag, env, or a rev-tat-nef fusion protein for several days in cultured cells. Thus, d106 shows many of the properties desirable in a vaccine vector: limited expression of HSV gene products and cytopathogenicity, high level expression of transgenes, ability to induce durable immune responses, and an ability to transduce dendritic cells and induce their maturation and migration to lymph nodes.« less

Role for herpes simplex virus 1 ICP27 in the inhibition of type I interferon signaling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johnson, Karen E.; Song, Byeongwoon; Knipe, David M.

2008-05-10

Host cells respond to viral infection by many mechanisms, including the production of type I interferons which act in a paracrine and autocrine manner to induce the expression of antiviral interferon-stimulated genes (ISGs). Viruses have evolved means to inhibit interferon signaling to avoid induction of the innate immune response. Herpes simplex virus 1 (HSV-1) has several mechanisms to inhibit type I interferon production, the activities of ISGs, and the interferon signaling pathway itself. We report that the inhibition of the Jak/STAT pathway by HSV-1 requires viral gene expression and that viral immediate-early protein ICP27 plays a role in downregulating STAT-1more » phosphorylation and in preventing the accumulation of STAT-1 in the nucleus. We also show that expression of ICP27 by transfection causes an inhibition of IFN-induced STAT-1 nuclear accumulation. Therefore, ICP27 is necessary and sufficient for at least some of the effects of HSV infection on STAT-1.« less

An escalating dose study to assess the safety, tolerability and immunogenicity of a Herpes Simplex Virus DNA vaccine, COR-1.

PubMed

Dutton, Julie L; Woo, Wai-Ping; Chandra, Janin; Xu, Yan; Li, Bo; Finlayson, Neil; Griffin, Paul; Frazer, Ian H

2016-12-01

This paper describes a single site, open-label Phase I clinical trial evaluating the safety, tolerability and immunogenicity in healthy volunteers of a herpes simplex polynucleotide vaccine that has previously been shown to enhance immunogenicity and protect against lethal herpes simplex virus type 2 (HSV-2) challenge in mice. Five escalating doses of the vaccine, COR-1, were given by intradermal injection to HSV-1 and 2 seronegative healthy individuals. COR-1 was found to be safe and well-tolerated; the only vaccine-related adverse events were mild. While vaccine-induced antibody responses were not detectable, cell-mediated immune responses to HSV-specific peptide groups were identified in 19 of the 20 subjects who completed the study, and local inflammation at the immunisation site was observed. This study indicates COR-1 has potential to be used as a therapeutic vaccine for HSV-2 infection.

Entry of Herpes Simplex Virus Type 1 (HSV-1) into the Distal Axons of Trigeminal Neurons Favors the Onset of Nonproductive, Silent Infection

PubMed Central

Eing, Bodo R.; Müller, Marcus; King, Nicholas J. C.; Klupp, Barbara; Mettenleiter, Thomas C.; Kühn, Joachim E.

2012-01-01

Following productive, lytic infection in epithelia, herpes simplex virus type 1 (HSV-1) establishes a lifelong latent infection in sensory neurons that is interrupted by episodes of reactivation. In order to better understand what triggers this lytic/latent decision in neurons, we set up an organotypic model based on chicken embryonic trigeminal ganglia explants (TGEs) in a double chamber system. Adding HSV-1 to the ganglion compartment (GC) resulted in a productive infection in the explants. By contrast, selective application of the virus to distal axons led to a largely nonproductive infection that was characterized by the poor expression of lytic genes and the presence of high levels of the 2.0-kb major latency-associated transcript (LAT) RNA. Treatment of the explants with the immediate-early (IE) gene transcriptional inducer hexamethylene bisacetamide, and simultaneous co-infection of the GC with HSV-1, herpes simplex virus type 2 (HSV-2) or pseudorabies virus (PrV) helper virus significantly enhanced the ability of HSV-1 to productively infect sensory neurons upon axonal entry. Helper-virus-induced transactivation of HSV-1 IE gene expression in axonally-infected TGEs in the absence of de novo protein synthesis was dependent on the presence of functional tegument protein VP16 in HSV-1 helper virus particles. After the establishment of a LAT-positive silent infection in TGEs, HSV-1 was refractory to transactivation by superinfection of the GC with HSV-1 but not with HSV-2 and PrV helper virus. In conclusion, the site of entry appears to be a critical determinant in the lytic/latent decision in sensory neurons. HSV-1 entry into distal axons results in an insufficient transactivation of IE gene expression and favors the establishment of a nonproductive, silent infection in trigeminal neurons. PMID:22589716

Construction of Poxviruses as Cloning Vectors: Insertion of the Thymidine Kinase Gene from Herpes Simplex Virus into the DNA of Infectious Vaccinia Virus

NASA Astrophysics Data System (ADS)

Panicali, Dennis; Paoletti, Enzo

1982-08-01

We have constructed recombinant vaccinia viruses containing the thymidine kinase gene from herpes simplex virus. The gene was inserted into the genome of a variant of vaccinia virus that had undergone spontaneous deletion as well as into the 120-megadalton genome of the large prototypic vaccinia variant. This was accomplished via in vivo recombination by contransfection of eukaryotic tissue culture cells with cloned BamHI-digested thymidine kinase gene from herpes simplex virus containing flanking vaccinia virus DNA sequences and infectious rescuing vaccinia virus. Pure populations of the recombinant viruses were obtained by replica filter techniques or by growth of the recombinant virus in biochemically selective medium. The herpes simplex virus thymidine kinase gene, as an insert in vaccinia virus, is transcribed in vivo and in vitro, and the fidelity of in vivo transcription into a functional gene product was detected by the phosphorylation of 5-[125I]iodo-2'-deoxycytidine.

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.

Association between Psychopathic Disorder and Serum Antibody to Herpes Simplex Virus (Type 1)

PubMed Central

Cleobury, J. F.; Skinner, G. R. B.; Thouless, M. E.; Wildy, P.

1971-01-01

The sera of a small of patients has been examined for herpes simplex virus antibody. Three clinically-defined groups of patients were compared: (a) aggressive psychopaths, (b) psychiatric controls, and (c) general hospital patients. The first group had an unusually high average kinetic neutralization constant against type 1 herpes simplex virus. PMID:5543996

Association between psychopathic disorder and serum antibody to herpes simplex virus (type 1).

PubMed

Cleobury, J F; Skinner, G R; Thouless, M E; Wildy, P

1971-02-20

The sera of a small of patients has been examined for herpes simplex virus antibody. Three clinically-defined groups of patients were compared: (a) aggressive psychopaths, (b) psychiatric controls, and (c) general hospital patients. The first group had an unusually high average kinetic neutralization constant against type 1 herpes simplex virus.

Induction of reactivation of herpes simplex virus in murine sensory ganglia in vivo by cadmium.

PubMed Central

Fawl, R L; Roizman, B

1993-01-01

Herpes simplex viruses maintained in a latent state in sensory neurons in mice do not reactivate spontaneously, and therefore the factors or procedures which cause the virus to reactivate serve as a clue to the mechanisms by which the virus is maintained in a latent state. We report that cadmium sulfate induces latent virus to reactivate in 75 to 100% of mice tested. The following specific findings are reported. (i) The highest frequency of induction was observed after two to four daily administrations of 100 micrograms of cadmium sulfate. (ii) Zinc, copper, manganese, or nickel sulfate administered in equimolar amounts under the same regimen did not induce viral reactivation; however, zinc sulfate in molar ratios 25-fold greater than those of cadmium induced viral replication in 2 of 16 ganglia tested. (iii) Administration of zinc, nickel, or manganese prior to the cadmium sulfate reduced the incidence of ganglia containing infectious virus. (iv) Administration of cadmium daily during the first week after infection and at 2-day intervals to 13 days after infection resulted in the recovery from ganglia of infectious virus in titers 10- to 100-fold higher than those obtained from animals given saline. Moreover, infectious virus was recovered as late as 11 days after infection compared with 6 days in mice administered saline. (v) Administration of cadmium immediately after infection or repeatedly after establishment of latency did not exhaust the latent virus harbored by sensory neurons, inasmuch as the fraction of ganglia of mice administered cadmium and yielding infectious virus was similar to that observed in mice treated with saline. We conclude that induction of cadmium tolerance precludes reactivation of latent virus. If the induction of metallothionein genes was the sole factor required to cause reactivation of latent virus, it would have been expected that all metals which induce metallothioneins would also induce reactivation, which was not observed. The results therefore raise the possibility that in addition to inducing the metallothionein genes, cadmium inactivates the factors which maintain the virus in latent state. PMID:8230427

Glutamine supplementation suppresses herpes simplex virus reactivation.

PubMed

Wang, Kening; Hoshino, Yo; Dowdell, Kennichi; Bosch-Marce, Marta; Myers, Timothy G; Sarmiento, Mayra; Pesnicak, Lesley; Krause, Philip R; Cohen, Jeffrey I

2017-06-30

Chronic viral infections are difficult to treat, and new approaches are needed, particularly those aimed at reducing reactivation by enhancing immune responses. Herpes simplex virus (HSV) establishes latency and reactivates frequently, and breakthrough reactivation can occur despite suppressive antiviral therapy. Virus-specific T cells are important to control HSV, and proliferation of activated T cells requires increased metabolism of glutamine. Here, we found that supplementation with oral glutamine reduced virus reactivation in latently HSV-1-infected mice and HSV-2-infected guinea pigs. Transcriptome analysis of trigeminal ganglia from latently HSV-1-infected, glutamine-treated WT mice showed upregulation of several IFN-γ-inducible genes. In contrast to WT mice, supplemental glutamine was ineffective in reducing the rate of HSV-1 reactivation in latently HSV-1-infected IFN-γ-KO mice. Mice treated with glutamine also had higher numbers of HSV-specific IFN-γ-producing CD8 T cells in latently infected ganglia. Thus, glutamine may enhance the IFN-γ-associated immune response and reduce the rate of reactivation of latent virus infection.

Medical Surveillance Monthly Report (MSMR). Volume 20, Number 2, February 2013

DTIC Science & Technology

2013-02-01

have viral etiologies: infections with human papillomavirus (HPV) and genital herpes simplex virus (HSV). Sexually transmitted infections have...infertility No Genital herpes simplex virus (HSV) 3 Virus No Yes Genital sores, infection of newborn babies No Acute gonorrhea 4 Bacterium Yes . PID...796.79 Chlamydia 099.41, 099.5 Genital herpes simplex virus (HSV) 054.1 Acute gonorrhea 098.0x, 098.1x, 098.4x, 098.8x Syphilis, all types All of those

Smallpox Antiviral Drug

DTIC Science & Technology

2007-01-01

viruses, herpes simplex virus (HSV), cytomegalovirus (CMV), varicella-zoster virus (VZV), influenza A and B viruses, and respiratory syncytial virus...Rouzioux C. 2004. Penetration of enfuvirtide, tenofovir, efavirenz, and protease inhibitors in the genital tract of HIV-1-infected men. Aids 18:1958...1968. Sensitivity of herpes simplex virus, vaccinia virus, and adenoviruses to deoxyribonucleic acid inhibitors and thiosemicarbazones in a plaque

Varicella-zoster virus complements herpes simplex virus type 1 temperature-sensitive mutants.

PubMed Central

Felser, J M; Straus, S E; Ostrove, J M

1987-01-01

Varicella-zoster virus (VZV) can complement temperature-sensitive mutants of herpes simplex virus. Of seven mutants tested, two, carrying mutations in the immediate-early ICP4 and ICP27 proteins, were complemented. This complementation was not seen in coinfections with adenovirus type 5 or cytomegalovirus. Following transfection into CV-1 cells, a DNA fragment containing the VZV short repeat sequence complemented the ICP4 mutant. These data demonstrate a functional relationship between VZV and herpes simplex virus and have allowed localization of a putative VZV immediate-early gene. PMID:3023701

Herpes simplex virus-1 infection causes the secretion of a type I interferon-antagonizing protein and inhibits signaling at or before Jak-1 activation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johnson, Karen E.; Knipe, David M., E-mail: david_knipe@hms.harvard.ed

2010-01-05

Host cells respond to viral infection by the production of type I interferons (IFNs), which induce the expression of antiviral genes. Herpes simplex virus I (HSV-1) encodes many mechanisms that inhibit the type I IFN response, including the ICP27-dependent inhibition of type I IFN signaling. Here we show inhibition of Stat-1 nuclear accumulation in cells that express ICP27. ICP27 expression also induces the secretion of a small, heat-stable type I IFN antagonizing protein that inhibits Stat-1 nuclear accumulation. We show that the inhibition of IFN-induced Stat-1 phosphorylation occurs at or upstream of Jak-1 phosphorylation. Finally, we show that ISG15 expressionmore » is induced after IFNalpha treatment in mock-infected cells, but not cells infected with WT HSV-1 or ICP27{sup -} HSV-1. These data suggest that HSV-1 has evolved multiple mechanisms to inhibit IFN signaling not only in infected cells, but also in neighboring cells, thereby allowing for increased viral replication and spread.« less

Involvement of the UL24 protein in herpes simplex virus 1-induced dispersal of B23 and in nuclear egress

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lymberopoulos, Maria H.; Bourget, Amelie; Abdeljelil, Nawel Ben

2011-04-10

UL24 of herpes simplex virus 1 (HSV-1) is widely conserved within the Herpesviridae family. Herein, we tested the hypothesis that UL24, which we have previously shown to induce the redistribution of nucleolin, also affects the localization of the nucleolar protein B23. We found that HSV-1-induced dispersal of B23 was dependent on UL24. The conserved N-terminal portion of UL24 was sufficient to induce the redistribution of B23 in transient transfection assays. Mutational analysis revealed that the endonuclease motif of UL24 was important for B23 dispersal in both transfected and infected cells. Nucleolar protein relocalization during HSV-1 infection was also observed inmore » non-immortalized cells. Analysis of infected cells by electron microscopy revealed a decrease in the ratio of cytoplasmic versus nuclear viral particles in cells infected with a UL24-deficient strain compared to KOS-infected cells. Our results suggest that UL24 promotes nuclear egress of nucleocapsids during HSV-1 infection, possibly though effects on nucleoli.« less

Oncolytic Herpes Simplex Viral Therapy: A Stride toward Selective Targeting of Cancer Cells.

PubMed

Sanchala, Dhaval S; Bhatt, Lokesh K; Prabhavalkar, Kedar S

2017-01-01

Oncolytic viral therapy, which makes use of replication-competent lytic viruses, has emerged as a promising modality to treat malignancies. It has shown meaningful outcomes in both solid tumor and hematologic malignancies. Advancements during the last decade, mainly genetic engineering of oncolytic viruses have resulted in improved specificity and efficacy of oncolytic viruses in cancer therapeutics. Oncolytic viral therapy for treating cancer with herpes simplex virus-1 has been of particular interest owing to its range of benefits like: (a) large genome and power to infiltrate in the tumor, (b) easy access to manipulation with the flexibility to insert multiple transgenes, (c) infecting majority of the malignant cell types with quick replication in the infected cells and (d) as Anti-HSV agent to terminate HSV replication. This review provides an exhaustive list of oncolytic herpes simplex virus-1 along with their genetic alterations. It also encompasses the major developments in oncolytic herpes simplex-1 viral therapy and outlines the limitations and drawbacks of oncolytic herpes simplex viral therapy.

Herpes simplex ulcerative esophagitis in healthy children.

PubMed

Al-Hussaini, Abdulrahman A; Fagih, Mosa A

2011-01-01

Herpes simplex virus is a common cause of ulcerative esophagitis in the immunocompromised or debilitated host. Despite a high prevalence of primary and recurrent Herpes simplex virus infection in the general population, Herpes simplex virus esophagitis (HSVE) appears to be rare in the immunocompetent host. We report three cases of endoscopically-diagnosed HSVE in apparently immunocompetent children; the presentation was characterized by acute onset of fever, odynophagia, and dysphagia. In two cases, the diagnosis was confirmed histologically by identification of herpes viral inclusions and culture of the virus in the presence of inflammation. The third case was considered to have probable HSVE based on the presence of typical cold sore on his lip, typical endoscopic finding, histopathological evidence of inflammation in esophageal biopsies and positive serologic evidence of acute Herpes simplex virus infection. Two cases received an intravenous course of acyclovir and one had self-limited recovery. All three cases had normal immunological workup and excellent health on long-term follow-up.

Immune- and Nonimmune-Compartment-Specific Interferon Responses Are Critical Determinants of Herpes Simplex Virus-Induced Generalized Infections and Acute Liver Failure.

PubMed

Parker, Zachary M; Pasieka, Tracy Jo; Parker, George A; Leib, David A

2016-12-01

The interferon (IFN) response to viral pathogens is critical for host survival. In humans and mouse models, defects in IFN responses can result in lethal herpes simplex virus 1 (HSV-1) infections, usually from encephalitis. Although rare, HSV-1 can also cause fulminant hepatic failure, which is often fatal. Although herpes simplex encephalitis has been extensively studied, HSV-1 generalized infections and subsequent acute liver failure are less well understood. We previously demonstrated that IFN-αβγR -/- mice are exquisitely susceptible to liver infection following corneal infection with HSV-1. In this study, we used bone marrow chimeras of IFN-αβγR -/- (AG129) and wild-type (WT; 129SvEv) mice to probe the underlying IFN-dependent mechanisms that control HSV-1 pathogenesis. After infection, WT mice with either IFN-αβγR -/- or WT marrow exhibited comparable survival, while IFN-αβγR -/- mice with WT marrow had a significant survival advantage over their counterparts with IFN-αβγR -/- marrow. Furthermore, using bioluminescent imaging to maximize data acquisition, we showed that the transfer of IFN-competent hematopoietic cells controlled HSV-1 replication and damage in the livers of IFN-αβγR -/- mice. Consistent with this, the inability of IFN-αβγR -/- immune cells to control liver infection in IFN-αβγR -/- mice manifested as profoundly elevated aspartate transaminase (AST) and alanine transaminase (ALT) levels, indicative of severe liver damage. In contrast, IFN-αβγR -/- mice receiving WT marrow exhibited only modest elevations of AST and ALT levels. These studies indicate that IFN responsiveness of the immune system is a major determinant of viral tropism and damage during visceral HSV infections. Herpes simplex virus 1 (HSV-1) infection is an incurable viral infection with the most significant morbidity and mortality occurring in neonates and patients with compromised immune systems. Severe pathologies from HSV include the blindness-inducing herpetic stromal keratitis, highly debilitating and lethal herpes simplex encephalitis, and generalized infections that can lead to herpes simplex virus-induced acute liver failure. While immune compromise is a known factor, the precise mechanisms that lead to generalized HSV infections are unknown. In this study, we used and developed a mouse model system in combination with real-time bioluminescence imaging to demonstrate the relative importance of the immune and nonimmune compartments for containing viral spread and promoting host survival after corneal infection. Our results shed light on the pathogenesis of HSV infections that lead to generalized infection and acute liver failure. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Glycoprotein D actively induces rapid internalization of two nectin-1 isoforms during herpes simplex virus entry

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stiles, Katie M., E-mail: stileskm@mail.med.upenn.ed; Krummenacher, Claude

2010-03-30

Entry of herpes simplex virus (HSV) occurs either by fusion at the plasma membrane or by endocytosis and fusion with an endosome. Binding of glycoprotein D (gD) to a receptor such as nectin-1 is essential in both cases. We show that virion gD triggered the rapid down-regulation of nectin-1 with kinetics similar to those of virus entry. In contrast, nectin-1 was not constitutively recycled from the surface of uninfected cells. Both the nectin-1alpha and beta isoforms were internalized in response to gD despite having different cytoplasmic tails. However, deletion of the nectin-1 cytoplasmic tail slowed down-regulation of nectin-1 and internalizationmore » of virions. These data suggest that nectin-1 interaction with a cytoplasmic protein is not required for its down-regulation. Overall, this study shows that gD binding actively induces the rapid internalization of various forms of nectin-1. We suggest that HSV activates a nectin-1 internalization pathway to use for endocytic entry.« less

Laboratory diagnosis and epidemiology of herpes simplex 1 and 2 genital infections.

PubMed

Glinšek Biškup, Urška; Uršič, Tina; Petrovec, Miroslav

2015-01-01

Herpes simplex virus types 1 and 2 are the main cause of genital ulcers worldwide. Although herpes simplex virus type 2 is the major cause of genital lesions, herpes simplex virus type 1 accounts for half of new cases in developed countries. Herpes simplex virus type 2 seroprevalence rises with sexual activity from adolescence through adulthood. Slovenian data in a high-risk population shows 16% seroprevalence of HSV-2. HSV-1 and HSV-2 DNA in genital swabs was detected in 19% and 20.7%, respectively. In most cases, genital herpes is asymptomatic. Primary genital infection with herpes simplex virus types 1 and 2 can be manifested by a severe clinical picture, involving the vesicular skin and mucosal changes and ulcerative lesions of the vulva, vagina, and cervix in women and in the genital region in men. Direct methods of viral genome detection are recommended in the acute stage of primary and recurrent infections when manifest ulcers or lesions are evident. Serological testing is recommended as an aid in diagnosing genital herpes in patients with reinfection in atypical or already healed lesions. When herpes lesions are present, all sexual activities should be avoided to prevent transmission of infection. Antiviral drugs can reduce viral shedding and thus reduce the risk of sexual transmission of the virus.

T cell-macrophage interaction in arginase-mediated resistance to herpes simplex virus.

PubMed

Bonina, L; Nash, A A; Arena, A; Leung, K N; Wildy, P

1984-09-01

Peritoneal macrophages activated by-products derived from a herpes simplex virus-specific helper T cell clone were used to investigate intrinsic and extrinsic resistance mechanisms to herpes simplex virus type 1 infection in vitro. T cell-activated macrophages produced fewer infective centres, indicating enhanced intrinsic resistance, and markedly reduced the growth of virus in a permissive cell line. The reduction in virus growth correlated with the depletion of arginine in the support medium, presumably resulting from increased arginase production by activated macrophages. The significance of these findings for antiviral immunity in vivo is discussed.

Herpes Simplex Virus Selectively Induces Expression of the CC Chemokine RANTES/CCL5 in Macrophages through a Mechanism Dependent on PKR and ICP0

PubMed Central

Melchjorsen, Jesper; Pedersen, Finn S.; Mogensen, Søren C.; Paludan, Søren R.

2002-01-01

Recruitment of leukocytes is essential for eventual control of virus infections. Macrophages represent a leukocyte population involved in the first line of defense against many infections, including herpes simplex virus (HSV) infection. Through presentation of antigens to T cells and production of cytokines and chemokines, macrophages also constitute an important link between the innate and adaptive immune systems. Here, we have investigated the chemokine expression profile of macrophages after HSV infection and the virus-cell interactions involved. By reverse transcription-PCR and cDNA arrays, we found that HSV type 1 (HSV-1) and HSV-2 induced expression of the CC chemokine RANTES/CCL5 in murine macrophage cell lines and peritoneal cells. The CXC chemokine BCA-1/CXCL13 was also induced in peritoneal cells. Twenty-six other chemokines tested were not affected. Accumulation of RANTES mRNA was detectable after 5 h of infection, was sensitive to UV irradiation of the virus, and was preceded by accumulation of viral immediate-early mRNA and proteins. The viral components responsible for initiation of RANTES expression were examined with virus mutants and RAW 264.7 macrophage-like cells expressing a dominant negative mutant of the double-stranded-RNA-activated protein kinase (PKR). The PKR mutant cell line displayed reduced constitutive and HSV-inducible RANTES expression compared to the control cell line. HSV-1 mutants deficient in genes encoding the immediate-early proteins ICP4, ICP22, and ICP27 remained fully capable of inducing RANTES expression in macrophages. By contrast, the ability of an ICP0-deficient HSV-1 mutant to induce RANTES expression was compromised. Thus, HSV selectively induces expression of RANTES in macrophages through a mechanism dependent on cellular PKR and viral ICP0. PMID:11861845

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.

Gene transfer to brain using herpes simplex virus vectors.

PubMed

Glorioso, J C; Goins, W F; Meaney, C A; Fink, D J; DeLuca, N A

1994-01-01

Herpes simplex virus type 1 represents an ideal candidate for development as a vehicle for gene transfer to postmitotic neurons of the central nervous system. The natural biology of this virus makes it well suited for this purpose as it is capable of infecting a variety of neuronal cell types in the brain where the viral genome can persist indefinitely in a latent state. In latency, the viral lytic genes are transcriptionally silent and a unique set of latency-associated transcripts are expressed. Two impediments to using herpes simplex virus vectors must be overcome: (1) A noncytotoxic mutant virus backbone must be engineered, and (2) a suitable promoter-regulator that stably expresses foreign genes from the vector genome during latency must be constructed. Deletion of specific immediate early genes from the vector can render the virus nontoxic to neurons in culture and in vivo following stereotactic inoculation into specific regions of the brain. Because these viruses cannot replicate, they enter latency on infection of central nervous system neurons. A number of viral and cellular promoters have been tested for their ability to express genes during latency. Strong viral promoters and neurospecific promoters display transient activity. Although the promoter regions for the latency-associated transcripts are highly active in the peripheral nervous system, they show low-level but persistent activity in the brain. Experiments are in progress to exploit RNA polymerase III gene promoters or novel recombinant promoters capable of auto-inducing their own expression in order to increase gene expression during latency in brain neurons.

Localization of the herpes simplex virus type 1 major capsid protein VP5 to the cell nucleus requires the abundant scaffolding protein VP22a.

PubMed

Nicholson, P; Addison, C; Cross, A M; Kennard, J; Preston, V G; Rixon, F J

1994-05-01

The intracellular distributions of three herpes simplex virus type 1 (HSV-1) capsid proteins, VP23, VP5 and VP22a, were examined using vaccinia virus and plasmid expression systems. During infection of cells with HSV-1 wild-type virus, all three proteins were predominantly located in the nucleus, which is the site of capsid assembly. However, when expressed in the absence of any other HSV-1 proteins, although VP22a was found exclusively in the nucleus as expected, VP5 and VP23 were distributed throughout the cell. Thus nuclear localization is not an intrinsic property of these proteins but must be mediated by one or more HSV-1-induced proteins. Co-expression experiments demonstrated that VP5 was efficiently transported to the nucleus in the presence of VP22a, but the distribution of VP23 was unaffected by the presence of either or both of the other two proteins.

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.

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.

Induction of Suppressor of Cytokine Signaling-3 by Herpes Simplex Virus Type 1 Contributes to Inhibition of the Interferon Signaling Pathway

PubMed Central

Yokota, Shin-ichi; Yokosawa, Noriko; Okabayashi, Tamaki; Suzutani, Tatsuo; Miura, Shunsuke; Jimbow, Kowichi; Fujii, Nobuhiro

2004-01-01

We showed previously that herpes simplex virus type 1 (HSV-1) suppresses the interferon (IFN) signaling pathway during the early infection stage in the human amnion cell line FL. HSV-1 inhibits the IFN-induced phosphorylation of Janus kinases (JAK) in infected FL cells. In the present study, we showed that the suppressor of cytokine signaling-3 (SOCS3), a host negative regulator of the JAK/STAT pathway, is rapidly induced in FL cells after HSV-1 infection. Maximal levels of SOCS3 protein were detected at around 1 to 2 h after infection. This is consistent with the occurrence of HSV-1-mediated inhibition of IFN-induced JAK phosphorylation. The HSV-1 wild-type strain VR3 induced SOCS3 more efficiently than did mutants that are defective in UL41 or UL13 and that are hyperresponsive to IFN. Induction of the IRF-7 protein and transcriptional activation of IFN-α4, which occur in a JAK/STAT pathway-dependent manner, were poorly induced by VR3 but efficiently induced by the mutant viruses. In contrast, phosphorylation of IRF-3 and transcriptional activation of IFN-β, which are JAK/STAT pathway-independent process, were equally well induced by the wild-type strain and the mutants. In conclusion, the SOCS3 protein appears to be mainly responsible for the suppression of IFN signaling and IFN production that occurs during HSV-1 infection. PMID:15163721

Tranylcypromine Reduces Herpes Simplex Virus 1 Infection in Mice

PubMed Central

Yao, Hui-Wen; Lin, Pin-Hung; Shen, Fang-Hsiu; Perng, Guey-Chuen; Tung, Yuk-Ying

2014-01-01

Herpes simplex virus 1 (HSV-1) infects the majority of the human population and establishes latency by maintaining viral genomes in neurons of sensory ganglia. Latent virus can undergo reactivation to cause recurrent infection. Both primary and recurrent infections can cause devastating diseases, including encephalitis and corneal blindness. Acyclovir is used to treat patients, but virus resistance to acyclovir is frequently reported. Recent in vitro findings reveal that pretreatment of cells with tranylcypromine (TCP), a drug widely used in the clinic to treat neurological disorders, restrains HSV-1 gene transcription by inhibiting the histone-modifying enzyme lysine-specific demethylase 1. The present study was designed to examine the anti-HSV-1 efficacy of TCP in vivo because of the paucity of reports on this issue. Using the murine model, we found that TCP decreased the severity of wild-type-virus-induced encephalitis and corneal blindness, infection with the acyclovir-resistant (thymidine kinase-negative) HSV-1 mutant, and tissue viral loads. Additionally, TCP blocked in vivo viral reactivation in trigeminal ganglia. These results support the therapeutic potential of TCP for controlling HSV-1 infection. PMID:24590478

Laryngopharyngeal reflux and herpes simplex virus type 2 are possible risk factors for adult-onset recurrent respiratory papillomatosis (prospective case-control study).

PubMed

Formánek, M; Jančatová, D; Komínek, P; Matoušek, P; Zeleník, K

2017-06-01

The human papillomavirus (HPV) causes recurrent respiratory papillomatosis (RRP). Although HPV prevalence is high, the incidence of papillomatosis is low. Thus, factors other than HPV infection probably contribute to RRP. This study investigated whether patients with papillomatosis are more often infected with herpes simplex virus type 2 and chlamydia trachomatis (ChT) and whether laryngopharyngeal reflux (LPR) occurs in this group of patients more often. Prospective case-control study. Department of Otorhinolaryngology of University Hospital. The study included 20 patients with adult-onset RRP and 20 adult patients with vocal cord cyst and no pathology of laryngeal mucosa (control group). Immunohistochemical analysis of pepsin, HPV, herpes simplex virus type 2 and ChT was performed in biopsy specimens of laryngeal papillomas and of healthy laryngeal mucosa (control group) obtained from medial part of removed vocal cord cyst during microlaryngoscopy procedures. Pathologic LPR (pepsin in tissue) was diagnosed in 8/20 (40.0%) patients with papillomatosis and in 0/20 control patients (P = .003). Herpes simplex virus type 2 was present in 9/20 (45.0%) patients with papillomatosis and in 0/20 control patients (P = .001). Five specimens were positive for both pepsin and herpes simplex virus type 2. No samples were positive for ChT. There were no significant differences between groups for age, body mass index, diabetes mellitus and gastrooesophageal reflux disease. Tobacco exposure was not more frequent in RRP group either (P = .01). Results show that LPR and herpes simplex virus type 2 are significantly more often present in patients with RRP. LPR and herpes simplex virus type 2 might activate latent HPV infection and thereby be possible risk factors for RRP. © 2016 John Wiley & Sons Ltd.

Helicase-primase inhibitors for herpes simplex virus: looking to the future of non-nucleoside inhibitors for treating herpes virus infections.

PubMed

Biswas, Subhajit; Sukla, Soumi; Field, Hugh J

2014-01-01

Helicase-primase inhibitors (HPIs) are the first new family of potent herpes virus (herpes simplex and varicella-zoster virus) inhibitors to go beyond the preliminary stages of investigation since the emergence of the original nucleoside analog inhibitors. To consider the clinical future of HPIs, this review puts the exciting new findings with two HPIs, amenamevir and pritelivir, into the historical context of antiviral development for the prevention and treatment of herpes simplex virus over the last century and, on this basis, the authors speculate on the potential evolution of these and other non-nucleoside inhibitors in the future.

Herpes simplex virus type 2: Cluster of unrelated cases in an intensive care unit.

PubMed

Troché, Gilles; Marque Juillet, Stephanie; Burrel, Sonia; Boutolleau, David; Bédos, Jean-Pierre; Legriel, Stephane

2016-10-01

Herpes simplex viruses, which are associated with various clinical manifestations, can be transmitted to critically ill patients from other patients or health care staff. We report an apparent outbreak of mucocutaneous herpes simplex virus 2 infections (5 cases in 10 weeks). An epidemiologic investigation and genotype analysis showed no connections among the 5 cases. Copyright © 2016 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.

Herpes simplex encephalitis with thalamic, brainstem and cerebellar involvement.

PubMed

Garg, Meenal; Kulkarni, Shilpa; Udwadia Hegde, Anaita

2018-04-01

Herpes simplex virus encephalitis is a common and treatable cause of acute encephalitis in all age groups. Certain radiological features such as temporal parenchymal involvement facilitate the diagnosis. The use of herpes simplex virus polymerase chain reaction has expanded the clinical and imaging spectrum. We report the case of a young patient who presented with a movement disorder and predominant involvement of thalami, brainstem and cerebellum on magnetic resonance imaging, and was diagnosed with herpes simplex virus encephalitis. Differentiation from Japanese encephalitis may be difficult in these patients, especially in endemic areas, and may necessitate the use of relevant investigations in all patients.

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

Cheshenko, Natalia; Trepanier, Janie B; González, Pablo A; Eugenin, Eliseo A; Jacobs, William R; Herold, Betsy C

2014-09-01

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. 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. These epidemiological findings underscore the urgency to develop novel HSV treatment or prevention strategies. This study addresses this gap by further defining the signaling pathways the virus usurps to enter human genital tract epithelial cells. Specifically, the study defines the role played by integrins and by the viral envelope glycoprotein H in entry and cell-to-cell spread. This knowledge will facilitate the identification of new targets for the development of treatment and prevention. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Genital herpes simplex virus infections.

PubMed

Rosenthal, M S

1979-09-01

In recent years, a great increase in interest in genital herpes has been stimulated partly by the rising prevalence of this disease and partly by observations suggesting that genital herpes is a cause of cervical cancer. The clinical pictures produced by genital herpes simplex virus infections are similar in men and women. In contrast to recurrent attacks, initial episodes of infection are generally more extensive, last longer, and are more often associated with regional lymphadenopathy and systemic symptoms. Genital herpes in pregnancy may pose a serious threat to the newborn infant. Although the data suggesting genital herpes simplex virus infection is a cause of cervical cancer are quite extensive, the evidence is largely circumstantial. In spite of these more serious aspects of genital herpes simplex virus infection, episodes of genital herpes are almost always self-limited and benign. Frequent recurrences pose the major therapeutic and management problem. At present, there is no satisfactory treatment for recurrent genital herpes simplex virus in fection. Many of the suggested therapies, although some sound very promising, are potentially dangerous and should be used only under carefully controlled conditions.

Pediatric herpes simplex virus infections: an evidence-based approach to treatment.

PubMed

Sanders, Jennifer E; Garcia, Sylvia E

2014-01-01

Herpes simplex virus is a common virus that causes a variety of clinical presentations ranging from mild to life-threatening. Orolabial and genital herpes are common disorders that can often be managed in an outpatient setting; however, some patients do present to the emergency department with those conditions, and emergency clinicians should be aware of possible complications in the pediatric population. Neonatal herpes is a rare disorder, but prompt recognition and initiation of antiviral therapy is imperative, as the morbidity and mortality of the disease is high. Herpes encephalitis is an emergency that also requires a high index of suspicion to diagnose. Herpes simplex virus is also responsible for a variety of other clinical presentations, including herpes gladiatorum, herpetic whitlow, eczema herpeticum, and ocular herpes. This issue reviews the common clinical presentations of the herpes simplex virus, the life-threatening infections that require expedient identification and management, and recommended treatment regimens.

Amplification of Herpes Simplex Virus Types 1 and 2 and Human Herpes Virus Type 5 Polymerase Gene Segment From Formalin-Fixed Brain Tissue From Alzheimer’s Disease Patients

DTIC Science & Technology

2005-08-01

The neuronal nitric oxide synthase (NOS1) gene target was amplified and sequenced in all samples tested, in addition to HSV1 , HSV2 , or Human Herpes...Triphosphate DNA Deoxyribonucleic acid GAPDH Glyceraldehyde-3 -phosphate dehydrogenase HSV Herpes Simplex Virus HSV1 Herpes Simplex Virus Type 1 HSV2 Herpes... HSV2 ) share 50-70 % homology. HSV1 is primarily associated with oral and ocular lesions, while HSV2 is primarily associated with genital and anal lesions

Preparation of herpes simplex virus-infected primary neurons for transmission electron microscopy.

PubMed

Miranda-Saksena, Monica; Boadle, Ross; Cunningham, Anthony L

2014-01-01

Transmission electron microscopy (TEM) provides the resolution necessary to identify both viruses and subcellular components of cells infected with many types of viruses, including herpes simplex virus. Recognized as a powerful tool in both diagnostic and research-based virology laboratories, TEM has made possible the identification of new viruses and has contributed to the elucidation of virus life cycle and virus-host cell interaction. Whilst there are many sample preparation techniques for TEM, conventional processing using chemical fixation and resin embedding remains a useful technique, available in virtually all EM laboratories, for studying virus/cell ultrastructure. In this chapter, we describe the preparation of herpes simplex virus-infected primary neurons, grown on plastic cover slips, to allow sectioning of neurons and axons in their growth plane. This technique allows TEM examination of cell bodies, axons, growth cones, and varicosities, providing powerful insights into virus-cell interaction.

Disabled infectious single cycle-herpes simplex virus (DISC-HSV) as a vector for immunogene therapy of cancer.

PubMed

Rees, Robert C; McArdle, Stephanie; Mian, Shahid; Li, Geng; Ahmad, Murrium; Parkinson, Richard; Ali, Selman A

2002-02-01

Disabled infectious single cycle-herpes simplex viruses (DISC-HSV) have been shown to be safe for use in humans and may be considered efficacious as vectors for immunogene therapy in cancer. Preclinical studies show that DISC-HSV is an efficient delivery system for cytokine genes and antigens. DISC-HSV infects a high proportion of cells, resulting in rapid gene expression for at least 72 h. The DISC-HSV-mGM-CSF vector, when inoculated into tumors, induces tumor regression in a high percentage of animals, concomitant with establishing a cytotoxic T-cell response, which is MHC class I restricted and directed against peptides of known tumor antigens. The inherent properties of DISC-HSV makes it a suitable vector for consideration in human immunogene therapy trials.

[Inactivated herpes simplex virus types 1 and 2 divaccine as an agent for effective immunoprophylaxis of recurrent genital herpes].

PubMed

Barinskiĭ, I F; Makhmudov, F R

2010-01-01

Prevention of recurrent genital herpes with the inactivated herpetic divaccine Vitaherpavac against herpes simplex virus types 1 and 2 has a number of advantages over the most commonly used symptomatic therapy: it ceases or significantly reduces the number of recurrences and accordingly prolongs a relapse-free interval, abolishes viremia and the manifestations of clinical symptoms of recurrences, induces no dependence to the vaccine. Coadministration of the Vitaherpavac vaccine and the immunomodulator Giaferon has been shown to have some advantage over vaccination only. The new formulation of the agent as suppositories (per rectum) not only enhances the immunogenicity and protective properties of the vaccine, but also reduces the frequency of its application and makes more convenient for patients to use.

Deoxypyrimidine kinases of herpes simplex viruses types 1 and 2: comparison of serological and structural properties.

PubMed

Thouless, M E; Wildy, P

1975-02-01

The kinetics of formation, the stability at 40 degrees C and the serological properties of thymidine kinase and deoxycytidine kinase activities induced by herpes simplex virus have been examined. The results are consistent with the hypothesis that both activities are carried on the same molecule-a deoxypyrimidine kinase. Mutants deficient in deoxypyrimidine kinase have been used to produce, by absorption of general antisera, deoxypyrimidine kinase-specific antisera. Using immunoprecipitation and SDS-polyacrylamide gel electrophoresis, only one size of polypeptide (mol. wt. 42400 plus or minus 200) has been found, constituting the type 2 enzyme. This is close to published values for the type i enzyme but co-electrophoresis demonstrated that the polypeptide of the type i enzyme was slightly bigger.

Imbalanced Oxidative Stress Causes Chlamydial Persistence during Non-Productive Human Herpes Virus Co-Infection

PubMed Central

Prusty, Bhupesh K.; Böhme, Linda; Bergmann, Birgit; Siegl, Christine; Krause, Eva; Mehlitz, Adrian; Rudel, Thomas

2012-01-01

Both human herpes viruses and Chlamydia are highly prevalent in the human population and are detected together in different human disorders. Here, we demonstrate that co-infection with human herpes virus 6 (HHV6) interferes with the developmental cycle of C. trachomatis and induces persistence. Induction of chlamydial persistence by HHV6 is independent of productive virus infection, but requires the interaction and uptake of the virus by the host cell. On the other hand, viral uptake is strongly promoted under co-infection conditions. Host cell glutathione reductase activity was suppressed by HHV6 causing NADPH accumulation, decreased formation of reduced glutathione and increased oxidative stress. Prevention of oxidative stress restored infectivity of Chlamydia after HHV6-induced persistence. We show that co-infection with Herpes simplex virus 1 or human Cytomegalovirus also induces chlamydial persistence by a similar mechanism suggesting that Chlamydia -human herpes virus co-infections are evolutionary shaped interactions with a thus far unrecognized broad significance. PMID:23077614

Herpes Simplex Encephalitis during Treatment with Tumor Necrosis Factor-α Inhibitors

PubMed Central

Bradford, Russell D.; Pettit, April C.; Wright, Patty W.; Mulligan, Mark J.; Moreland, Larry W.; McLain, David A.; Gnann, John W.; Bloch, Karen C.

2012-01-01

We report 3 cases of herpes simplex virus encephalitis in patients receiving tumor necrosis factor-alpha (TNF-α) inhibitors for rheumatologic disorders. Although TNF-α inhibitors have been reported to increase the risk of other infectious diseases, to our knowledge, an association between anti–TNF-α drugs and herpes simplex virus encephalitis has not been previously described. PMID:19681709

Herpes simplex virus type 2 (Mollaret's) meningitis: a case report.

PubMed

Abu Khattab, Mohammed; Al Soub, Hussam; Al Maslamani, Mona; Al Khuwaiter, Jameela; El Deeb, Yasser

2009-11-01

Mollaret's meningitis is an unusual and under-appreciated syndrome of benign, recurrent aseptic meningitis. The available literature indicates that the causative agent is herpes simplex virus type 2 (HSV-2) in the majority of cases and much less frequently herpes simplex virus type 1 (HSV-1). We report the case of a 49-year-old Indian female who had four attacks of recurrent lymphocytic meningitis (Mollaret's meningitis) occurring over a 7-year period. The diagnosis of herpes simplex meningitis was made at the time of the fourth episode by a positive PCR for herpes simplex virus infection in the cerebrospinal fluid. During the first three episodes, the patient was treated with anti-tuberculous drugs and antibiotics for bacterial meningitis; however for the last episode, once the diagnosis of herpes simplex meningitis was confirmed, only symptomatic treatment was given. No long-term suppressive therapy was given and no recurrence has been experienced so far. Mollaret's meningitis should be suspected in all cases of recurrent lymphocytic meningitis. Early diagnosis may prevent prolonged hospital admissions, unnecessary investigations, and exposure to unnecessary medications, with the associated considerable costs. Treatment with acyclovir may be beneficial in decreasing the severity and duration of attacks and in preventing further episodes. [Au?1].

[The Spanish Society of Paediatric Infectious Diseases guidelines on the prevention, diagnosis and treatment of neonatal herpes simplex infections].

PubMed

2018-02-13

Neonatal herpes simplex virus infections are rare, but are associated with significant morbidity and mortality. Most newborns acquire herpes simplex virus infection in the peripartum period. For peripartum transmission to occur, women must be shedding the virus in their genital tracts symptomatically or asymptomatically around the time of delivery. There are evidence-based interventions in pregnancy to prevent the transmission to the newborn. Caesarean section should be performed in the presence of herpetic lesions, and antiviral prophylaxis in the last weeks of pregnancy is recommended to suppress genital tract herpes simplex virus at the time of delivery. The diagnosis and early treatment of neonatal herpes simplex virus infections require a high index of suspicion, especially in the absence of skin lesions. It is recommended to rule out herpes simplex virus infections in those newborns with mucocutaneous lesions, central nervous system involvement, or septic appearance. The prognosis of newborns with skin, eye, and/or mouth disease in the high-dose acyclovir era is very good. Antiviral treatment not only improves mortality rates in disseminated and central nervous system disease, but also improves the rates of long-term neurodevelopmental impairment in the cases of disseminated disease. Interestingly, a 6-month suppressive course of oral acyclovir following the acute infection has improved the neurodevelopmental prognosis in patients with CNS involvement. Copyright © 2017 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

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)

Herpes simplex type 1 pneumonitis and acute respiratory distress syndrome in a patient with chronic lymphatic leukemia: a case report.

PubMed

Luginbuehl, Miriam; Imhof, Alexander; Klarer, Alexander

2017-11-23

Pulmonary pathogenicity of herpes simplex virus type 1 in patients in intensive care without classic immunosuppression as well as the necessity of antiviral treatment in the case of herpes simplex virus detection in respiratory specimens in these patients is controversial. We present a case of acute respiratory distress syndrome in a patient with stable chronic lymphatic leukemia not requiring treatment, in whom we diagnosed herpes simplex virus type 1 bronchopneumonitis based on herpes simplex virus type 1 detection in bronchoalveolar lavage fluid and clinical response to antiviral treatment. A 72-year-old white man presented with symptoms of lower respiratory tract infection. His medical history was significant for chronic lymphatic leukemia, which had been stable without treatment, arterial hypertension, multiple squamous cell carcinomas of the scalp, and alcohol overuse. Community-acquired pneumonia was suspected and appropriate broad-spectrum antibacterial treatment was initiated. Within a few hours, rapid respiratory deterioration led to cardiac arrest. He was successfully resuscitated, but developed acute respiratory distress syndrome. Furthermore, he remained febrile and inflammation markers remained elevated despite antibacterial treatment. Polymerase chain reaction from bronchoalveolar lavage fluid and viral culture from tracheobronchial secretions tested positive for herpes simplex virus type 1. We initiated antiviral treatment with acyclovir. Concomitantly we further escalated the antibacterial treatment, although no bacterial pathogen had been isolated at any point. Defervescence occurred rapidly and his C-reactive protein and leukocyte levels decreased. He was successfully weaned from mechanical ventilation, transferred to the ward, and eventually discharged to home. Herpes simplex virus should be considered a cause for lower respiratory tract infection in critically ill patients, especially in the setting of an underlying disease.

The Characteristics of Herpes Simplex Virus Type 1 Infection in Rhesus Macaques and the Associated Pathological Features.

PubMed

Fan, Shengtao; Cai, Hongzhi; Xu, Xingli; Feng, Min; Wang, Lichun; Liao, Yun; Zhang, Ying; He, Zhanlong; Yang, Fengmei; Yu, Wenhai; Wang, Jingjing; Zhou, Jumin; Li, Qihan

2017-01-30

As one of the major pathogens for human herpetic diseases, herpes simplex virus type 1 (HSV1) causes herpes labialis, genital herpes and herpetic encephalitis. Our aim here was to investigate the infectious process of HSV1 in rhesus macaques and the pathological features induced during this infection. Clinical symptoms that manifested in the rhesus macaque during HSV1 infection included vesicular lesions and their pathological features. Viral distribution in the nervous tissues and associated pathologic changes indicated the typical systematic pathological processes associated with viral distribution of HSV1.Interestingly, vesicular lesions recurred in oral skin or in mucosa associated with virus shedding in macaques within four to five months post-infection,and viral latency-associated transcript (LAT) mRNA was found in the trigeminal ganglia (TG)on day 365 post-infection. Neutralization testing and enzyme-linked immunospot (ELISpot) detection of specific T cell responses confirmed the specific immunity induced by HSV1 infection. Thus, rhesus macaques could serve as an infectious model for HSV1 due to their typical clinical symptoms and the pathological recurrence associated with viral latency in nervous tissues.

Amino-terminal sequence of glycoprotein D of herpes simplex virus types 1 and 2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Eisenberg, R.J.; Long, D.; Hogue-Angeletti, R.

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.more » 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.« less

Identification of rep-associated factors in herpes simplex virus type 1-induced adeno-associated virus type 2 replication compartments.

PubMed

Nicolas, Armel; Alazard-Dany, Nathalie; Biollay, Coline; Arata, Loredana; Jolinon, Nelly; Kuhn, Lauriane; Ferro, Myriam; Weller, Sandra K; Epstein, Alberto L; Salvetti, Anna; Greco, Anna

2010-09-01

Adeno-associated virus (AAV) is a human parvovirus that replicates only in cells coinfected with a helper virus, such as adenovirus or herpes simplex virus type 1 (HSV-1). We previously showed that nine HSV-1 factors are able to support AAV rep gene expression and genome replication. To elucidate the strategy of AAV replication in the presence of HSV-1, we undertook a proteomic analysis of cellular and HSV-1 factors associated with Rep proteins and thus potentially recruited within AAV replication compartments (AAV RCs). This study resulted in the identification of approximately 60 cellular proteins, among which factors involved in DNA and RNA metabolism represented the largest functional categories. Validation analyses indicated that the cellular DNA replication enzymes RPA, RFC, and PCNA were recruited within HSV-1-induced AAV RCs. Polymerase delta was not identified but subsequently was shown to colocalize with Rep within AAV RCs even in the presence of the HSV-1 polymerase complex. In addition, we found that AAV replication is associated with the recruitment of components of the Mre11/Rad50/Nbs1 complex, Ku70 and -86, and the mismatch repair proteins MSH2, -3, and -6. Finally, several HSV-1 factors were also found to be associated with Rep, including UL12. We demonstrated for the first time that this protein plays a role during AAV replication by enhancing the resolution of AAV replicative forms and AAV particle production. Altogether, these analyses provide the basis to understand how AAV adapts its replication strategy to the nuclear environment induced by the helper virus.

MYC-induced reprogramming of glutamine catabolism supports optimal virus replication

PubMed Central

Thai, Minh; Thaker, Shivani K.; Feng, Jun; Du, Yushen; Hu, Hailiang; Ting Wu, Ting; Graeber, Thomas G.; Braas, Daniel; Christofk, Heather R.

2015-01-01

Viruses rewire host cell glucose and glutamine metabolism to meet the bioenergetic and biosynthetic demands of viral propagation. However, the mechanism by which viruses reprogram glutamine metabolism and the metabolic fate of glutamine during adenovirus infection have remained elusive. Here, we show MYC activation is necessary for adenovirus-induced upregulation of host cell glutamine utilization and increased expression of glutamine transporters and glutamine catabolism enzymes. Adenovirus-induced MYC activation promotes increased glutamine uptake, increased use of glutamine in reductive carboxylation and increased use of glutamine in generating hexosamine pathway intermediates and specific amino acids. We identify glutaminase (GLS) as a critical enzyme for optimal adenovirus replication and demonstrate that GLS inhibition decreases replication of adenovirus, herpes simplex virus 1 and influenza A in cultured primary cells. Our findings show that adenovirus-induced reprogramming of glutamine metabolism through MYC activation promotes optimal progeny virion generation, and suggest that GLS inhibitors may be useful therapeutically to reduce replication of diverse viruses. PMID:26561297

The biology of herpes simplex virus infection in humans.

PubMed

Baringer, J R

1976-01-01

Herpes simplex virus is a frequent cause of recurrent ocular, oral, genital or cutaneous eruptions in man. Lesions are highly localized and tend to recur at the same site. Among the most consistent factors provoking recurrence is root section of the trigeminal nerve. Clinical and experimental data suggest that herpes simplex virus is commonly resident within the trigeminal ganglia of man, where it may be responsible for recurrent oral or lip lesions, and is less frequently a resident of the second or third sacral ganglia where it might be responsible for genital eruptions. Generally, the trigeminal virus is type 1 and the sacral virus is type 2; the virus is only rarely recoverable from other sensory ganglia. Factors provoking the reactivation from the virus' latent site and the mechanism for reactivation remain largely unknown. Further study is needed to understand the behavior of HSV and other viruses in nervous system tissue.

Cerebrospinal fluid cyto-/chemokine profile during acute herpes simplex virus induced anti-N-methyl-d-aspartate receptor encephalitis and in chronic neurological sequelae.

PubMed

Kothur, Kavitha; Gill, Deepak; Wong, Melanie; Mohammad, Shekeeb S; Bandodkar, Sushil; Arbunckle, Susan; Wienholt, Louise; Dale, Russell C

2017-08-01

To examine the cytokine/chemokine profile of cerebrospinal fluid (CSF) during acute herpes simplex virus-induced N-methyl-d-aspartate receptor (NMDAR) autoimmunity and in chronic/relapsing post-herpes simplex virus encephalitis (HSE) neurological syndromes. We measured longitudinal serial CSF cyto-/chemokines (n=34) and a glial marker (calcium-binding astroglial protein, S100B) in one patient during acute HSE and subsequent anti-NMDAR encephalitis, and compared the results with those from two patients with anti-NMDAR encephalitis without preceding HSE. We also compared cyto-/chemokines in cross-sectional CSF samples from three children with previous HSE who had ongoing chronic or relapsing neurological symptoms (2yr 9 mo-16y after HSE) with those in a group of children having non-inflammatory neurological conditions (n=20). Acute HSE showed elevation of a broad range of all T-helper-subset-related cyto-/chemokines and S100B whereas the post-HSE anti-NMDAR encephalitis phase showed persistent elevation of two of five T-helper-1 (chemokine [C-X-C motif] ligand 9 [CXCL9], CXCL10), three of five predominantly B-cell (CXCL13, CCL19, a proliferation-inducing ligand [APRIL])-mediated cyto-/chemokines, and interferon-α. The post-HSE anti-NMDAR encephalitis inflammatory response was more pronounced than anti-NMDAR encephalitis. All three chronic post-HSE cases showed persistent elevation of CXCL9, CXCL10, and interferon-α, and there was histopathological evidence of chronic lymphocytic inflammation in one biopsied case 7 years after HSE. Two of three chronic cases showed a modest response to immune therapy. HSE-induced anti-NMDAR encephalitis is a complex and pronounced inflammatory syndrome. There is persistent CSF upregulation of cyto-/chemokines in chronic or relapsing post-HSE neurological symptoms, which may be modifiable with immune therapy. The elevated cyto-/chemokines may be targets of monoclonal therapies. © 2017 Mac Keith Press.

Mutagenic analysis of herpes simplex virus type 1 glycoprotein L reveals the importance of an arginine-rich region for function

DOE Office of Scientific and Technical Information (OSTI.GOV)

Klyachkin, Yuri M.; Geraghty, Robert J.

2008-04-25

Herpes simplex virus type 1 (HSV-1) glycoproteins H and L (gH and gL) are required for virus-induced membrane fusion. Expression of gH at the virion or infected cell surface is mediated by the chaperone-like activity of gL. We have previously shown that a region between amino acids 155 and 161 is critical for gL chaperone-like activity. Here, we conducted Ala substitution mutagenesis of residues in this region and found that substitution of Cys160, Arg156, Arg158, or Arg156/158/159 with Ala resulted in a gL mutant that bound gH but displayed a reduced ability in gH trafficking and membrane fusion. Substitution ofmore » Arg156 with another positively charged amino acid, Lys, restored function. Substitution of Arg158 with Lys restored function in gH trafficking and cell fusion but not virus entry. These results indicate that an arginine-rich region of gL is critical for function.« less

Herpes simplex virus triggers activation of calcium-signaling pathways

PubMed Central

Cheshenko, Natalia; Del Rosario, Brian; Woda, Craig; Marcellino, Daniel; Satlin, Lisa M.; Herold, Betsy C.

2003-01-01

The cellular pathways required for herpes simplex virus (HSV) invasion have not been defined. To test the hypothesis that HSV entry triggers activation of Ca2+-signaling pathways, the effects on intracellular calcium concentration ([Ca2+]i) after exposure of cells to HSV were examined. Exposure to virus results in a rapid and transient increase in [Ca2+]i. Pretreatment of cells with pharmacological agents that block release of inositol 1,4,5-triphosphate (IP3)–sensitive endoplasmic reticulum stores abrogates the response. Moreover, treatment of cells with these pharmacological agents inhibits HSV infection and prevents focal adhesion kinase (FAK) phosphorylation, which occurs within 5 min after viral infection. Viruses deleted in glycoprotein L or glycoprotein D, which bind but do not penetrate, fail to induce a [Ca2+]i response or trigger FAK phosphorylation. Together, these results support a model for HSV infection that requires activation of IP3-responsive Ca2+-signaling pathways and that is associated with FAK phosphorylation. Defining the pathway of viral invasion may lead to new targets for anti-viral therapy. PMID:14568989

Mersalyl: a Diuretic with Antiviral Properties

PubMed Central

Kramer, M. J.; Cleeland, R.; Grunberg, E.

1975-01-01

Mersalyl (Salyrgan), an organic mercurial diuretic, was tested against human and animal viruses with in vivo model infections in mice and tissue culture systems. Mersalyl was active against coxsackieviruses A21 and B1 in mice if administered intraperitoneally immediately after infection. No effect was observed if intraperitoneal treatment was delayed 1 or 2 h postinfection, or if treatment was administered either subcutaneously or per os. Topical treatment with a 5% aqueous solution of mersalyl produced a statistically significant effect against herpes simplex dermatitis in mice but the substance was inactive against systemic infections in mice with herpes simplex as well as Columbia SK, influenza, Semliki Forest, and Sendai viruses. Contact inactivation of coxsackieviruses A21 and B1 and herpes simplex virus was observed, but mersalyl was inactive in tissue culture against coxackieviruses A21 and B1, herpes simplex, influenza, rhinovirus, Semliki Forest, Sendai, and vaccinia viruses. PMID:810082

A 9 year-old girl with herpes simplex virus type 2 acute retinal necrosis treated with intravitreal foscarnet.

PubMed

King, John; Chung, Mina; DiLoreto, David A

2007-01-01

A 9-year-old girl presented with a 2-week history of redness in the left eye. Examination revealed vitritis, retinal whitening, vasculitis, and optic nerve head edema. Polymerase chain reaction testing of the aqueous fluid revealed herpes simplex virus type 2. The retinitis was controlled with intravenous acyclovir and intravitreal foscarnet. The clinical course was complicated by retinal neovascularization and vitreous hemorrhage, which was treated by pars plana vitrectomy and endolaser. While there are few case reports of herpes simplex virus type 2 retinitis in children, this one is unique for the following reasons: it is the first reported case of herpes simplex virus type 2 retinitis in a child less than 10 years old without a previous history of neonatal infection or central nervous system involvement; no other children have been reported to have been treated with intravitreal foscarnet; and retinal neovascularization complicated the recovery.

Selection and Characterization of Drug-Resistant Variants of Human Immunodeficiency Virus (AIDS).

DTIC Science & Technology

1995-10-01

on Antiviral Reserach, Santa Fe, New Mexico , 1995. Page 18 APPENDIX Page 19 p - FACTFILE Mutations in HIV-1 Reverse Transcriptase and Protease...including herpes simplex viruses, varicella -zoster Resistance of clinical HIV-1 isolates to foscarnet has not virus, cytomegalovirus (CMV), hepatitis B...This effect of the Tyr-208 substitution was not ob- reported previously for herpes simplex viruses, varicella -zoster served in MT-2 cells, however. virus

The molecular basis of herpes simplex virus latency

PubMed Central

Nicoll, Michael P; Proença, João T; Efstathiou, Stacey

2012-01-01

Herpes simplex virus type 1 is a neurotropic herpesvirus that establishes latency within sensory neurones. Following primary infection, the virus replicates productively within mucosal epithelial cells and enters sensory neurones via nerve termini. The virus is then transported to neuronal cell bodies where latency can be established. Periodically, the virus can reactivate to resume its normal lytic cycle gene expression programme and result in the generation of new virus progeny that are transported axonally back to the periphery. The ability to establish lifelong latency within the host and to periodically reactivate to facilitate dissemination is central to the survival strategy of this virus. Although incompletely understood, this review will focus on the mechanisms involved in the regulation of latency that centre on the functions of the virus-encoded latency-associated transcripts (LATs), epigenetic regulation of the latent virus genome and the molecular events that precipitate reactivation. This review considers current knowledge and hypotheses relating to the mechanisms involved in the establishment, maintenance and reactivation herpes simplex virus latency. PMID:22150699

The requirements for herpes simplex virus type 1 cell-cell spread via nectin-1 parallel those for virus entry.

PubMed

Even, Deborah L; Henley, Allison M; Geraghty, Robert J

2006-08-01

Herpes simplex virus type 1 (HSV-1) spreads from an infected cell to an uninfected cell by virus entry, virus-induced cell fusion, and cell-cell spread. The three forms of virus spread require the viral proteins gB, gD, and gH-gL, as well as a cellular gD receptor. The mutual requirement for the fusion glycoproteins and gD receptor suggests that virus entry, cell fusion, and cell-cell spread occur by a similar mechanism. The goals of this study were to examine the role of the nectin-1alpha transmembrane domain and cytoplasmic tail in cell-cell spread and to obtain a better understanding of the receptor-dependent events occurring at the plasma membrane during cell-cell spread. We determined that an intact nectin-1alpha V-like domain was required for cell-cell spread, while a membrane-spanning domain and cytoplasmic tail were not. Chimeric forms of nectin-1 that were non-functional for virus entry did not mediate cell-cell spread regardless of whether they could mediate cell fusion. Also, cell-cell spread of syncytial isolates was dependent upon nectin-1alpha expression and occurred through a nectin-1-dependent mechanism. Taken together, our results indicate that nectin-1-dependent events occurring at the plasma membrane during cell-cell spread were equivalent to those for virus entry.

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).

Viral unmasking of cellular 5S rRNA pseudogene transcripts induces RIG-I-mediated immunity.

PubMed

Chiang, Jessica J; Sparrer, Konstantin M J; van Gent, Michiel; Lässig, Charlotte; Huang, Teng; Osterrieder, Nikolaus; Hopfner, Karl-Peter; Gack, Michaela U

2018-01-01

The sensor RIG-I detects double-stranded RNA derived from RNA viruses. Although RIG-I is also known to have a role in the antiviral response to DNA viruses, physiological RNA species recognized by RIG-I during infection with a DNA virus are largely unknown. Using next-generation RNA sequencing (RNAseq), we found that host-derived RNAs, most prominently 5S ribosomal RNA pseudogene 141 (RNA5SP141), bound to RIG-I during infection with herpes simplex virus 1 (HSV-1). Infection with HSV-1 induced relocalization of RNA5SP141 from the nucleus to the cytoplasm, and virus-induced shutoff of host protein synthesis downregulated the abundance of RNA5SP141-interacting proteins, which allowed RNA5SP141 to bind RIG-I and induce the expression of type I interferons. Silencing of RNA5SP141 strongly dampened the antiviral response to HSV-1 and the related virus Epstein-Barr virus (EBV), as well as influenza A virus (IAV). Our findings reveal that antiviral immunity can be triggered by host RNAs that are unshielded following depletion of their respective binding proteins by the virus.

Molecular Basis of Latency in Pathogenic Human Viruses

NASA Astrophysics Data System (ADS)

Garcia-Blanco, Mariano A.; Cullen, Bryan R.

1991-11-01

Several human viruses are able to latently infect specific target cell populations in vivo. Analysis of the replication cycles of herpes simplex virus, Epstein-Barr virus, and human immunodeficiency virus suggests that the latent infections established by these human pathogens primarily result from a lack of host factors critical for the expression of viral early gene products. The subsequent activation of specific cellular transcription factors in response to extracellular stimuli can induce the expression of these viral regulatory proteins and lead to a burst of lytic viral replication. Latency in these eukaryotic viruses therefore contrasts with latency in bacteriophage, which is maintained primarily by the expression of virally encoded repressors of lytic replication.

Dendritic cells in the cornea during Herpes simplex viral infection and inflammation.

PubMed

Kwon, Min S; Carnt, Nicole A; Truong, Naomi R; Pattamatta, Ushasree; White, Andrew J; Samarawickrama, Chameen; Cunningham, Anthony L

Herpes simplex keratitis is commonly caused by Herpes simplex virus type 1, which primarily infects eyelids, corneas, or conjunctiva. Herpes simplex virus type 1-through sophisticated interactions with dendritic cells (DCs), a type of antigen-presenting cell)-initiates proinflammatory responses in the cornea. Corneas were once thought to be an immune-privileged region; however, with the recent discovery of DCs that reside in the cornea, this long-held conjecture has been overturned. Therefore, evaluating the clinical, preclinical, and cell-based studies that investigate the roles of DCs in corneas infected with Herpes simplex virus is critical. With in vivo confocal microscopy, animal models, and cell culture experiments, we may further the understanding of the sophisticated interactions of Herpes simplex virus with DCs in the cornea and the molecular mechanism associated with it. It has been shown that specific differentiation of DCs using immunohistochemistry, flow cytometry, and polymerase chain reaction analysis in both human and mice tissues and viral tissue infections are integral to increasing understanding. As for in vivo confocal microscopy, it holds promise as it is the least invasive and a real-time investigation. These tools will facilitate the discovery of various targets to develop new treatments. Copyright © 2017 Elsevier Inc. All rights reserved.

IL-12 Expressing oncolytic herpes simplex virus promotes anti-tumor activity and immunologic control of metastatic ovarian cancer in mice.

PubMed

Thomas, Eric D; Meza-Perez, Selene; Bevis, Kerri S; Randall, Troy D; Gillespie, G Yancey; Langford, Catherine; Alvarez, Ronald D

2016-10-27

Despite advances in surgical aggressiveness and conventional chemotherapy, ovarian cancer remains the most lethal cause of gynecologic cancer mortality; consequently there is a need for new therapeutic agents and innovative treatment paradigms for the treatment of ovarian cancer. Several studies have demonstrated that ovarian cancer is an immunogenic disease and immunotherapy represents a promising and novel approach that has not been completely evaluated in ovarian cancer. Our objective was to evaluate the anti-tumor activity of an oncolytic herpes simplex virus "armed" with murine interleukin-12 and its ability to elicit tumor-specific immune responses. We evaluated the ability of interleukin-12-expressing and control oncolytic herpes simplex virus to kill murine and human ovarian cancer cell lines in vitro. We also administered interleukin-12-expressing oncolytic herpes simplex virus to the peritoneal cavity of mice that had developed spontaneous, metastatic ovarian cancer and determined overall survival and tumor burden at 95 days. We used flow cytometry to quantify the tumor antigen-specific CD8 + T cell response in the omentum and peritoneal cavity. All ovarian cancer cell lines demonstrated susceptibility to oncolytic herpes simplex virus in vitro. Compared to controls, mice treated with interleukin-12-expressing oncolytic herpes simplex virus demonstrated a more robust tumor antigen-specific CD8 + T-cell immune response in the omentum (471.6 cells vs 33.1 cells; p = 0.02) and peritoneal cavity (962.3 cells vs 179.5 cells; p = 0.05). Compared to controls, mice treated with interleukin-12-expressing oncolytic herpes simplex virus were more likely to control ovarian cancer metastases (81.2 % vs 18.2 %; p = 0.008) and had a significantly longer overall survival (p = 0.02). Finally, five of 6 mice treated with interleukin-12-expressing oHSV had no evidence of metastatic tumor when euthanized at 6 months, compared to two of 4 mice treated with sterile phosphate buffer solution. Our pilot study demonstrates that an interleukin-12-expressing oncolytic herpes simplex virus effectively kills both murine and human ovarian cancer cell lines and promotes tumor antigen-specific CD8 + T-cell responses in the peritoneal cavity and omentum, leading to reduced peritoneal metastasis and improved survival in a mouse model.

In vitro stimulation of rabbit T lymphocytes by cells expressing herpes simplex antigens.

PubMed

Kapoor, A K; Ling, N R; Nash, A A; Bachan, A; Wildy, P

1982-04-01

Lymphocyte stimulation responses to herpes antigens were studied using virus-infected X-irradiated cells. Rabbits were immunized with herpes simplex virus type 1 (strain HFEM) grown in RK 13 cells. For in vitro stimulation assay BHK21 cells were X-irradiated (15 000 rad) and infected with a high m.o.i. of a temperature-sensitive (ts) mutant (N102) of HFEM strain at the non-permissive temperature (38.5 degrees C) of virus. Virus antigens were expressed on the infected cells and there was no leakage of infectious virus into the medium at 38.5 degrees C. T lymphocytes from rabbits immunized with herpes simplex virus were specifically activated by herpesvirus-infected X-irradiated cells; lymph node cells from rabbits immunized with RK13 cells and from non-immune rabbits showed no proliferative response.

Virus specific antigens in mammalian cells infected with herpes simplex virus

PubMed Central

Watson, D. H.; Shedden, W. I. H.; Elliot, A.; Tetsuka, T.; Wildy, P.; Bourgaux-Ramoisy, D.; Gold, E.

1966-01-01

Antisera to specific proteins in herpes simplex infected cells were produced by immunization of rabbits with infected rabbit kidney cells. These antisera were highly virus specific and produced up to twelve lines in immunodiffusion tests against infected cell extracts. Acrylamide electrophoresis and immunoelectrophoresis revealed up to ten virus specific proteins of varying size. ImagesFIG. 1FIG. 2FIG. 3FIG. 4FIG. 5 PMID:4288648

Amplification of bovine papillomavirus DNA by N-methyl-N'-nitro-N-nitrosoguanidine, ultraviolet irradiation, or infection with herpes simplex virus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schmitt, J.; Schlehofer, J.R.; Mergener, K.

1989-09-01

Treatment with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) or irradiation with ultraviolet light (uv254 nm) induces amplification of integrated as well as episomal sequences of bovine papillomavirus (BPV) type 1 DNA in BPV-1-transformed mouse C127 cells (i.e., ID13 cells). This is shown by filter in situ hybridization and Southern blot analysis of cellular DNA. Similarly, infection of ID13 cells with herpes simplex virus (HSV) type 1 which has been shown to be mutagenic for host cell DNA leads to amplification of BPV DNA sequences. In contrast to this induction of DNA amplification by initiators, treatment of ID13 cells with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA)more » does not result in increased synthesis of BPV DNA nor does TPA treatment modulate the initiator-induced DNA amplification. Similar to other cell systems infection with adeno-associated virus (AAV) type 2 inhibits BPV-1 DNA amplification irrespective of the inducing agent. In contrast to initiator-induced DNA amplification, treatment with carcinogen (MNNG) or tumor promoters or combination of MNNG and promoter of C127 cells prior to transformation by BPV-1 does not lead to an increase in the number of transformed foci. The induction of amplification of papillomavirus DNA by initiating agents possibly represents one of the mechanisms by which the observed synergism between papillomavirus infection and initiators in tumorigenesis might occur.« less

Bcl-2 Blocks a Caspase-Dependent Pathway of Apoptosis Activated by Herpes Simplex Virus 1 Infection in HEp-2 Cells

PubMed Central

Galvan, Veronica; Brandimarti, Renato; Munger, Joshua; Roizman, Bernard

2000-01-01

Earlier reports have shown that herpes simplex virus 1 (HSV-1) mutants induce programmed cell death and that wild-type virus blocks the execution of the cell death program triggered by expression of viral genes, by the Fas and tumor necrosis factor pathways, or by nonspecific stress agents. In particular, an earlier report from this laboratory showed that the mutant virus d120 lacking the genes encoding infected cell protein 4 (ICP4), the major regulatory protein of the virus, induces a caspase-3-independent pathway of apoptosis in human SK-N-SH cells. Here we report that the pathway of apoptosis induced by the d120 mutant in human HEp-2 cells is caspase dependent. Specifically, in HEp-2 cells infected with d120, (i) a broad-range inhibitor of caspase activity, z-vad-FMK, efficiently blocked DNA fragmentation, (ii) cytochrome c was released into the cytoplasm, (iii) caspase-3 was activated inasmuch as poly(ADP-ribose) polymerase was cleaved, and (iv) chromatin condensation and fragmentation of cellular DNA were observed. In parallel studies, HEp-2 cells were transfected with a plasmid encoding human Bcl-2 and a clone (VAX-3) expressing high levels of Bcl-2 was selected. This report shows that Bcl-2 blocked all of the manifestations associated with programmed cell death caused by infection with the d120 mutant. Consistent with their resistance to programmed cell death, VAX-3 cells overproduced infected cell protein 0 (ICP0). An unexpected observation was that ICP0 encoded by the d120 mutant accumulated late in infection in small, quasi-uniform vesicle-like structures in all cell lines tested. Immunofluorescence-based colocalization studies indicated that these structures were not mitochondria or components of the endoplasmic reticulum or the late endosomal compartment. These studies affirm the conclusion that HSV can induce programmed cell death at multiple steps in the course of its replication, that the d120 mutant can induce both caspase-dependent and -independent pathways of programmed cell death, and that virus-induced stimuli of programmed cell death may differ with respect to the pathway that they activate. PMID:10644366

Biochemical transformation of mouse cells by herpes simplex virus type 2: enhancement by means of low-level photodynamic treatment.

PubMed Central

Verwoerd, D W; Rapp, F

1978-01-01

The biochemical transformation of thymidine kinase-deficient cells by UV-inactivated herpes simplex virus is enhanced by low-level photodynamic treatment of the infected cells. At the concentration of proflavine used, the virus was not inactivated and both virus and cellular DNA syntheses were only marginally inhibited. The observed enhancement of the transfer of a virus gene to the cell genome suggests a possible cocarcinogenic role for photodynamically active dyes at very low concentrations. PMID:206727

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

Mediators and mechanisms of herpes simplex virus entry into ocular cells.

PubMed

Farooq, Asim V; Valyi-Nagy, Tibor; Shukla, Deepak

2010-06-01

The entry of herpes simplex virus into cells was once thought to be a general process. It is now understood that the virus is able to use multiple mechanisms for entry and spread, including the use of receptors and co-receptors that have been determined to be cell-type specific. This is certainly true for ocular cell types, which is important as the virus may use different mechanisms to gain access to multiple anatomic structures in close proximity, leading to various ocular diseases. There are some patterns that may be utilized by the virus in the eye and elsewhere, including surfing along filopodia in moving from cell to cell. There are common themes as well as intriguing differences in the entry mechanisms of herpes simplex virus into ocular cells. We discuss these issues in the context of conjunctivitis, keratitis, acute retinal necrosis, and other ocular diseases.

Evasion of Early Antiviral Responses by Herpes Simplex Viruses

PubMed Central

Suazo, Paula A.; Ibañez, Francisco J.; Retamal-Díaz, Angello R.; Paz-Fiblas, Marysol V.; Bueno, Susan M.; Kalergis, Alexis M.; González, Pablo A.

2015-01-01

Besides overcoming physical constraints, such as extreme temperatures, reduced humidity, elevated pressure, and natural predators, human pathogens further need to overcome an arsenal of antimicrobial components evolved by the host to limit infection, replication and optimally, reinfection. Herpes simplex virus-1 (HSV-1) and herpes simplex virus-2 (HSV-2) infect humans at a high frequency and persist within the host for life by establishing latency in neurons. To gain access to these cells, herpes simplex viruses (HSVs) must replicate and block immediate host antiviral responses elicited by epithelial cells and innate immune components early after infection. During these processes, infected and noninfected neighboring cells, as well as tissue-resident and patrolling immune cells, will sense viral components and cell-associated danger signals and secrete soluble mediators. While type-I interferons aim at limiting virus spread, cytokines and chemokines will modulate resident and incoming immune cells. In this paper, we discuss recent findings relative to the early steps taking place during HSV infection and replication. Further, we discuss how HSVs evade detection by host cells and the molecular mechanisms evolved by these viruses to circumvent early antiviral mechanisms, ultimately leading to neuron infection and the establishment of latency. PMID:25918478

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yedowitz, Jamie C.; Blaho, John A.

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 5more » 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.« less

Prediction of conserved sites and domains in glycoproteins B, C and D of herpes viruses.

PubMed

Rasheed, Muhammad Asif; Ansari, Abdur Rahman; Ihsan, Awais; Navid, Muhammad Tariq; Ur-Rehman, Shahid; Raza, Sohail

2018-03-01

Glycoprotein B (gB), C (gC) and D (gD) of herpes simplex virus are implicated in virus adsorption and penetration. The gB, gC and gD are glycoproteins for different processes of virus binding and attachment to the host cells. Moreover, their expression is necessary and sufficient to induce cell fusion in the absence of other glycoproteins. Egress of herpes simplex virus (HSV) and other herpes viruses from cells involves extensive modification of cellular membranes and sequential envelopment, de-envelopment and re-envelopment steps. Viral glycoproteins are important in these processes, and frequently two or more glycoproteins can largely suffice in any step. Hence, we target the 3 important glycoproteins (B, C and D) of eight different herpes viruses of different species. These species include human (HSV1 and 2), bovine (BHV1), equine (EHV1 and 4), chicken (ILT1 and MDV2) and pig (PRV1). By applying different bioinformatics tools, we highlighted the conserved sites in these glycoproteins which might be most significant regarding attachment and infection of the viruses. Moreover the conserved domains in these glycoproteins are also highlighted. From this study, we will able to analyze the role of different viral glycoproteins of different species during herpes virus adsorption and penetration. Moreover, this study will help to construct the antivirals that target the glycoproteins of different herpes viruses. Copyright © 2018 Elsevier Ltd. All rights reserved.

In vivo Expression of Inducible Nitric Oxide Synthase in Experimentally Induced Neurologic Diseases

NASA Astrophysics Data System (ADS)

Koprowski, Hilary; Zheng, Yong Mu; Heber-Katz, Ellen; Fraser, Nigel; Rorke, Lucy; Fu, Zhen Fang; Hanlon, Cathleen; Dietzschold, Bernhard

1993-04-01

The purpose of this study was to investigate the induction of inducible nitric oxide synthase (iNOS) mRNA in the brain tissue of rats and mice under the following experimental conditions: in rats infected with borna disease virus and rabies virus, in mice infected with herpes simplex virus, and in rats after the induction of experimental allergic encephalitis. The results showed that iNOS mRNA, normally nondetectable in the brain, was present in animals after viral infection or after induction of experimental allergic encephalitis. The induction of iNOS mRNA coincided with the severity of clinical signs and in some cases with the presence of inflammatory cells in the brain. The results indicate that nitric oxide produced by cells induced by iNOS may be the toxic factor accounting for cell damage and this may open the door to approaches to the study of the pathogenesis of neurological diseases.

Chemical composition of Propolis Extract ACF® and activity against herpes simplex virus.

PubMed

Bankova, V; Galabov, A S; Antonova, D; Vilhelmova, N; Di Perri, B

2014-09-25

Propolis Extract ACF(®) (PPE) is a purified extract manufactured from propolis collected in a Canadian region rich in poplar trees, and it is the active substance of a topical ointment used against herpes labialis (cold sores or fever blisters). Aim of this study was to analyze the chemical composition of PPE in order to understand the plant origin and possible relations between compounds and antiviral activity, and to characterize the antiviral activity of the extract against herpes simplex virus in vitro. The analysis of the propolis extract samples was conducted by Gas Chromatography-Mass Spectrometry (GC-MS). The antiviral activity was tested against herpes simplex viruses type 1 and type 2 in MDBK cell cultures by treating the cells with PPE at the time of virus adsorption, and by incubating the virus with the extract before infection (virucidal assay). Results from the GC-MS analyses revealed a dual plant origin of PPE, with components derived from resins of two different species of poplar. The chemical composition appeared standardized between extract samples and was also reproduced in the sample of topical ointment. The antiviral studies showed that PPE had a pronounced virucidal effect against herpes simplex viruses type 1 and type 2, and also interfered with virus adsorption. Copyright © 2014 Elsevier GmbH. All rights reserved.

Capsaicin-induced reactivation of latent herpes simplex virus type 1 in sensory neurons in culture.

PubMed

Hunsperger, Elizabeth A; Wilcox, Christine L

2003-05-01

Herpes simplex virus type 1 (HSV-1) produces a life-long latent infection in neurons of the peripheral nervous system, primarily in the trigeminal and dorsal root ganglia. Neurons of these ganglia express high levels of the capsaicin receptor, also known as the vanilloid receptor-1 (VR-1). VR-1 is a non-selective ion channel, found on sensory neurons, that primarily fluxes Ca(2+) ions in response to various stimuli, including physiologically acidic conditions, heat greater than 45 degrees C and noxious compounds such as capsaicin. Using an in vitro neuronal model to study HSV-1 latency and reactivation, we found that agonists of the VR-1 channel - capsaicin and heat - resulted in reactivation of latent HSV-1. Capsaicin-induced reactivation of HSV-1 latently infected neurons was dose-dependent. Additionally, activation of VR-1 at its optimal temperature of 46 degrees C caused a significant increase in virus titres, which could be attenuated with the VR-1 antagonist, capsazepine. VR-1 activation that resulted in HSV-1 reactivation was calcium-dependent, since the calcium chelator BAPTA significantly reduced reactivation following treatment with caspsaicin and forskolin. Taken together, these results suggest that activation of the VR-1 channel, often associated with increases in intracellular calcium, results in HSV-1 reactivation in sensory neurons.

Herpes Simplex Virus 1 Inhibits TANK-Binding Kinase 1 through Formation of the Us11-Hsp90 Complex.

PubMed

Liu, Xing; Main, David; Ma, Yijie; He, Bin

2018-05-09

The Us11 protein of herpes simplex virus 1 (HSV-1) is an accessory factor with multiple functions. In virus-infected cells, it inhibits double-stranded RNA dependent protein kinase PKR, 2',5'-oligoadenylate synthetase, RIG-I and MDA-5. However, its precise role is incompletely defined. By screening human cDNA library, we show that the Us11 protein targets heat shock protein 90 (Hsp90), which inactivates TANK binding kinase 1 (TBK1) and antiviral immunity. When ectopically expressed, HSV-1 Us11 precludes the access of TBK1 to Hsp90 and IFN promoter activation. Consistently, upon HSV infection the Us11 protein suppresses the expression of IFN-β, RANTES, and interferon stimulated genes. This is mirrored by a blockade in the phosphorylation of interferon regulatory factor 3. Mechanistically, the Us11 protein associates with endogenous Hsp90 to disrupt the Hsp90-TBK1 complex. Furthermore, Us11 induces destabilization of TBK1 through a proteasome dependent pathway. Accordingly, Us11 expression facilitates HSV growth. Conversely, TBK1 expression restricts viral replication. These results suggest that control of TBK1 by Us11 promotes HSV-1 infection. IMPORTANCE TANK binding kinase 1 plays a key role in antiviral immunity. Although multiple factors are thought to participate in this process, the picture is obscure in herpes simplex virus infection. We demonstrate that the Us11 protein of HSV-1 forms a complex with heat shock protein 90, which inactivates TANK binding kinase 1 and IFN induction. As a result, expression of the Us11 protein promotes HSV replication. These experimental data provide a new insight into the molecular network of virus-host interactions. Copyright © 2018 American Society for Microbiology.

Association of interferon lambda-1 with herpes simplex viruses-1 and -2, Epstein-Barr virus, and human cytomegalovirus in chronic periodontitis.

PubMed

Muzammil; Jayanthi, D; Faizuddin, Mohamed; Noor Ahamadi, H M

2017-05-01

Periodontal tissues facilitate the homing of herpes viruses that elicit the immune-inflammatory response releasing the interferons (IFN). IFN lambda-1 (λ1) can suppress the replication of viruses, and induces the antiviral mechanism. The aim of the present study was to evaluate the association between IFN-λ1 and periodontal herpes viruses in the immunoregulation of chronic periodontal disease. The cross-sectional study design included 30 chronic periodontitis patients with a mean age of 42.30 ± 8.63 years. Gingival crevicular fluid collected was assessed for IFN-λ1 using enzyme-linked immunosorbent assay and four herpes viruses were detected using multiplex polymerase chain reaction technique. IFN-λ1 levels were compared between virus-positive and -negative patients for individual and total viruses. Fifty per cent (n = 15) of patients were positive for the four herpes viruses together; 50% (n = 15), 30% (n = 9), 26.7% (n = 8), and 40% (n = 12) were positive for herpes simplex virus (HSV)-1, Epstein-Barr virus, HSV-2, and human cytomegalovirus, respectively. The mean concentrations of IFN-λ1 in virus-positive patients (14.38 ± 13.95) were lower than those of virus-negative patients (228.26 ± 215.35). INF-λ1 levels in individual virus groups were also lower in virus-positive patients compared to virus-negative patients, with P < 0.001. These results suggest that IFN-λ1 could have antiviral and therapeutic value against the viruses in the pathogenesis of chronic periodontitis. © 2015 Wiley Publishing Asia Pty Ltd.

Prevalence of Intrathecal Acyclovir Resistant Virus in Herpes Simplex Encephalitis Patients.

PubMed

Mitterreiter, Johanna G; Titulaer, Maarten J; van Nierop, Gijsbert P; van Kampen, Jeroen J A; Aron, Georgina I; Osterhaus, Albert D M E; Verjans, Georges M G M; Ouwendijk, Werner J D

2016-01-01

Herpes simplex encephalitis (HSE) is a life-threatening complication of herpes simplex virus (HSV) infection. Acyclovir (ACV) is the antiviral treatment of choice, but may lead to emergence of ACV-resistant (ACVR) HSV due to mutations in the viral UL23 gene encoding for the ACV-targeted thymidine kinase (TK) protein. Here, we determined the prevalence of intrathecal ACVR-associated HSV TK mutations in HSE patients and compared TK genotypes of sequential HSV isolates in paired cerebrospinal fluid (CSF) and blister fluid of mucosal HSV lesions. Clinical samples were obtained from 12 HSE patients, encompassing 4 HSV type 1 (HSV-1) and 8 HSV-2 encephalitis patients. HSV DNA load was determined by real-time PCR and complete HSV TK gene sequences were obtained by nested PCR followed by Sanger sequencing. All HSV-1 HSE patients contained viral TK mutations encompassing 30 unique nucleotide and 13 distinct amino acid mutations. By contrast, a total of 5 unique nucleotide and 4 distinct amino acid changes were detected in 7 of 8 HSV-2 patients. Detected mutations were identified as natural polymorphisms located in non-conserved HSV TK gene regions. ACV therapy did not induce the emergence of ACVR-associated HSV TK mutations in consecutive CSF and mucocutaneous samples of 5 individual patients. Phenotypic susceptibility analysis of these mucocutaneous HSV isolates demonstrated ACV-sensitive virus in 2 HSV-1 HSE patients, whereas in two HSV-2 HSE patients ACVR virus was detected in the absence of known ACVR-associated TK mutations. In conclusion, we did not detect intrathecal ACVR-associated TK mutations in HSV isolates obtained from 12 HSE patients.

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.

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…

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 Herpes...

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 Herpes...

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 Herpes...

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 Herpes...

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 Herpes...

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

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.

Effect of Acycloguanosine Treatment on Acute and Latent Herpes Simplex Infections in Mice

PubMed Central

Field, Hugh J.; Bell, Susanne E.; Elion, Gertrude B.; Nash, Anthony A.; Wildy, Peter

1979-01-01

Systemic treatment of mice with the nucleoside analog 9-(2-hydroxyethoxymethyl)guanine (acycloguanosine [aciclovir]) was found to be highly effective against acute type 1 herpes simplex virus infection of the pinna. The drug ablated clinical signs and reduced virus replication both in tissue local to the inoculation site and within the nervous system. Provided that moderate-sized virus inocula were used, acycloguanosine treatment reduced or prevented the establishment of a latent infection in the dorsal root ganglia relating to the sensory nerve supply of the ear. However, although it aborted artificially produced infections in dorsal root ganglia, acycloguanosine was found not to be effective against the latent infection once established. This finding strongly indicated that latent herpes simplex virus in mice can exist in a nonreplicating form. PMID:464587

Effect of acycloguanosine treatment of acute and latent herpes simplex infections in mice.

PubMed

Field, H J; Bell, S E; Elion, G B; Nash, A A; Wildy, P

1979-04-01

Systemic treatment of mice with the nucleoside analog 9-(2-hydroxyethoxymethyl)guanine (acycloguanosine [aciclovir]) was found to be highly effective against acute type 1 herpes simplex virus infection of the pinna. The drug ablated clinical signs and reduced virus replication both in tissue local to the inoculation site and within the nervous system. Provided that moderate-sized virus inocula were used, acycloguanosine treatment reduced or prevented the establishment of a latent infection in the dorsal root ganglia relating to the sensory nerve supply of the ear. However, although it aborted artificially produced infections in dorsal root ganglia, acycloguanosine was found not to be effective against the latent infection once established. This finding strongly indicated that latent herpes simplex virus in mice can exist in a nonreplicating form.

Expression and regulation of glycoprotein C gene of herpes simplex virus 1 resident in a clonal L-cell line.

PubMed Central

Arsenakis, M; Tomasi, L F; Speziali, V; Roizman, B; Campadelli-Fiume, G

1986-01-01

Ltk- cells were transfected with a plasmid containing the entire domain of glycoprotein C (gC), a true gamma or gamma 2 gene of herpes simplex virus 1 (HSV-1) and the methotrexate-resistant mouse dihydrofolate reductase mutant gene. The resulting methotrexate-resistant cell line was cloned; of the 39 clonal lines tested only 1, L3153(28), expressed gC after infection with HSV-1(MP), a gC- mutant, and none expressed gC constitutively. The induction of gC was optimal at multiplicities ranging between 0.5 and 2 PFU per cell, and the quantities produced were equivalent to or higher than those made by methotrexate-resistant gC- L cells infected with wild-type (gC+) virus. The gC gene resident in the L3153(28) cells was regulated as a beta gene inasmuch as the amounts of gC made in infected L3153(28) cells exposed to concentrations of phosphonoacetate that inhibited viral DNA synthesis were higher than those made in the absence of the drug, gC was induced at both permissive and nonpermissive temperatures by the DNA- mutant tsHA1 carrying a lesion in the gene specifying the major DNA-binding protein and which does not express gamma 2 genes at the nonpermissive temperature, and gC was induced only at the permissive temperature in cells infected with ts502 containing a mutation in the alpha 4 gene. The gC induced in L3153(28) cells was made earlier and processed faster to the mature form than that induced in a gC- clone of methotrexate-resistant cells infected with wild-type virus. Unlike virus stocks made in gC- cells, HSV-1(MP) made in L3153(28) cells was susceptible to neutralization by anti-gC monoclonal antibody. Images PMID:3009854

Identification of B- and T-cell epitopes from glycoprotein B of herpes simplex virus 2 and evaluation of their immunogenicity and protection efficacy.

PubMed

Liu, Kun; Jiang, Deyu; Zhang, Liangyan; Yao, Zhidong; Chen, Zhongwei; Yu, Sanke; Wang, Xiliang

2012-04-19

Herpes simplex virus (HSV) infection is a major health concern worldwide. Evidence obtained from animals and humans indicates that B- and T-cell responses contribute to protective immunity against herpes virus infection. Glycoprotein B is a transmembrane envelope component of HSV-1 and HSV-2, which plays an important role in virion morphogenesis and penetration into host cells, and can induce neutralizing antibodies and protective T-cell response when it is used to immunize humans and animals. However, little is known about gB epitopes that are involved in B- and T-cell activities in vitro and in vivo. Thus, the HSV-2 gB sequence was screened using B- and T-cell epitope prediction systems, and the B-cell regions and the HLA-A*0201-restricted epitopes were identified. These B-cell epitopes elicited high IgG antibody titers in Balb/C mice, with a predominantly IgG1 subclass distribution, which indicated a Th2 bias. Specific IgGs induced by these two epitopes were evaluated as the neutralizing antibodies for virus neutralization. The predicted T-cell epitopes stabilized the HLA-A*0201 molecules on T(2) cells, and stimulate interferon-γ-secreting and cytotoxic CD8(+) T cells. Immunization with the predicted peptides reduced virus shedding and protected against lethal viral challenge in mice. The functional epitopes described herein, both B- and T-cell epitopes, are potentially implicated in vaccine development. Copyright © 2012. Published by Elsevier Ltd.

Completely assembled virus particles detected by transmission electron microscopy in proximal and mid-axons of neurons infected with herpes simplex virus type 1, herpes simplex virus type 2 and pseudorabies virus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huang Jialing, E-mail: hjialing@mail.med.upenn.edu; Lazear, Helen M., E-mail: Hlazear@DOM.wustl.edu; Friedman, Harvey M., E-mail: hfriedma@mail.med.upenn.ed

2011-01-05

The morphology of alphaherpesviruses during anterograde axonal transport from the neuron cell body towards the axon terminus is controversial. Reports suggest that transport of herpes simplex virus type 1 (HSV-1) nucleocapsids and envelope proteins occurs in separate compartments and that complete virions form at varicosities or axon termini (subassembly transport model), while transport of a related alphaherpesvirus, pseudorabies virus (PRV) occurs as enveloped capsids in vesicles (assembled transport model). Transmission electron microscopy of proximal and mid-axons of primary superior cervical ganglion (SCG) neurons was used to compare anterograde axonal transport of HSV-1, HSV-2 and PRV. SCG cell bodies were infectedmore » with HSV-1 NS and 17, HSV-2 2.12 and PRV Becker. Fully assembled virus particles were detected intracellularly within vesicles in proximal and mid-axons adjacent to microtubules after infection with each virus, indicating that assembled virions are transported anterograde within axons for all three alphaherpesviruses.« less

Cornea lymphatics drive the CD8+ T-cell response to herpes simplex virus-1.

PubMed

Gurung, Hem R; Carr, Meghan M; Carr, Daniel J J

2017-01-01

Herpes simplex virus-1 (HSV-1) infection of the cornea induces vascular endothelial growth factor A (VEGF-A)-dependent lymphangiogenesis. However, the extent to which HSV-1-induced corneal lymphangiogenesis impacts the adaptive immune response has not been characterized. Here, we used floxed VEGF-A mice to study the importance of newly created corneal lymphatic vessels in the host adaptive immune response to infection. Whereas the mice infected with the parental virus (strain SC16) exhibited robust corneal lymphangiogenesis, mice that received the recombinant virus (SC16 ICP0-Cre) that expresses Cre recombinase under the control of infected cell protein 0 (ICP0), an HSV-1 immediate-early gene, showed a significant reduction in lymphangiogenesis. There was no difference in virus recovered from the cornea of mice infected with SC16 vs SC16 ICP0-Cre. However, viral loads were significantly elevated in the trigeminal ganglia (TG) of mice with reduced corneal lymphangiogenesis. The increase in viral titer correlated with a significant loss of HSV-1-specific CD8 + T cells that traffic to the TG of mice infected with the recombinant virus. Intrastromal delivery of size-exclusion dye (fluorescein isothiocyanate-dextran) revealed a time-dependent defect in the ability of the lymphatic vessels in SC16 ICP0-Cre-infected mice to transport soluble antigen from the cornea to the draining lymph nodes. We interpret these results to suggest that the newly created lymphatic vessels in the cornea driven by HSV-1 infection are critical in the delivery of soluble viral antigen to the draining lymph node and subsequent development of the CD8 + T-cell response to HSV-1.

Inhibition of herpes simplex virus type 1 entry by chloride channel inhibitors tamoxifen and NPPB

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zheng, Kai; College of Life Science and Technology, Jinan University, Guangzhou; Chen, Maoyun

2014-04-18

Highlights: • We analyze the anti-HSV potential of chloride channel inhibitors. • Tamoxifen and NPPB show anti-HSV-1 and anti-ACV-resistant HSV-1 activities. • HSV-1 infection induces intracellular chloride concentration increasing. • Tamoxifen and NPPB inhibit HSV-1 early infection. • Tamoxifen and NPPB prevent the fusion process of HSV-1. - Abstract: Herpes simplex virus type 1 (HSV-1) infection is very common worldwide and can cause significant health problems from periodic skin and corneal lesions to encephalitis. Appearance of drug-resistant viruses in clinical therapy has made exploring novel antiviral agents emergent. Here we show that chloride channel inhibitors, including tamoxifen and 5-nitro-2-(3-phenyl-propylamino) benzoicmore » acid (NPPB), exhibited extensive antiviral activities toward HSV-1 and ACV-resistant HSV viruses. HSV-1 infection induced chloride ion influx while treatment with inhibitors reduced the increase of intracellular chloride ion concentration. Pretreatment or treatment of inhibitors at different time points during HSV-1 infection all suppressed viral RNA synthesis, protein expression and virus production. More detailed studies demonstrated that tamoxifen and NPPB acted as potent inhibitors of HSV-1 early entry step by preventing viral binding, penetration and nuclear translocation. Specifically the compounds appeared to affect viral fusion process by inhibiting virus binding to lipid rafts and interrupting calcium homeostasis. Taken together, the observation that tamoxifen and NPPB can block viral entry suggests a stronger potential for these compounds as well as other ion channel inhibitors in antiviral therapy against HSV-1, especially the compound tamoxifen is an immediately actionable drug that can be reused for treatment of HSV-1 infections.« less

Transient neuropathic bladder following herpes simplex genitalis.

PubMed

Riehle, R A; Williams, J J

1979-08-01

A case of transient bladder dysfunction and urinary retention concomitant with herpes genitalis is presented. The protean manifestations of the herpes simplex virus, the similar neurotropic behavior of simplex and zoster, and the neurologic sequelae of the cutaneous simplex eruption are discussed. The possibility of sacral radiculopathy after herpes genitalis must be considered when evaluating acute or episodic neurogenic bladders.

Herpes Simplex Virus 2 Infection Impacts Stress Granule Accumulation

PubMed Central

Finnen, Renée L.; Pangka, Kyle R.

2012-01-01

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

Herpes Simplex Virus Infections of the Central Nervous System.

PubMed

Whitley, Richard J

2015-12-01

This article summarizes knowledge of herpes simplex virus (HSV) infections of the central nervous system (CNS). Disease pathogenesis, detection of DNA polymerase chain reaction (PCR) for diagnosis and prognosis, and approaches to therapy warrant consideration. HSV infection of the CNS is one of few treatable viral diseases. Clinical trials indicate that outcome following neonatal herpes simplex virus type 2 (HSV-2) infections of the CNS is significantly improved when 6 months of suppressive oral acyclovir therapy follows IV antiviral therapy. In contrast, herpes simplex virus type 1 (HSV-1) infections of the brain do not benefit from extended oral antiviral therapy. This implies a difference in disease pathogenesis between HSV-2 and HSV-1 infections of the brain. PCR detection of viral DNA in the CSF is the gold standard for diagnosis. Use of PCR is now being adopted as a basis for determining the duration of therapy in the newborn. HSV infections are among the most common encountered by humans; seropositivity occurs in 50% to 90% of adult populations. Herpes simplex encephalitis, however, is an uncommon result of this infection. Since no new antiviral drugs have been introduced in nearly 3 decades, much effort has focused on learning how to better use acyclovir and how to use existing databases to establish earlier diagnosis.

In vitro and in vivo antiviral activity of scopadulcic acid B from Scoparia dulcis, Scrophulariaceae, against herpes simplex virus type 1.

PubMed

Hayashi, K; Niwayama, S; Hayashi, T; Nago, R; Ochiai, H; Morita, N

1988-09-01

The antiviral activity of five diterpenoids isolated from Scoparia dulcis L., Scrophulariaceae, was examined in vitro against herpes simplex virus type 1. Among these compounds, only scopadulcic acid B was found to inhibit the viral replication with the in vitro therapeutic index of 16.7. The action of scopadulcic acid B was not due to a direct virucidal effect or inhibition of virus attachment to host cells. Single-cycle replication experiments indicated that the compound interfered with considerably early events of virus growth. The influence of scopadulcic acid B on the course of the primary corneal herpes simplex virus infection was investigated by means of a hamster test model. When the treatment was initiated immediately after virus inoculation, scopadulcic acid B, when applied orally or intraperitoneally, effectively prolonged both the appearance of herpetic lesions and the survival time at the dose of 100 and 200 mg/kg per day.

New frontiers in oncolytic viruses: optimizing and selecting for virus strains with improved efficacy

PubMed Central

2018-01-01

Oncolytic viruses have demonstrated selective replication and killing of tumor cells. Different types of oncolytic viruses – adenoviruses, alphaviruses, herpes simplex viruses, Newcastle disease viruses, rhabdoviruses, Coxsackie viruses, and vaccinia viruses – have been applied as either naturally occurring or engineered vectors. Numerous studies in animal-tumor models have demonstrated substantial tumor regression and prolonged survival rates. Moreover, clinical trials have confirmed good safety profiles and therapeutic efficacy for oncolytic viruses. Most encouragingly, the first cancer gene-therapy drug – Gendicine, based on oncolytic adenovirus type 5 – was approved in China. Likewise, a second-generation oncolytic herpes simplex virus-based drug for the treatment of melanoma has been registered in the US and Europe as talimogene laherparepvec. PMID:29445265

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

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

Yu, Xiaoliang; Li, Yun; Chen, Qin; Su, Chenhe; Zhang, Zili; Yang, Chengkui; Hu, Zhilin; Hou, Jue; Zhou, Jinying; Gong, Ling; Jiang, Xuejun; Zheng, Chunfu; He, Sudan

2016-01-15

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. 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. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

A limited innate immune response is induced by a replication-defective herpes simplex virus vector following delivery to the murine central nervous system

PubMed Central

Zeier, Zane; Aguilar, J Santiago; Lopez, Cecilia M; Devi-Rao, G B; Watson, Zachary L; Baker, Henry V; Wagner, Edward K; Bloom, David C

2010-01-01

Herpes simplex virus type 1 (HSV-1)–based vectors readily transduce neurons and have a large payload capacity, making them particularly amenable to gene therapy applications within the central nervous system (CNS). Because aspects of the host responses to HSV-1 vectors in the CNS are largely unknown, we compared the host response of a nonreplicating HSV-1 vector to that of a replication-competent HSV-1 virus using microarray analysis. In parallel, HSV-1 gene expression was tracked using HSV-specific oligonucleotide-based arrays in order to correlate viral gene expression with observed changes in host response. Microarray analysis was performed following stereotactic injection into the right hippocampal formation of mice with either a replication-competent HSV-1 or a nonreplicating recombinant of HSV-1, lacking the ICP4 gene (ICP4−). Genes that demonstrated a significant change (P < .001) in expression in response to the replicating HSV-1 outnumbered those that changed in response to mock or nonreplicating vector by approximately 3-fold. Pathway analysis revealed that both the replicating and nonreplicating vectors induced robust antigen presentation but only mild interferon, chemokine, and cytokine signaling responses. The ICP4− vector was restricted in several of the Toll-like receptor-signaling pathways, indicating reduced stimulation of the innate immune response. These array analyses suggest that although the nonreplicating vector induces detectable activation of immune response pathways, the number and magnitude of the induced response is dramatically restricted compared to the replicating vector, and with the exception of antigen presentation, host gene expression induced by the non-replicating vector largely resembles mock infection. PMID:20095947

75 FR 59670 - Immunology and Microbiology Devices; Reclassification of the Herpes Simplex Virus Serological...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-28

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration 21 CFR Part 866 [Docket No. FDA-2010-N-0429] Immunology and Microbiology Devices; Reclassification of the Herpes Simplex Virus... proposed that 21 CFR part 866 be amended as follows: PART 866--IMMUNOLOGY AND MICROBIOLOGY DEVICES 1. The...

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

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration 21 CFR Part 866 [Docket No. FDA-2009-N-0344] Microbiology Devices; Reclassification of Herpes Simplex Virus Types 1 and 2 Serological Assays; Confirmation of Effective Date AGENCY: Food and Drug Administration, HHS. ACTION: Direct...

76 FR 48715 - Immunology and Microbiology Devices; Reclassification of the Herpes Simplex Virus Serological...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-09

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration 21 CFR Part 866 [Docket No. FDA-2010-N-0429] Immunology and Microbiology Devices; Reclassification of the Herpes Simplex Virus... CFR part 866 is amended as follows: PART 866--IMMUNOLOGY AND MICROBIOLOGY DEVICES 0 1. The authority...

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:…

The impact of oral herpes simplex virus infection and candidiasis on chemotherapy-induced oral mucositis among patients with hematological malignancies.

PubMed

Chen, Y-K; Hou, H-A; Chow, J-M; Chen, Y-C; Hsueh, P-R; Tien, H-F

2011-06-01

The aim of this study was to evaluate the influences of oral candidiasis and herpes simplex virus 1 (HSV-1) infections in chemotherapy-induced oral mucositis (OM). The medical records of 424 consecutive patients with hematological malignancies who had received chemotherapy at a medical center in Taiwan from January 2006 to November 2007 were retrospectively reviewed. The results of swab cultures of fungus and HSV-1 for OM were correlated with associated clinical features. Younger age, myeloid malignancies, and disease status other than complete remission before chemotherapy were significantly correlated with the development of OM. Risks of fever (p < 0.001) and bacteremia were higher in patients with OM. Among 467 episodes of OM with both swab cultures available, 221 were non-infection (47.3%) and 246 were related to either fungal infections, HSV-1 infections, or both (52.7%); of the 246 episodes, 102 were associated with fungal infections alone (21.8%), 98 with HSV-1 infections alone (21%), and 46 with both infections (9.9%). Patients who had received antifungal agents prior to OM occurrence tended to have HSV-1 infection (p < 0.001). Our results suggest that Candida albicans and HSV-1 play an important role in chemotherapy-induced OM in patients with hematological malignancies.

Ultraviolet-B radiation induces modulation of antigen presentation of herpes simplex virus by human epidermal cells.

PubMed

van der Molen, R G; Out-Luiting, C; Claas, F H; Norval, M; Koerten, H K; Mommaas, A M

2001-06-01

Although ultraviolet (UV) B radiation is known to be immunosuppressive, there is little information regarding a relevant immunological endpoint to assess human subjects in vivo. Therefore, we have examined the effect of in vivo UV radiation on the ability of human epidermal cells (EC) to present herpes simplex virus (HSV) antigens to memory T cells. Human volunteers, who were seropositive for HSV, were exposed to one minimal erythemal dose (MED) for four consecutive days. EC, prepared from suction blister roofs, were co-cultured with autologous T cells in the presence of HSV. HSV antigen presentation by UV-exposed EC was increased compared with control, nonexposed EC. This up-regulation correlated with an influx of macrophages into the epidermis, which are considered to be associated with UV-induced tolerance. Altering the UV protocol to a sub-erythemal UV dose for four consecutive days or to a single high dose of 2 MED, resulted in suppressed HSV antigen presentation, without the influx of the UV-macrophages. One of the goals of the present study was to eventually use this HSV system to investigate sunscreen immunoprotection. A pilot study with a TiO2-containing sunscreen suggested that the endpoint for UV-induced immunosuppression presented here is promising to be used for human in vivo sunscreen immunoprotection studies.

Antiviral Activity of Crude Hydroethanolic Extract from Schinus terebinthifolia against Herpes simplex Virus Type 1.

PubMed

Nocchi, Samara Requena; Companhoni, Mychelle Vianna Pereira; de Mello, João Carlos Palazzo; Dias Filho, Benedito Prado; Nakamura, Celso Vataru; Carollo, Carlos Alexandre; Silva, Denise Brentan; Ueda-Nakamura, Tânia

2017-04-01

Herpes simplex virus infections persist throughout the lifetime of the host and affect more than 80 % of the humans worldwide. The intensive use of available therapeutic drugs has led to undesirable effects, such as drug-resistant strains, prompting the search for new antiherpetic agents. Although diverse bioactivities have been identified in Schinus terebinthifolia , its antiviral activity has not attracted much attention. The present study evaluated the antiherpetic effects of a crude hydroethanolic extract from the stem bark of S. terebinthifolia against Herpes simplex virus type 1 in vitro and in vivo as well as its genotoxicity in bone marrow in mammals and established the chemical composition of the crude hydroethanolic extract based on liquid chromatography-diode array detector-mass spectrometry and MS/MS. The crude hydroethanolic extract inhibited all of the tested Herpes simplex virus type 1 strains in vitro and was effective in the attachment and penetration stages, and showed virucidal activity, which was confirmed by transmission electron microscopy. The micronucleus test showed that the crude hydroethanolic extract had no genotoxic effect at the concentrations tested. The crude hydroethanolic extract afforded protection against lesions that were caused by Herpes simplex virus type 1 in vivo . Liquid chromatography-diode array detector-mass spectrometry and MS/MS identified 25 substances, which are condensed tannins mainly produced by a B-type linkage and prodelphinidin and procyanidin units. Georg Thieme Verlag KG Stuttgart · New York.

Radiation enhanced reactivation of herpes simplex virus: effect of caffeine.

PubMed

Hellman, K B; Lytle, C D; Bockstahler, L E

1976-09-01

Ultaviolet enhanced (Weigle) reactivation of UV-irradiated herpes simplex virus in UV-irradiated CV-1 monkey kidney cell monolayers was decreased by caffeine. X-ray enhanced reactivation of UV-irradiated virus in X-irradiated monolayers (X-ray reactivation) and UV- or X-ray-inactivated capacity of the cells to support unirradiated virus plaque formation were unaffected by caffeine. The results suggest that a caffeine-sensitive process is necessary for the expression of Weigle reactivation for herpes virus. Since cafeine did not significantly affect X-ray reactivation, different mechanisms may be responsible for the expression of Weigle reactivation and X-ray reactivation.

A novel immunization method to induce cytotoxic T-lymphocyte responses (CTL) against plasmid-encoded herpes simplex virus type-1 glycoprotein D.

PubMed

Cruz, P E; Khalil, P L; Dryden, T D; Chiou, H C; Fink, P S; Berberich, S J; Bigley, N J

1999-03-05

DNA molecules complexed with an asialoglycoprotein-polycation conjugate, consisting of asialoorosomucoid (ASOR) coupled to poly-L-lysine, can enter hepatocytes which bear receptors for ASOR. We used this receptor-mediated DNA delivery system to deliver plasmid DNA encoding glycoprotein D (gD) of herpes simplex virus type 1 to ASOR-positive cells. Maximum expression of gD protein was seen at 3 days after injection of this preparation in approximately 13% of cells from BALB/c mice [hepatocytes from mice injected intravenously (i.v.) or peritoneal exudate cells from mice injected intraperitoneally (i.p.)]. In comparison with mice injected with either the plasmid vector alone or the gD-containing plasmid uncomplexed to ASOR, mice immunized with gD-containing plasmid complexed with ASOR-poly-L-lysine induced marked antigen-specific CTL responses. BALB/c mice immunized with gD-DNA developed a T-cell-mediated CTL response against target cells expressing gD and MHC class II glycoproteins, but not against cells expressing only gD and MHC class I molecules. In C3H mice, gD-DNA induced a T-cell-mediated CTL response against target cells expressing gD and class I MHC molecules. Serum anti-gD antibody in low titers were produced in both strains of mice. DNA complexed with ASOR-poly-L-lysine induced CTL responses in mice.

Herpes Simplex Virus Type 2 Triggers Reactivation of Kaposi's Sarcoma-Associated Herpesvirus from Latency and Collaborates with HIV-1 Tat

PubMed Central

Zhu, Xiaolei; Ma, Xinting; Yan, Qin; Zeng, Yi; Guo, Yuanyuan; Feng, Ninghan; Lu, Chun

2012-01-01

Kaposi's sarcoma-associated herpesvirus (KSHV) infection was necessary but not sufficient for Kaposi's sarcoma (KS) development without other cofactors. Previously, we identified that both human immunodeficiency type 1 (HIV-1) Tat and herpes simplex virus 1 (HSV-1) were important cofactors reactivating KSHV from latency. Here, we further investigated the potential of herpes simplex virus 2 (HSV-2) to influence KSHV replication and examined the role of Tat in this procedure. We demonstrated that HSV-2 was a potentially important factor in the pathogenesis of KS, as determined by production of lytic phase mRNA transcripts, viral proteins and infectious viral particles in BCBL-1 cells. These results were further confirmed by an RNA interference experiment using small interfering RNA targeting KSHV Rta and a luciferase reporter assay testing Rta promoter-driven luciferase activity. Mechanistic studies showed that HSV-2 infection activated nuclear factor-kappa B (NF-κB) signaling pathway. Inhibition of NF-κB pathway enhanced HSV-2-mediated KSHV activation, whereas activation of NF-κB pathway suppressed KSHV replication in HSV-2-infected BCBL-1 cells. Additionally, ectopic expression of Tat enhanced HSV-2-induced KSHV replication. These novel findings suggest a role of HSV-2 in the pathogenesis of KS and provide the first laboratory evidence that Tat may participate HSV-2-mediated KSHV activation, implying the complicated pathogenesis of acquired immunodeficiency syndrome (AIDS)-related KS (AIDS-KS) patients. PMID:22347501

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…

Identification of ribonucleotide reductase mutation causing temperature-sensitivity of herpes simplex virus isolates from whitlow by deep sequencing.

PubMed

Daikoku, Tohru; Oyama, Yukari; Yajima, Misako; Sekizuka, Tsuyoshi; Kuroda, Makoto; Shimada, Yuka; Takehara, Kazuhiko; Miwa, Naoko; Okuda, Tomoko; Sata, Tetsutaro; Shiraki, Kimiyasu

2015-06-01

Herpes simplex virus 2 caused a genital ulcer, and a secondary herpetic whitlow appeared during acyclovir therapy. The secondary and recurrent whitlow isolates were acyclovir-resistant and temperature-sensitive in contrast to a genital isolate. We identified the ribonucleotide reductase mutation responsible for temperature-sensitivity by deep-sequencing analysis.

A case of urinary retention in the early stages of herpes simplex virus type-1 encephalitis.

PubMed

Fukuoka, Takuya; Nakazato, Yoshihiko; Miyake, Akifumi; Tamura, Naotoshi; Araki, Nobuo; Yamamoto, Toshimasa

2017-06-01

A 70-year-old man developed urinary retention in the early stages of herpes simplex virus (HSV) type-1 encephalitis. A nerve conduction study suggested latent myeloradiculitis. This is the first report of human herpes simplex virus-1 encephalitis followed by urinary retention at early stage from the onset like the Elsberg syndrome. Although relatively few similar cases have been reported, we consider that urinary retention is common in HSV-1 encephalitis, in which disturbances of consciousness usually require bladder catheterization from the onset. We further emphasize that urinary retention may occasionally occur in early stages of HSV-1 encephalitis, with a significant possibility of recovery. Copyright © 2017. Published by Elsevier B.V.

Evaluation of recombinant adenovirus vaccines based on glycoprotein D and truncated UL25 against herpes simplex virus type 2 in mice.

PubMed

Liu, Wei; Zhou, Yan; Wang, Ziyan; Zhang, Zeqiang; Wang, Qizhi; Su, Weiheng; Chen, Yan; Zhang, Yan; Gao, Feng; Jiang, Chunlai; Kong, Wei

2017-05-01

The high prevalence of herpes simplex virus 2 (HSV-2) infections in humans necessitates the development of a safe and effective vaccine that will need to induce vigorous T-cell responses to control viral infection and transmission. We designed rAd-gD2, rAd-gD2ΔUL25, and rAd-ΔUL25 to investigate whether recombinant replication-defective adenoviruses vaccine could induce specific T-cell responses and protect mice against intravaginal HSV-2 challenge compared with FI-HSV-2. In the present study, recombinant adenovirus-based HSV-2 showed higher reductions in mortality and stronger antigen-specific T-cell responses compared with FI-HSV-2 and the severity of genital lesions in mice immunized with rAd-gD2ΔUL25 was significantly decreased by eliciting IFN-γ-secreting T-cell responses compared with rAd-gD2 and rAd-ΔUL25 groups. Our results demonstrated the immunogenicity and protective efficacy of recombinant adenovirus vaccines in acute HSV-2 infection following intravaginal challenge in mice. © 2017 The Societies and John Wiley & Sons Australia, Ltd.

An Anti-Inflammatory Role of VEGFR2/Src Kinase Inhibitor in Herpes Simplex Virus 1-Induced Immunopathology▿

PubMed Central

Sharma, Shalini; Mulik, Sachin; Kumar, Naveen; Suryawanshi, Amol; Rouse, Barry T.

2011-01-01

Corneal neovascularization represents a key step in the blinding inflammatory stromal keratitis (SK) lesion caused by ocular infection with herpes simplex virus (HSV). In this report, we describe a novel approach for limiting the angiogenesis caused by HSV infection of the mouse eye. We show that topical or systemic administration of the Src kinase inhibitor (TG100572) that inhibits downstream molecules involved in the vascular endothelial growth factor (VEGF) signaling pathway resulted in markedly diminished levels of HSV-induced angiogenesis and significantly reduced the severity of SK lesions. Multiple mechanisms were involved in the inhibitory effects. These included blockade of IL-8/CXCL1 involved in inflammatory cells recruitment that are a source of VEGF, diminished cellular infiltration in the cornea, and reduced proliferation and migration of CD4+ T cells into the corneas. As multiple angiogenic factors (VEGF and basic fibroblast growth factor [bFGF]) play a role in promoting angiogenesis during SK and since Src kinases are involved in signaling by many of them, the use of Src kinase inhibition represents a promising way of limiting the severity of SK lesions the most common cause of infectious blindness in the Western world. PMID:21471229

Concurrent detection of herpes simplex and varicella-zoster viruses by polymerase chain reaction from the same anatomic location.

PubMed

Dhiman, Neelam; Wright, Patricia A; Espy, Mark J; Schneider, Susan K; Smith, Thomas F; Pritt, Bobbi S

2011-08-01

Herpes simplex virus (HSV) and varicella-zoster virus (VZV) may cause latent infection of the same peripheral nerve ganglia. However, there are no large studies addressing the frequency of concurrent HSV/VZV PCR positivity from the same anatomic location. In an eight-year retrospective study, we observed 1.3% dual positivity from dermal, genital, and oral mucosal sources. Copyright © 2011 Elsevier Inc. All rights reserved.

A Fusogenic Oncolytic Herpes Simplex Virus for Therapy of Advanced Ovarian Cancer

DTIC Science & Technology

2007-06-01

to demonstrate that fusogenic oncolytic HSVs are a potent anti -tumor agent for advanced ovarian cancer; 2) to prove that fusogenic oncolytic HSVs...oncolytic herpes simplex virus (HSV) can significantly enhance the anti -tumor effect of the virus. Three specific aims have been proposed and they are: 1...have the same safety profile as their non-fusogenic counterparts; 3) to explore novel delivery strategies that can evade host’s anti -viral immunity

Herpes simplex virus type 2 latency in the footpad of mice: effect of acycloguanosine on the recovery of virus.

PubMed

Al-Saadi, S A; Gross, P; Wildy, P

1988-02-01

Herpes simplex virus type 2 has been reactivated from the latent state in the footpad and dorsal root ganglia of acycloguanosine-treated BALB/c mice. Virus was also recovered from the footpad tissue but not from the ganglia of denervated, latently infected mice. Treatment in vitro of explanted footpad cultures with acycloguanosine or phosphonoacetic acid did not affect the rate of virus reactivation. In all the isolates examined the virus was found to be acycloguanosine-sensitive. Recovery of virus from footpad tissue of mice after a long period of acycloguanosine treatment supports the theory that virus had been truly latent in the footpad and not in a state of persistent infection.

A Herpes Simplex Virus 2 (HSV-2) gD Mutant Impaired for Neural Tropism Is Superior to an HSV-2 gD Subunit Vaccine To Protect Animals from Challenge with HSV-2.

PubMed

Wang, Kening; Goodman, Kyle N; Li, Daniel Y; Raffeld, Mark; Chavez, Mayra; Cohen, Jeffrey I

2016-01-01

A recent phase 3 trial with soluble herpes simplex virus 2 (HSV-2) glycoprotein D (gD2t) in adjuvant failed to show protection against genital herpes. We postulated that live attenuated HSV-2 would provide more HSV antigens for induction of virus-specific antibodies and cellular immunity than would gD2t. We previously reported an HSV-2 mutant, HSV2-gD27, in which the nectin-1 binding domain of gD2 is altered so that the virus is impaired for infecting neural cells, but not epithelial cells, in vitro and is impaired for infecting dorsal root ganglia in mice (K. Wang, J. D. Kappel, C. Canders, W. F. Davila, D. Sayre, M. Chavez, L. Pesnicak, and J. I. Cohen, J Virol 86:12891-12902, 2012, doi:10.1128/JVI.01055-12). Here we report that the mutations in HSV2-gD27 were stable when the virus was passaged in cell culture and during acute infection of mice. HSV2-gD27 was attenuated in mice when it was inoculated onto the cornea, intramuscularly (i.m.), intravaginally, and intracranially. Vaccination of mice i.m. with HSV2-gD27 provided better inhibition of challenge virus replication in the vagina than when the virus was used to vaccinate mice intranasally or subcutaneously. Comparison of i.m. vaccinations with HSV2-gD27 versus gD2t in adjuvant showed that HSV2-gD27 induced larger reductions of challenge virus replication in the vagina and reduced latent viral loads in dorsal root ganglia but induced lower serum neutralizing antibody titers than those obtained with gD2t in adjuvant. Taken together, our data indicate that a live attenuated HSV-2 vaccine impaired for infection of neurons provides better protection from vaginal challenge with HSV-2 than that obtained with a subunit vaccine, despite inducing lower titers of HSV-2 neutralizing antibodies in the serum. Genital herpes simplex is one of the most prevalent sexually transmitted diseases. Though HSV-2 disease is usually mild, it can be life threatening in neonates and immunocompromised persons. In addition, genital herpes increases the frequency of HIV infection and transmission. HSV-2 maintains a latent infection in sensory neurons and cannot be cleared with antiviral drugs. The virus frequently reactivates, resulting in virus shedding in the genital area, which serves as a source for transmission. A prophylactic vaccine is needed to prevent disease and to control the spread of the virus. Previous human trials of subunit vaccines have been unsuccessful. Here we report the results of vaccinating mice with a new type of live attenuated HSV-2 vaccine that is impaired for infection of neurons and provides better protection of mice than that obtained with a subunit vaccine. The strategy of altering the cell tropism of a virus is a new approach for a live attenuated vaccine. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Palella, T.D.; Silverman, L.J.; Schroll, C.T.

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 isolationmore » 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.« less

Hydrocephalus in herpes simplex type 2 meningitis.

PubMed

Yap, Elaine; Ellis-Pegler, Rod

2006-08-01

A 34-year-old woman presented to hospital with symptoms of meningitis, later confirmed to be due to herpes simplex virus type 2. She developed hydrocephalus on day 2 of her admission. We describe the first case of hydrocephalus associated with herpes simplex type 2 meningitis in an adult.

Recent advances in vaccine development for herpes simplex virus types I and II.

PubMed

Coleman, Jeffrey L; Shukla, Deepak

2013-04-01

Despite recent advances in vaccine design and strategies, latent infection with herpes simplex virus (HSV) remains a formidable challenge. Approaches involving live-attenuated viruses and inactivated viral preparations were popular throughout the twentieth century. In the past ten years, many vaccine types, both prophylactic or therapeutic, have contained a replication-defective HSV, viral DNA or glycoproteins. New research focused on the mechanism of immune evasion by the virus has involved developing vaccines with various gene deletions and manipulations combined with the use of new and more specific adjuvants. In addition, new "prime-boost" methods of strengthening the vaccine efficacy have proven effective, but there have also been flaws with some recent strategies that appear to have compromised vaccine efficacy in humans. Given the complicated lifecycle of HSV and its unique way of spreading from cell-to-cell, it can be concluded that the development of an ideal vaccine needs new focus on cell-mediated immunity, better understanding of the latent viral genome and serious consideration of gender-based differences in immunity development among humans. This review summarizes recent developments made in the field and sheds light on some potentially new ways to conquer the problem including development of dual-action prophylactic microbicides that prohibit viral entry and, in addition, induce a strong antigen response.

Comparative Efficacy and Immunogenicity of Replication-Defective, Recombinant Glycoprotein, and DNA Vaccines for Herpes Simplex Virus 2 Infections in Mice and Guinea Pigs

PubMed Central

Hoshino, Yo; Dalai, Sarat K.; Wang, Kening; Pesnicak, Lesley; Lau, Tsz Y.; Knipe, David M.; Cohen, Jeffrey I.; Straus, Stephen E.

2005-01-01

Many candidate vaccines are effective in animal models of genital herpes simplex virus type 2 (HSV-2) infection. Among them, clinical trials showed moderate protection from genital disease with recombinant HSV-2 glycoprotein D (gD2) in alum-monophosphoryl lipid A adjuvant only in HSV women seronegative for both HSV-1 and HSV-2, encouraging development of additional vaccine options. Therefore, we undertook direct comparative studies of the prophylactic and therapeutic efficacies and immunogenicities of three different classes of candidate vaccines given in four regimens to two species of animals: recombinant gD2, a plasmid expressing gD2, and dl5-29, a replication-defective strain of HSV-2 with the essential genes UL5 and UL29 deleted. Both dl5-29 and gD2 were highly effective in attenuating acute and recurrent disease and reducing latent viral load, and both were superior to the plasmid vaccine alone or the plasmid vaccine followed by one dose of dl5-29. dl5-29 was also effective in treating established infections. Moreover, latent dl5-29 virus could not be detected by PCR in sacral ganglia from guinea pigs vaccinated intravaginally. Finally, dl5-29 was superior to gD2 in inducing higher neutralizing antibody titers and the more rapid accumulation of HSV-2-specific CD8+ T cells in trigeminal ganglia after challenge with wild-type virus. Given its efficacy, its defectiveness for latency, and its ability to induce rapid, virus-specific CD8+-T-cell responses, the dl5-29 vaccine may be a good candidate for early-phase human trials. PMID:15596834

Comparative efficacy and immunogenicity of replication-defective, recombinant glycoprotein, and DNA vaccines for herpes simplex virus 2 infections in mice and guinea pigs.

PubMed

Hoshino, Yo; Dalai, Sarat K; Wang, Kening; Pesnicak, Lesley; Lau, Tsz Y; Knipe, David M; Cohen, Jeffrey I; Straus, Stephen E

2005-01-01

Many candidate vaccines are effective in animal models of genital herpes simplex virus type 2 (HSV-2) infection. Among them, clinical trials showed moderate protection from genital disease with recombinant HSV-2 glycoprotein D (gD2) in alum-monophosphoryl lipid A adjuvant only in HSV women seronegative for both HSV-1 and HSV-2, encouraging development of additional vaccine options. Therefore, we undertook direct comparative studies of the prophylactic and therapeutic efficacies and immunogenicities of three different classes of candidate vaccines given in four regimens to two species of animals: recombinant gD2, a plasmid expressing gD2, and dl5-29, a replication-defective strain of HSV-2 with the essential genes UL5 and UL29 deleted. Both dl5-29 and gD2 were highly effective in attenuating acute and recurrent disease and reducing latent viral load, and both were superior to the plasmid vaccine alone or the plasmid vaccine followed by one dose of dl5-29. dl5-29 was also effective in treating established infections. Moreover, latent dl5-29 virus could not be detected by PCR in sacral ganglia from guinea pigs vaccinated intravaginally. Finally, dl5-29 was superior to gD2 in inducing higher neutralizing antibody titers and the more rapid accumulation of HSV-2-specific CD8+ T cells in trigeminal ganglia after challenge with wild-type virus. Given its efficacy, its defectiveness for latency, and its ability to induce rapid, virus-specific CD8(+)-T-cell responses, the dl5-29 vaccine may be a good candidate for early-phase human trials.

Antiviral Effects of ABMA against Herpes Simplex Virus Type 2 In Vitro and In Vivo

PubMed Central

Dai, Wenwen; Wu, Yu; Bi, Jinpeng; Wang, Shuai; Li, Fang; Kong, Wei; Cintrat, Jean-Christophe; Gao, Feng; Su, Weiheng; Jiang, Chunlai

2018-01-01

Herpes simplex virus type 2 (HSV-2) is the causative pathogen of genital herpes and is closely associated with the occurrence of cervical cancer and human immunodeficiency virus (HIV) infection. The absence of an effective vaccine and the emergence of drug resistance to commonly used nucleoside analogs emphasize the urgent need for alternative antivirals against HSV-2. Recently, ABMA [1-adamantyl (5-bromo-2-methoxybenzyl) amine] has been demonstrated to be an inhibitor of several pathogens exploiting host-vesicle transport, which also participates in the HSV-2 lifecycle. Here, we showed that ABMA inhibited HSV-2-induced cytopathic effects and plaque formation with 50% effective concentrations of 1.66 and 1.08 μM, respectively. We also preliminarily demonstrated in a time of compound addition assay that ABMA exerted a dual antiviral mechanism by impairing virus entry, as well as the late stages of the HSV-2 lifecycle. Furthermore, in vivo studies showed that ABMA protected BALB/c mice from intravaginal HSV-2 challenge with an improved survival rate of 50% at 5 mg/kg (8.33% for the untreated virus infected control). Consequently, our study has identified ABMA as an effective inhibitor of HSV-2, both in vitro and in vivo, for the first time and presents an alternative to nucleoside analogs for HSV-2 infection treatment. PMID:29522484

RNA binding properties of the US11 protein from four primate simplexviruses.

PubMed

Tohme, Sarah; Cukier, Cyprian D; Severini, Alberto

2011-11-03

The protein encoded by the Us11 gene of herpes simplex viruses is a dsRNA binding protein which inhibits protein kinase R activity, thereby preventing the interferon-induced shut down of protein synthesis following viral infection. Us11 protein is not essential for infectivity in vitro and in mice in herpes simplex virus type 1 (HSV1), however this virus has a second, and apparently more important, inhibitor of PKR activity, the γ134.5 protein. Recently sequenced simian simplexviruses SA8, HVP2 and B virus do not have an ORF corresponding to the γ134.5 protein, yet they have similar, or greater, infectivity as HSV1 and HSV2. We have expressed the US11 proteins of the simplexviruses HSV1, HSV2, HVP2 and B virus and measured their abilities to bind dsRNA, in order to investigate possible differences that could complement the absence of the γ134.5 protein. We employed a filter binding technique that allows binding of the Us11 protein under condition of excess dsRNA substrate and therefore a measurement of the true Kd value of Us11-dsRNA binding. The results show a Kd of binding in the range of 0.89 nM to 1.82 nM, with no significant difference among the four Us11 proteins.

RNA binding properties of the US11 protein from four primate simplexviruses

PubMed Central

2011-01-01

Background The protein encoded by the Us11 gene of herpes simplex viruses is a dsRNA binding protein which inhibits protein kinase R activity, thereby preventing the interferon-induced shut down of protein synthesis following viral infection. Us11 protein is not essential for infectivity in vitro and in mice in herpes simplex virus type 1 (HSV1), however this virus has a second, and apparently more important, inhibitor of PKR activity, the γ134.5 protein. Recently sequenced simian simplexviruses SA8, HVP2 and B virus do not have an ORF corresponding to the γ134.5 protein, yet they have similar, or greater, infectivity as HSV1 and HSV2. Methods We have expressed the US11 proteins of the simplexviruses HSV1, HSV2, HVP2 and B virus and measured their abilities to bind dsRNA, in order to investigate possible differences that could complement the absence of the γ134.5 protein. We employed a filter binding technique that allows binding of the Us11 protein under condition of excess dsRNA substrate and therefore a measurement of the true Kd value of Us11-dsRNA binding. Results and Conclusions The results show a Kd of binding in the range of 0.89 nM to 1.82 nM, with no significant difference among the four Us11 proteins. PMID:22054255

Attenuated Phenotype and Immunogenic Characteristics of a Mutated Herpes Simplex Virus 1 Strain in the Rhesus Macaque.

PubMed

Fan, Shengtao; Xu, Xingli; Liao, Yun; Wang, Yongrong; Wang, Jianbin; Feng, Min; Wang, Lichun; Zhang, Ying; He, Zhanlong; Yang, Fengmei; Fraser, Nigel W; Li, Qihan

2018-05-02

Herpes simplex virus type 1(HSV-1) presents a conundrum to public health worldwide because of its specific pathogenicity and clinical features. Some experimental vaccines, such as the recombinant viral glycoproteins, exhibit the viral immunogenicity of a host-specific immune response, but none of these has achieved a valid epidemiological protective efficacy in the human population. In the present study, we constructed an attenuated HSV-1 strain M3 through the partial deletion of UL7, UL41 , and the latency-associated transcript ( LAT ) using the CRISPR/Cas9 system. The mutant strain exhibited lowered infectivity and virulence in macaques. Neutralization testing and ELISpot detection of the specific T-cell responses confirmed the specific immunity induced by M3 immunization and this immunity defended against the challenges of the wild-type strain and restricted the entry of the wild-type strain into the trigeminal ganglion. These results in rhesus macaques demonstrated the potential of the attenuated vaccine for the prevention of HSV-1 in humans.

Herpes simplex virus 1 induces de novo phospholipid synthesis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sutter, Esther; Oliveira, Anna Paula de; Tobler, Kurt

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 thatmore » 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.« less

Spectroscopic investigation of herpes simplex viruses infected cells and their response to antiviral therapy

NASA Astrophysics Data System (ADS)

Erukhimovitch, Vitaly; Talyshinsky, Marina; Souprun, Yelena; Huleihel, Mahmoud

2006-07-01

In the present study, we used microscopic Fourier transform infrared spectroscopy (FTIR) to evaluate the antiviral activity of known antiviral agents against herpes viruses. The antiviral activity of Caffeic acid phenethyl ester (CAPE) (which is an active compound of propolis) against herpes simplex type 1 and 2 was examined in cell culture. The advantage of microscopic FTIR spectroscopy over conventional FTIR spectroscopy is that it facilitates inspection of restricted regions of cell culture or tissue. Our results showed significant spectral differences at early stages of infection between infected and non-infected cells, and between infected cells treated with the used antiviral agent and those not treated. In infected cells, there was a considerable increase in phosphate levels. Our results show that treatment with used antiviral agent considerably abolish the spectral changes induced by the viral infection. In addition, it is possible to track by FTIR microscopy method the deferential effect of various doses of the drug.

TOPICAL TENOFOVIR, A MICROBICIDE EFFECTIVE AGAINST HIV, INHIBITS HERPES SIMPLEX VIRUS-2 REPLICATION

PubMed Central

Andrei, Graciela; Lisco, Andrea; Vanpouille, Christophe; Introini, Andrea; Balestra, Emanuela; van den Oord, Joost; Cihlar, Tomas; Perno, Carlo-Federico; Snoeck, Robert; Margolis, Leonid; Balzarini, Jan

2011-01-01

SUMMARY The HIV reverse transcriptase inhibitor tenofovir, was recently formulated into a vaginal gel for use as a microbicide. In human trials, a 1% tenofovir gel inhibited HIV sexual transmission by 39% and surprisingly herpes simplex virus-2 (HSV-2) transmission by 51%. We demonstrate that the concentration achieved intravaginally with a 1% tenofovir topical gel has direct anti-herpetic activity. Tenofovir inhibits the replication of HSV clinical isolates in human embryonic fibroblasts, keratinocytes, and organotypic epithelial 3D-rafts, decreases HSV replication in human lymphoid and cervical tissues ex vivo, and delays HSV-induced lesions and death of topically treated HSV-infected mice. The active tenofovir metabolite inhibits HSV DNA-polymerase and HIV reverse transcriptase. Tenofovir must be topically administered to achieve concentrations, which are higher than systemic levels after oral treatment, that exert these dual antiviral effects. These findings indicate that a single topical treatment, like tenofovir, can inhibit the transmission of HIV and its co-pathogens. PMID:22018238

Antiviral effects of herpes simplex virus specific anti-sense nucleic acids.

PubMed

Cantin, E M; Podsakoff, G; Willey, D E; Openshaw, H

1992-01-01

We have targeted mRNA sequences encompassing the translation initiation codon of the essential herpes simplex virus type 1 (HSV-1) IE3 gene with three kinds of anti-sense molecule. Addition of a 15mer oligodeoxyribonucleoside methylphosphonate to tissue culture cells resulted in suppression of viral replication. HSV-1 replication was also inhibited in cultured cells containing anti-sense vectors expressing transcripts complementary to the IE3 mRNA. We have also constructed a ribozyme which upon base pairing with the target IE3 mRNA induces cleavage at the predicted GUC site. A major obstacle to anti-sense studies in animals is drug delivery of preformed antisense molecules to ganglionic neurons, the site of HSV latency and reactivation. We speculate as to how this may be accomplished through carrier compounds which are taken up by nerve terminals and transported by retrograde axoplasmic flow. By the same route, HSV itself may be used as an anti-sense vector.

Photoinactivation of Latent Herpes Simplex Virus in Rabbit Kidney Cells

PubMed Central

Kelleher, J. J.; Varani, J.

1976-01-01

The photoinactivation of actively and nonactively growing herpes simplex virus by neutral red and proflavine was studied in rabbit kidney cells. Active virus growth was inhibited by both dyes under conditions which did not destroy the cells. Neutral red caused a much greater inhibition than proflavine. Neutral red also caused a reduction in the reactivation rate of latent virus when the infected cells were treated during the latent period. In the treated cultures that did reactivate virus, the average length of the latent period was increased over the control value. Proflavine treatment did not reduce the rate of reactivation of latent virus and did not increase the average latent period of the treated cultures. PMID:185948

The conserved N-terminal domain of herpes simplex virus 1 UL24 protein is sufficient to induce the spatial redistribution of nucleolin.

PubMed

Bertrand, Luc; Pearson, Angela

2008-05-01

UL24 is widely conserved among herpesviruses but its function during infection is poorly understood. Previously, we discovered a genetic link between UL24 and the herpes simplex virus 1-induced dispersal of the nucleolar protein nucleolin. Here, we report that in the absence of viral infection, transiently expressed UL24 accumulated in both the nucleus and the Golgi apparatus. In the majority of transfected cells, nuclear staining for UL24 was diffuse, but a minor staining pattern, whereby UL24 was present in nuclear foci corresponding to nucleoli, was also observed. Expression of UL24 correlated with the dispersal of nucleolin. This dispersal did not appear to be a consequence of a general disaggregation of nucleoli, as foci of fibrillarin staining persisted in cells expressing UL24. The conserved N-terminal region of UL24 was sufficient to cause this change in subcellular distribution of nucleolin. Interestingly, a bipartite nuclear localization signal predicted within the C terminus of UL24 was dispensable for nuclear localization. None of the five individual UL24 homology domains was required for nuclear or Golgi localization, but deletion of these domains resulted in the loss of nucleolin-dispersal activity. We determined that a nucleolar-targeting signal was contained within the first 60 aa of UL24. Our results show that the conserved N-terminal domain of UL24 is sufficient to specifically induce dispersal of nucleolin in the absence of other viral proteins or virus-induced cellular modifications. These results suggest that UL24 directly targets cellular factors that affect the composition of nucleoli.

The Amino Terminus of Herpes Simplex Virus 1 Glycoprotein K (gK) Is Required for gB Binding to Akt, Release of Intracellular Calcium, and Fusion of the Viral Envelope with Plasma Membranes.

PubMed

Musarrat, Farhana; Jambunathan, Nithya; Rider, Paul J F; Chouljenko, V N; Kousoulas, K G

2018-03-15

Previously, we have shown that the amino terminus of glycoprotein K (gK) binds to the amino terminus of gB and that deletion of the amino-terminal 38 amino acids of gK prevents herpes simplex virus 1 (HSV-1) infection of mouse trigeminal ganglia after ocular infection and virus entry into neuronal axons. Recently, it has been shown that gB binds to Akt during virus entry and induces Akt phosphorylation and intracellular calcium release. Proximity ligation and two-way immunoprecipitation assays using monoclonal antibodies against gB and Akt-1 phosphorylated at S473 [Akt-1(S473)] confirmed that HSV-1(McKrae) gB interacted with Akt-1(S473) during virus entry into human neuroblastoma (SK-N-SH) cells and induced the release of intracellular calcium. In contrast, the gB specified by HSV-1(McKrae) gKΔ31-68, lacking the amino-terminal 38 amino acids of gK, failed to interact with Akt-1(S473) and induce intracellular calcium release. The Akt inhibitor miltefosine inhibited the entry of McKrae but not the gKΔ31-68 mutant into SK-N-SH cells. Importantly, the entry of the gKΔ31-68 mutant but not McKrae into SK-N-SH cells treated with the endocytosis inhibitors pitstop-2 and dynasore hydrate was significantly inhibited, indicating that McKrae gKΔ31-68 entered via endocytosis. These results suggest that the amino terminus of gK functions to regulate the fusion of the viral envelope with cellular plasma membranes. IMPORTANCE HSV-1 glycoprotein B (gB) functions in the fusion of the viral envelope with cellular membranes during virus entry. Herein, we show that a deletion in the amino terminus of glycoprotein K (gK) inhibits gB binding to Akt-1(S473), the release of intracellular calcium, and virus entry via fusion of the viral envelope with cellular plasma membranes. Copyright © 2018 American Society for Microbiology.

Database of Autotransplants for Breast Cancer.

DTIC Science & Technology

1997-12-01

atypical bacteria; 301 Herpes Simplex (HSV1, HSV2) list bacterium for non-atypical bacteria.) 302 Herpes Zoster (Chicken pox, Varicella ) 100 Atypical...o 00 Varicella 500. 10 o0 Other, specify: 501. Documented viral infection: Virus involved: 1 U Yes Yes No o 0 No 502. 1 0 o0 Cytomegalovirus (CMV) 8 0...Unknown 503. 1 o 00 Human Herpes Virus Type 6 (HHV6) 504. 1 0o Herpes Simplex Virus (HSV) 505. 1 o 0 Varicella 506. 1 0 0 0 Other, specify: 507

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.

Further Characterization of the UL37 Protein of Herpes Simplex Virus Type 1 and its Interaction with ICP8, the Major DNA-Binding Protein of Herpes Simplex Virus

DTIC Science & Technology

1994-01-01

HSV envelopment and egress . Gross structures of the genomes of tbe buman herpesviruses . Layout of genes in the genome of HSV - 1 ........... . A... HSV - 1 capsid maturation . Seletion of recombinant vaccinia viruses Protein fusion and purification system . Generation of tbe recombinant plasmid...with purified HSV -I virions Effect of detergent treatment on the association of the UL37 protein with purified HSV - 1 vIrIons

Contributions of herpes simplex virus type 1 envelope proteins to entry by endocytosis

USDA-ARS?s Scientific Manuscript database

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 ...

Atypical presentations of genital herpes simplex virus in HIV-1 and HIV-2 effectively treated by imiquimod.

PubMed

McKendry, Anna; Narayana, Srinivasulu; Browne, Rita

2015-05-01

Atypical presentations of genital herpes simplex virus have been described in HIV. We report two cases with hypertrophic presentations which were effectively treated with imiquimod, one of which is the first reported case occurring in a patient with HIV-2. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Herpes simplex virus 2-induced activation in vaginal cells involves Toll-like receptors 2 and 9 and DNA sensors DAI and IFI16.

PubMed

Triantafilou, Kathy; Eryilmazlar, Dilan; Triantafilou, Martha

2014-02-01

The pathway by which herpes simplex virus 2 (HSV2) triggers the innate immune system in the urogenital system has not as yet been fully elucidated. In this study, we aimed to determine which pattern recognition receptors (PRRs) recognize HSV2 in primary vaginal epithelial cells. Once we deciphered the receptors involved, we aimed to target them to immunomodulate innate responses as a prophylactic or therapeutic intervention for early HSV2 infection. To determine which PRRs are involved, receptor silencing as well as confocal microscopy was utilized. For immunomodulation, PRR agonists were utilized to induce a strong, local response to limit the infection, and we used 2 quantitative methods, flow cytometry and plaque assays, to determine their effect on HSV2 replication. Our results show that HSV2 is detected by a plethora of PRRs: Toll-like receptors (TLR) 2 as well as deoxyribonucleic acid (DNA) sensors TLR9, DNA-dependent activator of interferon regulatory factors, and to a lesser extent interferon-inducible 16, which trigger cytokine secretion to protect the host. Using PRR agonists, such as lipoproteins, CpG DNA, and cyclic dinucleotides, we could significantly limit HSV2 replication. Different PRRs are strategically placed in different cell locations to detect virus invasion. Use of agonists that target and activate these PRRs appeared to be effective in preventing primary HSV2 infection in vaginal cells and could provide new insights in defense against HSV2 urogenital infections. Copyright © 2014 Mosby, Inc. All rights reserved.

Microarray profiling analysis uncovers common molecular mechanisms of rubella virus, human cytomegalovirus, and herpes simplex virus type 2 infections in ECV304 cells.

PubMed

Mo, X; Xu, L; Yang, Q; Feng, H; Peng, J; Zhang, Y; Yuan, W; Wang, Y; Li, Y; Deng, Y; Wan, Y; Chen, Z; Li, F; Wu, X

2011-08-01

To study the common molecular mechanisms of various viruses infections that might result in congential cardiovascular diseases in perinatal period, changes in mRNA expression levels of ECV304 cells infected by rubella virus (RUBV), human cytomegalovirus (HCMV), and herpes simplex virus type 2 (HSV-2) were analyzed using a microarray system representing 18,716 human genes. 99 genes were found to exhibit differential expression (80 up-regulated and 19 down-regulated). Biological process analysis showed that 33 signaling pathways including 22 genes were relevant significantly to RV, HCMV and HSV-II infections. Of these 33 biological processes, 28 belong to one-gene biological processes and 5 belong to multiple-gene biological processes. Gene annotation indicated that the 5 multiple-gene biological processes including regulation of cell growth, collagen fibril organization, mRNA transport, cell adhesion and regulation of cell shape, and seven down- or up-regulated genes [CRIM1 (cysteine rich transmembrane BMP regulator 1), WISP2 (WNT1 inducible signaling pathway protein 2), COL12A1 (collagen, type XII, alpha 1), COL11A2 (collagen, type XI, alpha 2), CNTN5 (contactin 5), DDR1 (discoidin domain receptor tyrosine kinase 1), VEGF (vascular endothelial growth factor precursor)], are significantly correlated to RUBV, HCMV and HSV-2 infections in ECV304 cells. The results obtained in this study suggested the common molecular mechanisms of viruses infections that might result in congential cardiovascular diseases.

Photodynamic treatment of herpes simplex virus during its replicative cycle.

PubMed Central

Khan, N C; Melnick, J L; Biswal, N

1977-01-01

Photodynamic treatment of herpes simplex virus type 1-infected hamster embryo fibroblasts (LSH strain) with a low concentration of proflavine (0.08 mug/10(5) cells per ml), a 3-9-diamine acridine dye, inhibited production not only of infectious progeny but also of virion particles. However, there was no appreciable inhibition of viral or cellular DNA synthesis, even when the infected cells were repeatedly exposed to this low concentration of dye and light during the replication cycle of the virus. It thus appears that photodynamic treatment of infected cells interferes with the processes involved in virus maturation. PMID:189063

Indirect micro-immunofluorescence test for detecting type-specific antibodies to herpes simplex virus.

PubMed

Forsey, T; Darougar, S

1980-02-01

A rapid indirect micro-immunofluorescence test capable of detecting and differentiating type-specific antibodies to herpes simplex virus is described. The test proved highly sensitive and, in 80 patients with active herpes ocular infection, antibody was detected in 94%. No anti-herpes antibody was detected in a control group of 20 patients with adenovirus infections. Testing of animal sera prepared against herpes simplex virus types 1 and 2 and of human sera from cases of ocular and genital herpes infections showed that the test can differentiate antibodies to the infecting serotypes. Specimens of whole blood, taken by fingerprick, and eye secretions, both collected on cellulose sponges, could be tested by indirect micro-immunofluorescence. Anti-herpes IgG, IgM, and IgA can also be detected.

Decline in Herpes Simplex Virus Type 2 Among Non-Injecting Heroin and Cocaine Users in New York City, 2005 to 2014: Prospects for Avoiding a Resurgence of Human Immunodeficiency Virus.

PubMed

Des Jarlais, Don C; Arasteh, Kamyar; Feelemyer, Jonathan; McKnight, Courtney; Tross, Susan; Perlman, David C; Campbell, Aimee N C; Hagan, Holly; Cooper, Hannah L F

2017-02-01

Herpes simplex virus type 2 (HSV-2) infection increases both susceptibility to and transmissibility of human immunodeficiency virus (HIV), and HSV-2 and HIV are often strongly associated in HIV epidemics. We assessed trends in HSV-2 prevalence among non-injecting drug users (NIDUs) when HIV prevalence declined from 16% to 8% among NIDUs in New York City. Subjects were current non-injecting users of heroin and/or cocaine and who had never injected illicit drugs. Three thousand one hundred fifty-seven NIDU subjects were recruited between 2005 and 2014 among persons entering Mount Sinai Beth Israel substance use treatment programs. Structured interviews, HIV, and HSV-2 testing were administered. Change over time was assessed by comparing 2005 to 2010 with 2011 to 2014 periods. Herpes simplex virus type 2 incidence was estimated among persons who participated in multiple years. Herpes simplex virus type 2 prevalence was strongly associated with HIV prevalence (odds ratio, 3.9; 95% confidence interval, 2.9-5.1) from 2005 to 2014. Herpes simplex virus type 2 prevalence declined from 60% to 56% (P = 0.01). The percentage of NIDUs with neither HSV-2 nor HIV infection increased from 37% to 43%, (P < 0.001); the percentage with HSV-2/HIV coinfection declined from 13% to 6% (P < 0.001). Estimated HSV-2 incidence was 1 to 2/100 person-years at risk. There were parallel declines in HIV and HSV-2 among NIDUs in New York City from 2005 to 2014. The increase in the percentage of NIDUs with neither HSV-2 nor HIV infection, the decrease in the percentage with HSV-2/HIV coinfection, and the low to moderate HSV-2 incidence suggest some population-level protection against resurgence of HIV. Prevention efforts should be strengthened to end the combined HIV/HSV-2 epidemic among NIDUs in New York City.

A new nucleoside analog, 9-[[2-hydroxy-1-(hydroxymethyl)ethoxyl]methyl]guanine, highly active in vitro against herpes simplex virus types 1 and 2.

PubMed Central

Smith, K O; Galloway, K S; Kennell, W L; Ogilvie, K K; Radatus, B K

1982-01-01

A novel nucleoside analog, 9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]-guanine (BIOLF-62), was found to have potent antiviral activity against herpes simplex virus types 1 and 2 at concentrations well below cytotoxic levels. For example, the Patton strain of herpes simplex virus type 1 was susceptible at concentrations 140- to 2,900-fold below that which inhibited cell division by 50%, depending upon the cell line used for assay. Different herpesvirus strains varied considerably in their susceptibility to the drug, as did results obtained with the same virus strain in different cell lines. BIOLF-62 compared favorably with 5-iodo-2'-deoxyuridine and acyclovir with respect to ratios of viral to cell inhibitory drug concentrations. Patterns of drug resistance to herpesvirus mutants suggested that the primary mode of action of BIOLF-62 is different from that of known antiviral compounds. Human adenovirus type 2, varicella-zoster virus, and Epstein-Barr virus were inhibited by this drug but at concentrations within the cell inhibitory range. Vaccinia virus and human cytomegalovirus were not inhibited at high drug concentrations. PMID:6289741

Combined antitumor gene therapy with herpes simplex virus-thymidine kinase and short hairpin RNA specific for mammalian target of rapamycin.

PubMed

Woo, Ha-Na; Lee, Won Il; Kim, Ji Hyun; Ahn, Jeonghyun; Han, Jeong Hee; Lim, Sue Yeon; Lee, Won Woo; Lee, Heuiran

2015-12-01

A proof-of-concept study is presented using dual gene therapy that employed a small hairpin RNA (shRNA) specific for mammalian target of rapamycin (mTOR) and a herpes simplex virus-thymidine kinase (HSV-TK) gene to inhibit the growth of tumors. Recombinant adeno-associated virus (rAAV) vectors containing a mutant TK gene (sc39TK) were transduced into HeLa cells, and the prodrug ganciclovir (GCV) was administered to establish a suicide gene-therapy strategy. Additionally, rAAV vectors expressing an mTOR-targeted shRNA were employed to suppress mTOR-dependent tumor growth. GCV selectively induced death in tumor cells expressing TK, and the mTOR-targeted shRNA altered the cell cycle to impair tumor growth. Combining the TK-GCV system with mTOR inhibition suppressed tumor growth to a greater extent than that achieved with either treatment alone. Furthermore, HSV-TK expression and mTOR inhibition did not mutually interfere with each other. In conclusion, gene therapy that combines the TK-GCV system and mTOR inhibition shows promise as a novel strategy for cancer therapy.

CTCF Occupation of the Herpes Simplex Virus 1 Genome Is Disrupted at Early Times Postreactivation in a Transcription-Dependent Manner

PubMed Central

Ertel, Monica K.; Cammarata, Amy L.; Hron, Rebecca J.

2012-01-01

In herpes simplex virus 1 (HSV-1), binding clusters enriched in CTCF during latency have been previously identified. We hypothesized that CTCF binding to CTCF clusters in HSV-1 would be disrupted in a reactivation event. To investigate, CTCF occupation of three CTCF binding clusters in HSV-1 was analyzed following sodium butyrate (NaB)- and explant-induced reactivation in the mouse. Our data show that the CTCF domains positioned within the HSV-1 genome, specifically around the latency-associated transcript (LAT) and ICP0 and ICP4 regions of the genome, lose CTCF occupancy following the application of reactivation stimuli in wild-type virus. We also found that CTCF binding clusters upstream of the ICP0 and ICP4 promoters both function as classical insulators capable of acting as enhancer blockers of the LAT enhancer. Finally, our results suggest that CTCF occupation of domains in HSV-1 may be differentially regulated both during latency and at early times following reactivation by the presence of lytic transcripts and further implicate epigenetic regulation of HSV-1 as a critical component of the latency-reactivation transition. PMID:22973047

The herpes simplex virus 2 virion-associated ribonuclease vhs interferes with stress granule formation.

PubMed

Finnen, Renée L; Hay, Thomas J M; Dauber, Bianca; Smiley, James R; Banfield, Bruce W

2014-11-01

In a previous study, it was observed that cells infected with herpes simplex virus 2 (HSV-2) failed to accumulate stress granules (SGs) in response to oxidative stress induced by arsenite treatment. As a follow-up to this observation, we demonstrate here that disruption of arsenite-induced SG formation by HSV-2 is mediated by a virion component. Through studies on SG formation in cells infected with HSV-2 strains carrying defective forms of UL41, the gene that encodes vhs, we identify vhs as a virion component required for this disruption. Cells infected with HSV-2 strains producing defective forms of vhs form SGs spontaneously late in infection. In addition to core SG components, these spontaneous SGs contain the viral immediate early protein ICP27 as well as the viral serine/threonine kinase Us3. As part of these studies, we reexamined the frameshift mutation known to reside within the UL41 gene of HSV-2 strain HG52. We demonstrate that this mutation is unstable and can rapidly revert to restore wild-type UL41 following low-multiplicity passaging. Identification of the involvement of virion-associated vhs in the disruption of SG formation will enable mechanistic studies on how HSV-2 is able to counteract antiviral stress responses early in infection. In addition, the ability of Us3 to localize to stress granules may indicate novel roles for this viral kinase in the regulation of translation. Eukaryotic cells respond to stress by rapidly shutting down protein synthesis and storing mRNAs in cytoplasmic stress granules (SGs). Stoppages in protein synthesis are problematic for all viruses as they rely on host cell machinery to synthesize viral proteins. Thus, many viruses target SGs for disruption or modification. Infection by herpes simplex virus 2 (HSV-2) was previously observed to disrupt SG formation induced by oxidative stress. In this follow-up study, we identify virion host shutoff protein (vhs) as a viral protein involved in this disruption. The identification of a specific viral protein involved in disrupting SG formation is a key step toward understanding how HSV-2 interacts with these antiviral structures. Additionally, this understanding may provide insights into the biology of SGs that may find application in studies on human motor neuron degenerative diseases, like amyotrophic lateral sclerosis (ALS), which may arise as a result of dysregulation of SG formation. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

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

A VP26-mNeonGreen Capsid Fusion HSV-2 Mutant Reactivates from Viral Latency in the Guinea Pig Genital Model with Normal Kinetics

PubMed Central

Pieknik, Julianna R.; Tang, Shuang

2018-01-01

Fluorescent herpes simplex viruses (HSV) are invaluable tools for localizing virus in cells, permitting visualization of capsid trafficking and enhancing neuroanatomical research. Fluorescent viruses can also be used to study virus kinetics and reactivation in vivo. Such studies would be facilitated by fluorescent herpes simplex virus recombinants that exhibit wild-type kinetics of replication and reactivation and that are genetically stable. We engineered an HSV-2 strain expressing the fluorescent mNeonGreen protein as a fusion with the VP26 capsid protein. This virus has normal replication and in vivo recurrence phenotypes, providing an essential improved tool for further study of HSV-2 infection. PMID:29738431

Coping strategies and behavioural changes following a genital herpes diagnosis among an urban sample of underserved Midwestern women.

PubMed

Davis, Alissa; Roth, Alexis; Brand, Juanita Ebert; Zimet, Gregory D; Van Der Pol, Barbara

2016-03-01

This study focused on understanding the coping strategies and related behavioural changes of women who were recently diagnosed with herpes simplex virus type 2. In particular, we were interested in how coping strategies, condom use, and acyclovir uptake evolve over time. Twenty-eight women screening positive for herpes simplex virus type 2 were recruited through a public health STD clinic and the Indianapolis Community Court. Participants completed three semi-structured interviews with a woman researcher over a six-month period. The interviews focused on coping strategies for dealing with a diagnosis, frequency of condom use, suppressive and episodic acyclovir use, and the utilisation of herpes simplex virus type 2 support groups. Interview data were analysed using content analysis to identify and interpret concepts and themes that emerged from the interviews. Women employed a variety of coping strategies following an herpes simplex virus type 2 diagnosis. Of the women, 32% reported an increase in religious activities, 20% of women reported an increase in substance use, and 56% of women reported engaging in other coping activities. A total of 80% of women reported abstaining from sex immediately following the diagnosis, but 76% of women reported engaging in sex again by the six-month interview. Condom and medication use did not increase and herpes simplex virus type 2 support groups were not utilised by participants. All participants reported engaging in at least one coping mechanism after receiving their diagnosis. A positive diagnosis did not seem to result in increased use of condoms for the majority of participants and the use of acyclovir was low overall. © The Author(s) 2015.

Use of Disposable Micro Tissue Culture Plates for Antiviral and Interferon Induction Studies

PubMed Central

Sidwell, Robert W.; Huffman, John H.

1971-01-01

A reproducible test system requiring small amounts of test compound was developed for evaluating antiviral and interferon-inducing activity. In the antiviral experiments, KB cells were grown in disposable polystyrene microplates covered with a standard domestic plastic wrap. Viruses used in the system were types 1 and 2 herpes simplex virus, vaccinia virus, type 3 adenovirus, myxoma virus, pseudorabies virus, type 3 parainfluenza virus, types 1A and 13 rhinovirus, vesicular stomatitis virus, coxsackievirus B, and type 2 poliovirus. Inhibition of viral cytopathogenic effect was the primary criterion of evaluation of antiviral activity. Reduction in cell and supernatant fluid virus titers was used as a secondary means of evaluation. The microplate system was adaptable for determining prophylactic, therapeutic, and inactivating effects against viruses. Mouse L-929 cells were used for the interferon induction studies, with vesicular stomatitis virus utilized as the indicator of interferon activity. Known active compounds evaluated in this microplate system had activity similar to that seen in macro in vitro systems. PMID:4332040

Trans activation of plasmid-borne promoters by adenovirus and several herpes group viruses.

PubMed Central

Everett, R D; Dunlop, M

1984-01-01

This paper describes experiments to test the ability of a number of viruses of the Herpes group, and also Adenovirus-2 and SV40, to activate transcription from the Herpes simplex virus-1 glycoprotein D and the rabbit beta-globin promoters. Plasmids containing these genes were transfected into HeLa cells which were then infected with various viruses. Transcriptional activation in trans of the plasmid-borne promoters was monitored by quantitative S1 nuclease analysis of total cytoplasmic RNA isolated after infection. The results showed that Herpes simplex viruses 1 and 2, Pseudorabies virus, Variella Zoster virus, Human Cytomegalovirus, Equine herpes virus-1 and Adenovirus-2 activate transcription from both promoters tested. In contrast, SV40 did not activate transcription in trans in this assay. The possible mechanisms of this activation are discussed. Images PMID:6089105

Affinity purification combined with mass spectrometry to identify herpes simplex virus protein-protein interactions.

PubMed

Meckes, David G

2014-01-01

The identification and characterization of herpes simplex virus protein interaction complexes are fundamental to understanding the molecular mechanisms governing the replication and pathogenesis of the virus. Recent advances in affinity-based methods, mass spectrometry configurations, and bioinformatics tools have greatly increased the quantity and quality of protein-protein interaction datasets. In this chapter, detailed and reliable methods that can easily be implemented are presented for the identification of protein-protein interactions using cryogenic cell lysis, affinity purification, trypsin digestion, and mass spectrometry.

Cell-mediated immunity in herpes simplex virus-infected mice: H-2 mapping of the delayed-type hypersensitivity response and the antiviral T cell response.

PubMed

Nash, A A; Phelan, J; Wildy, P

1981-04-01

An adoptive transfer system was used to investigate the H-2 restriction of delayed-type hypersensitivity (DTH) to herpes simplex virus. A successful DTH transfer was achieved when donor and recipient were compatible at the I-A region, with K and D region compatibility unnecessary. However, the rapid clearance of infectious virus from the inoculation site was found only when the donor and recipients were compatible at H-2K (and presumably D) and I-A regions.

Serum herpes simplex antibodies

MedlinePlus

... causes cold sores (oral herpes). HSV-2 causes genital herpes. How the Test is Performed A blood sample ... person has ever been infected with oral or genital herpes . It looks for antibodies to herpes simplex virus ...

Role of Autoantibodies to N-Methyl-d-Aspartate (NMDA) Receptor in Relapsing Herpes Simplex Encephalitis: A Retrospective, One-Center Experience.

PubMed

Sutcu, Murat; Akturk, Hacer; Somer, Ayper; Tatli, Burak; Torun, Selda Hancerli; Yıldız, Edibe Pembegul; Şık, Guntulu; Citak, Agop; Agacfidan, Ali; Salman, Nuran

2016-03-01

Post-herpes simplex virus encephalitis relapses have been recently associated with autoimmunity driven by autoantibodies against N-methyl-d-aspartate (NMDA) receptors. Because it offers different treatment options, determination of this condition is important. Between 2011 and 2014, 7 children with proven diagnosis of herpes simplex virus encephalitis were identified in a university hospital of Istanbul. Two patients had neurologic relapse characterized mainly by movement disorders 2 to 3 weeks after initial encephalitis. The first patient received a second 14 days of acyclovir treatment together with antiepileptic drugs and left with severe neurologic sequelae. The second patient was found to be NMDA receptors antibody positive in the cerebrospinal fluid. She was treated with intravenous immunoglobulin and prednisolone. She showed substantial improvement, gradually regaining lost neurologic abilities. Post-herpes simplex virus encephalitis relapses may frequently be immune-mediated rather than a viral reactivation, particularly in children displaying movement disorders like choreoathetosis. Immunotherapy may provide benefit for this potentially devastating condition, like the case described in this report. © The Author(s) 2015.

The Type I Interferon Response and Age-Dependent Susceptibility to Herpes Simplex Virus Infection.

PubMed

Giraldo, Daniel; Wilcox, Douglas R; Longnecker, Richard

2017-05-01

Herpes simplex virus type 1 (HSV-1) is a highly prevalent human neurotropic pathogen. HSV-1 infection is associated with a variety of diseases ranging from benign orolabial lesions to more serious and even life-threatening conditions such as herpes simplex keratitis and herpes simplex encephalitis (HSE). HSE is a rare occurrence among healthy adult individuals, but newborns are a particularly susceptible population. Type I IFN signaling has been identified as a crucial component of the innate immune response to the control of HSV-1 infection. In this study, we review the contribution of the type I IFN response to controlling HSV-1 infection, and differences in the early host response between adults and newborns that may contribute to the increased susceptibility to infection and central nervous system disease in newborns.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Myllys, Markko; Ruokolainen, Visa; Aho, Vesa

Lytic infection with herpes simplex virus type 1 (HSV-1) induces profound modification of the cell nucleus including formation of a viral replication compartment and chromatin marginalization into the nuclear periphery. Here, we used three-dimensional soft X-ray tomography, combined with cryogenic fluorescence, confocal and electron microscopy, to analyse the transformation of peripheral chromatin during HSV-1 infection. Our data showed an increased presence of low-density gaps in the marginalized chromatin at late infection. Advanced data analysis indicated the formation of virus-nucleocapsid-sized (or wider) channels extending through the compacted chromatin of the host. Importantly, confocal and electron microscopy analysis showed that these gapsmore » frequently contained viral nucleocapsids. Our results demonstrated that HSV-1 infection induces the formation of channels penetrating the compacted layer of cellular chromatin and allowing for the passage of progeny viruses to the nuclear envelope, their site of nuclear egress.« less

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

Challenges in designing a Taqman-based multiplex assay for the simultaneous detection of Herpes simplex virus types 1 and 2 and Varicella-zoster virus.

PubMed

Weidmann, Manfred; Armbruster, Katrin; Hufert, Frank T

2008-08-01

To optimise molecular detection of herpesviruses an internally controlled multiplex Taqman-PCR for the detection of Herpes simplex virus 1 (HSV1), Herpes simplex virus 2 (HSV2) and Varicella-zoster virus (VZV) was developed. The selection of the dye combination working on the ABI 7700 cycler for this multiplex PCR revealed crosstalk phenomena between several combinations of reference dyes and reporter dyes. A final dye combination with CY5 as reference dye and FAM/JOE/TXR as reporter dyes was selected. The influence of the concentration of the internal positive control (IPC) concentration on the quantitative results of HSV1, HSV2 and VZV positive patient samples was analysed. The results indicate that high IPC concentrations are detrimental for the sensitivity of the multiplex assay and that the presence of the IPC molecule narrows the dynamic range of the duplex PCRs between any of the virus PCRs and the IPC-PCR. The optimised multiplex assay detecting HSV1, HSV2 and VZV using 10(3) IPC molecules showed a performance and sensitivity comparable to that of the individual assays.

Susceptibility of Drug-Resistant Clinical Herpes Simplex Virus Type 1 Strains to Essential Oils of Ginger, Thyme, Hyssop, and Sandalwood▿

PubMed Central

Schnitzler, Paul; Koch, Christine; Reichling, Jürgen

2007-01-01

Acyclovir-resistant clinical isolates of herpes simplex virus type 1 (HSV-1) were analyzed in vitro for their susceptibilities to essential oils of ginger, thyme, hyssop, and sandalwood. All essential oils exhibited high levels of virucidal activity against acyclovir-sensitive strain KOS and acyclovir-resistant HSV-1 clinical isolates and reduced plaque formation significantly. PMID:17353250

Differential stability of host mRNAs in Friend erythroleukemia cells infected with herpes simplex virus type 1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mayman, B.A.; Nishioka, Y.

1985-01-01

The consequences of herpes simplex virus type 1 infection on cellular macromolecules were investigated in Friend erythroleukemia cells. The patterns of protein synthesis, examined by polyacrylamide gel electrophoresis, demonstrated that by 4 h postinfection the synthesis of many host proteins, with the exception of histones, was inhibited. Examination of the steady-state level of histone H3 mRNA by molecular hybridization of total RNA to a cloned mouse histone H3 complementary DNA probe demonstrated that the ratio of histone H3 mRNA to total RNA remained unchanged for the first 4 h postinfection. In contrast, the steady-state levels of globin and actin mRNAsmore » decreased progressively at early intervals postinfection. Studies on RNA synthesis in isolated nuclei demonstrated that the transcription of the histone H3 gene was inhibited to approximately the same extent as that of actin gene. It was concluded that the stabilization of preexisting histone H3 mRNA was responsible for the persistence of H3 mRNA and histone protein synthesis in herpes simplex virus type 1-infected Friend erythroleukemia cells. The possible mechanisms influencing the differential stability of host mRNAs during the course of productive infection with herpes simplex virus type 1 are discussed.« less

Mathematical Modeling of Herpes Simplex Virus Distribution in Solid Tumors: Implications for Cancer Gene Therapy

PubMed Central

Mok, Wilson; Stylianopoulos, Triantafyllos; Boucher, Yves; Jain, Rakesh K.

2010-01-01

Purpose Although oncolytic viral vectors show promise for the treatment of various cancers, ineffective initial distribution and propagation throughout the tumor mass often limit the therapeutic response. A mathematical model is developed to describe the spread of herpes simplex virus from the initial injection site. Experimental Design The tumor is modeled as a sphere of radius R. The model incorporates reversible binding, interstitial diffusion, viral degradation, and internalization and physiologic parameters. Three species are considered as follows: free interstitial virus, virus bound to cell surfaces, and internalized virus. Results This analysis reveals that both rapid binding and internalization as well as hindered diffusion contain the virus to the initial injection volume, with negligible spread to the surrounding tissue. Unfortunately, increasing the dose to saturate receptors and promote diffusion throughout the tumor is not a viable option: the concentration necessary would likely compromise safety. However, targeted modifications to the virus that decrease the binding affinity have the potential to increase the number of infected cells by 1.5-fold or more. An increase in the effective diffusion coefficient can result in similar gains. Conclusions This analysis suggests criteria by which the potential response of a tumor to oncolytic herpes simplex virus therapy can be assessed. Furthermore, it reveals the potential of modifications to the vector delivery method, physicochemical properties of the virus, and tumor extracellular matrix composition to enhance efficacy. PMID:19318482

Targeted entry of enveloped viruses: measles and herpes simplex virus I.

PubMed

Navaratnarajah, Chanakha K; Miest, Tanner S; Carfi, Andrea; Cattaneo, Roberto

2012-02-01

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 (HSV) 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 HSV can be applied to targeting other enveloped viruses, and alternatively how retargeted envelopes can be fitted on foreign capsids. Copyright © 2011 Elsevier B.V. All rights reserved.

Human Cytomegalovirus Secretome Contains Factors That Induce Angiogenesis and Wound Healing

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dumortier, Jerome; Streblow, Daniel N.; Moses, Ashlee V.

2008-07-01

Human cytomegalovirus (HCMV) is implicated in the acceleration of a number of vascular diseases including transplant vascular sclerosis (TVS), the lesion associated with chronic rejection (CR) of solid organ transplants. Although the virus persists in the allograft throughout the course of disease, few cells are directly infected by CMV. This observation is in contrast to the global effects that CMV has on the acceleration of TVS/CR, suggesting that CMV infection indirectly promotes the vascular disease process. Recent transcriptome analysis of CMV-infected heart allografts indicates that the virus induces cytokines and growth factors associated with angiogenesis (AG) and wound healing (WH),more » suggesting that CMV may accelerate TVS/CR through the induction and secretion of AG/WH factors from infected cells. We analyzed virus-free supernatants from HCMV-infected cells (HCMV secretomes) for growth factors, by mass spectrometry and immunoassays, and found that the HCMV secretome contains over 1,000 cellular proteins, many of which are involved in AG/WH. Importantly, functional assays demonstrated that CMV but not herpes simplex virus secretomes not only induce AG/WH but also promote neovessel stabilization and endothelial cell survival for 2 weeks. These findings suggest that CMV acceleration of TVS occurs through virus-induced growth factors and cytokines in the CMV secretome.« less

Psychosis in a 15-Year-Old Female with Herpes Simplex Encephalitis in a Background of Mannose-Binding Lecithin Deficiency.

PubMed

Asogwa, Kenneth; Buabeng, Kwame; Kaur, Amarjit

2017-01-01

Historically, psychotic disorder has been associated with viral infection. Herpes simplex infections and Epstein-Barr virus (EBV) among other viral infections have been implicated in psychotic disorder. Of note in this case report is psychotic disorder that occurred following reactivation of herpes simplex infection in a background of mannose-binding lecithin (MBL) deficiency, childhood EBV infection, and severe psychosocial stress. Herpes simplex encephalitis (HSE) remains a significant cause of morbidity and mortality despite advancement in its treatment with intravenous acyclovir. Many studies have reported psychiatric and neurological manifestation of herpes simplex infection following primary or reactivated infection, while others suggest milder clinical course of herpes simplex encephalitis in a background of immunosuppression. Another contributory factor to psychotic disorder in this case is childhood EBV exposure which has been reported to increase the risk of psychosis in adolescence and adulthood. This case report describes a 15-year-old female with MBL deficiency who presented with psychosis caused by reactivated herpes simplex infection and had good clinical recovery. Based on childhood Epstein-Barr virus exposure and psychosis in adolescence (current case), she is at increased risk of psychotic disorder in adulthood, which underscores the importance of long-term monitoring.

Identification and functional evaluation of cellular and viral factors involved in the alteration of nuclear architecture during herpes simplex virus 1 infection.

PubMed

Simpson-Holley, Martha; Colgrove, Robert C; Nalepa, Grzegorz; Harper, J Wade; Knipe, David M

2005-10-01

Herpes simplex virus 1 (HSV-1) replicates in the nucleus of host cells and radically alters nuclear architecture as part of its replication process. Replication compartments (RCs) form, and host chromatin is marginalized. Chromatin is later dispersed, and RCs spread past it to reach the nuclear edge. Using a lamin A-green fluorescent protein fusion, we provide direct evidence that the nuclear lamina is disrupted during HSV-1 infection and that the UL31 and UL34 proteins are required for this. We show nuclear expansion from 8 h to 24 h postinfection and place chromatin rearrangement and disruption of the lamina in the context of this global change in nuclear architecture. We show HSV-1-induced disruption of the localization of Cdc14B, a cellular protein and component of a putative nucleoskeleton. We also show that UL31 and UL34 are required for nuclear expansion. Studies with inhibitors of globular actin (G-actin) indicate that G-actin plays an essential role in nuclear expansion and chromatin dispersal but not in lamina alterations induced by HSV-1 infection. From analyses of HSV infections under various conditions, we conclude that nuclear expansion and chromatin dispersal are dispensable for optimal replication, while lamina rearrangement is associated with efficient replication.

Esophagitis - infectious

MedlinePlus

... include fungi, yeast, and viruses. Common organisms include: Candida albicans Cytomegalovirus (CMV) Herpes simplex virus (HSV) Human papillomavirus (HPV) Tuberculosis bacteria ( Mycobacterium tuberculosis )

Latent virus reactivation in astronauts on the international space station.

PubMed

Mehta, Satish K; Laudenslager, Mark L; Stowe, Raymond P; Crucian, Brian E; Feiveson, Alan H; Sams, Clarence F; Pierson, Duane L

2017-01-01

Reactivation of latent herpes viruses was measured in 23 astronauts (18 male and 5 female) before, during, and after long-duration (up to 180 days) spaceflight onboard the international space station . Twenty age-matched and sex-matched healthy ground-based subjects were included as a control group. Blood, urine, and saliva samples were collected before, during, and after spaceflight. Saliva was analyzed for Epstein-Barr virus, varicella-zoster virus, and herpes simplex virus type 1. Urine was analyzed for cytomegalovirus. One astronaut did not shed any targeted virus in samples collected during the three mission phases. Shedding of Epstein-Barr virus, varicella-zoster virus, and cytomegalovirus was detected in 8 of the 23 astronauts. These viruses reactivated independently of each other. Reactivation of Epstein-Barr virus, varicella-zoster virus, and cytomegalovirus increased in frequency, duration, and amplitude (viral copy numbers) when compared to short duration (10 to 16 days) space shuttle missions. No evidence of reactivation of herpes simplex virus type 1, herpes simplex virus type 2, or human herpes virus 6 was found. The mean diurnal trajectory of salivary cortisol changed significantly during flight as compared to before flight ( P  = 0.010). There was no statistically significant difference in levels of plasma cortisol or dehydoepiandosterone concentrations among time points before, during, and after flight for these international space station crew members, although observed cortisol levels were lower at the mid and late-flight time points. The data confirm that astronauts undertaking long-duration spaceflight experience both increased latent viral reactivation and changes in diurnal trajectory of salivary cortisol concentrations.

Participation of 3-O-sulfated heparan sulfates in the protection of macrophages by herpes simplex virus-1 glycoprotein D and cyclophilin B against apoptosis.

PubMed

Delos, Maxime; Hellec, Charles; Foulquier, François; Carpentier, Mathieu; Allain, Fabrice; Denys, Agnès

2017-02-01

Heparan sulfates (HS) are involved in numerous biological processes, which rely on their ability to interact with a large panel of proteins. Although the reaction of 3-O-sulfation can be catalysed by the largest family of HS sulfotransferases, very few mechanisms have been associated with this modification and to date, only glycoprotein D (gD) of herpes simplex virus-1 (HSV-1 gD) and cyclophilin B (CyPB) have been well-described as ligands for 3- O -sulfated HS. Here, we hypothesized that both ligands could induce the same responses via a mechanism dependent on 3- O -sulfated HS. First, we checked that HSV-1 gD was as efficient as CyPB to induce the activation of the same signalling events in primary macrophages. We then demonstrated that both ligands efficiently reduced staurosporin-induced apoptosis and modulated the expression of apoptotic genes. In addition to 3- O -sulfated HS, HSV-1 gD was reported to interact with other receptors, including herpes virus entry mediator (HVEM), nectin-1 and -2. Thus, we decided to identify the contribution of each binding site in the responses triggered by HSV-1 gD and CyPB. We found that knock-down of 3- O -sulfotransferase 2, which is the main 3- O -sulfated HS-generating enzyme in macrophages, strongly reduced the responses induced by both ligands. Moreover, silencing the expression of HVEM rendered macrophages unresponsive to either HSV-1 gD and CyPB, thus indicating that both proteins induced the same responses by interacting with a complex formed by 3- O -sulfated HS and HVEM. Collectively, our results suggest that HSV-1 might hijack the binding sites for CyPB in order to protect macrophages against apoptosis for efficient infection.

The use of human cornea organotypic cultures to study herpes simplex virus type 1 (HSV-1)-induced inflammation.

PubMed

Drevets, Peter; Chucair-Elliott, Ana; Shrestha, Priyadarsini; Jinkins, Jeremy; Karamichos, Dimitrios; Carr, Daniel J J

2015-10-01

To determine the utility of human organotypic cornea cultures as a model to study herpes simplex virus type 1 (HSV-1)-induced inflammation and neovascularization. Human organotypic cornea cultures were established from corneas with an intact limbus that were retrieved from donated whole globes. One cornea culture was infected with HSV-1 (10(4) plaque-forming units), while the other cornea from the same donor was mock-infected. Supernatants were collected at intervals post-culture with and without infection to determine viral titer (by plaque assay) and pro-angiogenic and proinflammatory cytokine concentration by suspension array analysis. In some experiments, the cultured corneas were collected and evaluated for HSV-1 antigens by immunohistochemical means. Another set of experiments measured susceptibility of human three-dimensional cornea fibroblast constructs, in the presence and absence of TGF-β1, to HSV-1 infection in terms of viral replication and the inflammatory response to infection as a comparison to the organotypic cornea cultures. Organotypic cornea cultures and three-dimensional fibroblast constructs exhibited varying degrees of susceptibility to HSV-1. Fibroblast constructs were more susceptible to infection in terms of infectious virus recovered in a shorter period of time. There were changes in the levels of select pro-angiogenic or proinflammatory cytokines that were dictated as much by the cultures producing them as by whether they were infected with HSV-1 or treated with TGF-β1. Organotypic cornea and three-dimensional fibroblast cultures are likely useful for the identification and short-term study of novel antiviral compounds and virus replication, but are limited in the study of the local immune response to infection.

Poxvirus-induced alteration of arachidonate metabolism.

PubMed Central

Palumbo, G J; Glasgow, W C; Buller, R M

1993-01-01

Recent evidence suggests that orthopoxviruses have an obligate requirement for arachidonic acid metabolites during replication in vivo and in vitro. Our report indicates that a virus family (Poxviridae) possesses multiple genes that function to regulate arachidonate metabolism. Analyses of BS-C-1 cells infected with cowpox virus or vaccinia virus detected enhanced arachidonate product formation from both the cyclooxygenase (specifically prostaglandins E2 and F2 alpha) and lipoxygenase (specifically 15-hydroxyeicosatetraenoic acid and 12-hydroxyeicosatetraenoic acid) pathways. In contrast, human parainfluenza type 3 or herpes simplex virus type 1 infections did not increase arachidonate metabolism. Results were consistent with a virus early-gene product either directly mediating or inducing a host factor that mediated the up-regulation of arachidonate metabolism, although vaccinia growth factor was not responsible. In addition, the cowpox virus 38-kDa protein-encoding gene, which is associated with inhibition of an inflammatory response, correlated with inhibition of formation of a product biochemically characteristic of (14R,15S)-dihydroxyeicosatetraenoic acid. We propose that orthopoxvirus-induced up-regulation of arachidonic acid metabolism during infection renders the infected cells susceptible to generation of inflammatory mediators from both the cyclooxygenase and the lipoxygenase pathways, and poxviruses, therefore, possess at least one gene (38K) that can alter the lipoxygenase-metabolite spectrum. PMID:8383332

HIV-associated hypertrophic herpes simplex genitalis with concomitant early invasive squamous cell carcinoma mimicking advanced genital cancer: case report and literature review.

PubMed

Strehl, Johanna D; Mehlhorn, Grit; Koch, Martin C; Harrer, Ellen G; Harrer, Thomas; Beckmann, Matthias W; Agaimy, Abbas

2012-05-01

Hypertrophic herpes simplex genitalis (HHSG) is an uncommon anogenital manifestation of herpes simplex virus (HSV) infection in immunocompromised patients. To date, 24 cases of HHSG have been reported; 23 of them were affected human immune deficiency virus (HIV) type 1-positive patients. We describe the case of a 44-year-old African HIV-1-positive woman who presented with painful ulcerated nodular lesions of the vulva and perianal area measuring up to 7 cm in diameter. Macroscopically, the lesions were highly suspicious of widely invasive cancer. The histologic workup of the resection specimen revealed patchy high-grade vulvar intraepithelial neoplasia Grade 3 (VIN 3) and 2 microscopic foci of superficially invasive squamous cell carcinoma. The nodular lesions were caused by massive tumefactive plasma cell-rich inflammatory infiltrates extending into the subcutis. Multinucleated herpes simplex virus 1 and herpes simplex virus 2-positive epithelial cells with glassy intranuclear inclusions were detected at the borders of the ulcerations, consistent with HHSG. Despite repeated surgery and medical treatment, the patient had 3 recurrences of HHSG within 18 months. The presence of intraepithelial neoplasia in HHSG lesions is relatively rare and has been described in 6 of 18 resected HHSG lesions in the literature so far. With regard to invasive malignancy, the present case is the first report of a superficially invasive squamous cell carcinoma associated with HHSG. Awareness of this condition is necessary to avoid misinterpretation of HHSG as widely invasive squamous cell carcinoma with the hazard of surgical and oncological overtreatment.

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

Properties of Cells Carrying the Herpes Simplex Virus Type 2 Thymidine Kinase Gene: Mechanisms of Reversion to a Thymidine Kinase-Negative Phenotype

PubMed Central

Bastow, K. F.; Darby, G.; Wildy, P.; Minson, A. C.

1980-01-01

We have isolated cells with a thymidine kinase-negative (tk−) phenotype from cells which carry the herpes simplex virus type 2 tk gene by selection in 5-bromodeoxyuridine or 9-(2-hydroxyethoxymethyl)guanine. Both selection routines generated revertants with a frequency of 10−3 to 10−4, and resistance to either compound conferred simultaneous resistance to the other. tk− revertants fell into three classes: (i) cells that arose by deletion of all virus sequences, (ii) cells that had lost the virus tk gene but retained a nonselected virus-specific function and arose by deletion of part of the virus-specific sequence, and (iii) cells that retained the potential to express all of the virus-specific functions of the parental cells and retained all of the virus-specific DNA sequences. Images PMID:16789205

Cognitive and Learning Strategies for Longstanding Temporal Lobe Lesions in a Child Who Suffered from "Herpes Simplex" Virus Encephalitis: A Case Study over 10 Years

ERIC Educational Resources Information Center

van Schoor, A. N.; Naude, H.; van Rensburg, M.; Pretorius, E.; Boon, J. M.

2005-01-01

This article presents a case study indicating that "Herpes simplex" virus (HSV) encephalitis may cause permanent learning disabilities due to damage to the temporal lobes as it discusses the results of a case study extending over 10 years to determine the long-term effects on both the anatomy of the brain and the intellectual functioning of the…

Houttuynoids A-E, anti-herpes simplex virus active flavonoids with novel skeletons from Houttuynia cordata.

PubMed

Chen, Shao-Dan; Gao, Hao; Zhu, Qin-Chang; Wang, Ya-Qi; Li, Ting; Mu, Zhen-Qiang; Wu, Hong-Ling; Peng, Tao; Yao, Xin-Sheng

2012-04-06

Houttuynoids A-E (1-5), a new type of flavonoid with houttuynin tethered to hyperoside, and their presumed biosynthetic precursor hyperoside (6) were isolated from the whole plant of Houttuynia cordata. Their structures were elucidated by analysis of 1D and 2D NMR. A hypothetical biogenetic pathway for houttuynoids A-E was proposed. Compounds 1-5 exhibited potent anti-HSV (herpes simplex viruses) activity.

Cognitive and Learning Strategies for Longstanding Temporal Lobe Lesions in a Child Who Suffered from "Herpes Simplex" Virus Encephalitis: A Case Study over 10 Years

ERIC Educational Resources Information Center

van Schoor, A. N.; Naude, H.; van Rensburg, M.; Pretorius, E.; Boon, J. M.

2004-01-01

This article presents a case study indicating that "Herpes simplex" virus (HSV) encephalitis may cause permanent learning disabilities due to damage to the temporal lobes, as it discusses the results of a case study extending over 10 years to determine the long-term effects on both the anatomy of the brain and the intellectual functioning of the…

Split T-cell tolerance in herpes simplex virus-infected mice and its implication for anti-viral immunity.

PubMed Central

Nash, A A; Ashford, N P

1982-01-01

Mice simultaneously injected intravenously and subcutaneously with herpes simplex virus fail to adoptively transfer delayed hypersensitivity (DH) to syngeneic recipients. The transferred lymph node cells also failed to rapidly eliminate infectious herpes from the pinna, despite the presence of cytotoxic T cells in the transferred suspension. Both primary and secondary cytotoxic cell responses in the draining lymph node were unaffected by the inhibition of DH. The lymph nodes from DH tolerized mice also contain lymphocytes capable of undergoing a proliferative response in vitro to herpes antigens. In addition, a neutralizing antibody response with IgG antibodies against herpes are also present in DH tolerized mice. These data suggest a form of split T-cell tolerance in which only DH responses are directly compromised. The implication of these findings for the pathogenesis of herpes simplex virus is discussed. PMID:6279490

Harmine blocks herpes simplex virus infection through downregulating cellular NF-κB and MAPK pathways induced by oxidative stress.

PubMed

Chen, Deyan; Su, Airong; Fu, Yuxuan; Wang, Xiaohui; Lv, Xiaowen; Xu, Wentao; Xu, Shijie; Wang, Huanru; Wu, Zhiwei

2015-11-01

Herpes simplex virus types 1 and 2 (HSV-1 and -2) are highly prevalent in many populations and therapeutic options are limited. Both viruses can establish latency by maintaining viral genomes in neurons of sensory ganglia. Primary or recurrent HSV infections may lead to deleterious outcomes: HSV-1 infection may result in corneal blindness and encephalitis and HSV-2 infection leads to herpes genitalis. While no effective vaccine is available, acyclovir is widely used for therapy, which targets and inhibits viral DNA polymerase. Although acyclovir is of low toxicity, resistant strains arise due to persistent use, mainly in immune compromised patients. In our effort to identify new HSV inhibitory molecules, harmine was found to potently inhibit HSV infection. Harmine, a beta-carbon alkaloid with an indole core structure and a pyridine ring, is widely distributed in plants. Earlier studies showed that harmine exhibited pharmacological activities such as antifungal, antimicrobial, antitumor, antiplasmodial and antioxidants. In the current study, we showed that harmine was a potent inhibitor of HSV-2 infection in vitro assays with EC50 value at around 1.47μM and CC50 value at around 337.10μM. The HSV RNA transcription, protein synthesis, and virus titers were reduced by the presence of harmine in a dose dependent manner. Further study on the mechanism of the anti-HSV activity showed that harmine blocked HSV-induced ROS production and the upregulated cytokine/chemokine expression, but our evidence showed that the inhibition of viral replication was unlikely mediated by the blocking of ROS production. We demonstrated that harmine significantly reduced HSV-2-induced NF-κB activation, as well as IκB-α degradation and p65 nuclear translocation. We found that harmine also inhibited HSV-2-mediated p38 kinase and c-Jun N-terminal kinases (JNK) phosphorylation. Copyright © 2015 Elsevier B.V. All rights reserved.

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

Herpes simplex virus glycoprotein D relocates nectin-1 from intercellular contacts

PubMed Central

Bhargava, Arjun K.; Rothlauf, Paul W.; Krummenacher, Claude

2016-01-01

Herpes simplex virus (HSV) uses the cell adhesion molecule nectin-1 as a receptor to enter neurons and epithelial cells. The viral glycoprotein D (gD) is used as a non-canonical ligand for nectin-1. The gD binding site on nectin-1 overlaps with a functional adhesive site involved in nectin-nectin homophilic trans-interaction. Consequently, when nectin-1 is engaged with a cellular ligand at cell junctions, the gD binding site is occupied. Here we report that HSV gD is able to disrupt intercellular homophilic trans-interaction of nectin-1 and induce a rapid redistribution of nectin-1 from cell junctions. This movement does not require the receptor’s interaction with the actin-binding adaptor afadin. Interaction of nectin-1 with afadin is also dispensable for virion surfing along nectin-1-rich filopodia. Cells seeded on gD-coated surfaces also fail to accumulate nectin-1 at cell contact. These data indicate that HSV gD affects nectin-1 locally through direct interaction and more globally through signaling. PMID:27723487

Proteomic Analysis of Secretomes of Oncolytic Herpes Simplex Virus-Infected Squamous Cell Carcinoma Cells

PubMed Central

Tada, Shinya; Hamada, Masakazu; Yura, Yoshiaki

2018-01-01

Oncolytic herpes simplex virus type 1 (HSV-1) strain RH2 induced immunogenic cell death (ICD) with the release and surface exposure of damage-associated molecular patterns (DAMPs) in squamous cell carcinoma (SCC) SCCVII cells. The supernatants of RH2-infected SCCVII cells also exhibited antitumor ability by intratumoral administration in SCCVII tumor-bearing mice. The supernatants of RH2-infected cells and mock-infected cells were concentrated to produce Med24 and MedC for proteomic analyses. In Med24, the up- and down-regulated proteins were observed. Proteins including filamin, tubulin, t-complex protein 1 (TCP-1), and heat shock proteins (HSPs), were up-regulated, while extracellular matrix (ECM) proteins were markedly down-regulated. Viral proteins were detected in Med 24. These results indicate that HSV-1 RH2 infection increases the release of danger signal proteins and viral gene products, but decreases the release of ECM components. These changes may alter the tumor microenvironment (TME) and contribute to enhancement of anti-tumor immunity against SCC. PMID:29360750

Herpes simplex virus glycoprotein D relocates nectin-1 from intercellular contacts.

PubMed

Bhargava, Arjun K; Rothlauf, Paul W; Krummenacher, Claude

2016-12-01

Herpes simplex virus (HSV) uses the cell adhesion molecule nectin-1 as a receptor to enter neurons and epithelial cells. The viral glycoprotein D (gD) is used as a non-canonical ligand for nectin-1. The gD binding site on nectin-1 overlaps with a functional adhesive site involved in nectin-nectin homophilic trans-interaction. Consequently, when nectin-1 is engaged with a cellular ligand at cell junctions, the gD binding site is occupied. Here we report that HSV gD is able to disrupt intercellular homophilic trans-interaction of nectin-1 and induce a rapid redistribution of nectin-1 from cell junctions. This movement does not require the receptor's interaction with the actin-binding adaptor afadin. Interaction of nectin-1 with afadin is also dispensable for virion surfing along nectin-1-rich filopodia. Cells seeded on gD-coated surfaces also fail to accumulate nectin-1 at cell contact. These data indicate that HSV gD affects nectin-1 locally through direct interaction and more globally through signaling. Copyright © 2016 Elsevier Inc. All rights reserved.

Antiviral Drug-Resistance Typing Reveals Compartmentalization and Dynamics of Acyclovir-Resistant Herpes Simplex Virus Type-2 (HSV-2) in a Case of Neonatal Herpes.

PubMed

Bache, Manon; Andrei, Graciela; Bindl, Lutz; Bofferding, Léon; Bottu, Jean; Géron, Christine; Neuhäuser, Christoph; Gillemot, Sarah; Fiten, Pierre; Opdenakker, Ghislain; Snoeck, Robert

2014-06-01

A neonate suffering from herpes simplex virus type 2 disease with central nervous system involvement developed an early recurrence under acyclovir therapy. Isolates from the cerebrospinal fluid and skin lesions were acyclovir resistant, while viruses from blood and trachea were not. Acyclovir combined with foscavir followed by long-term suppressive acyclovir therapy supported normal neurological development. © The Author 2013. Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Identification and Characterization of the UL37 Protein of Herpes Simplex Virus Type 1 and Demonstration that it Interacts with ICP8, the Major DNA Binding Protein of Herpes Simplex Virus

DTIC Science & Technology

1992-10-20

Identification of ORFs HSV DNA binding proteins • 1 3 3 5 7 7 11 17 18 22 reps and its role in HSV replication 23 Biochemical properties . . 23...Figure 1 . 2. 3 • 4. 5. 6. 7. 8. Structural model of the herpesvirus virion Schematic diagram of HSV pathogenesis . Diagram of the main...vaccinia virus- 13. Autoradiogram of an immunoblot of HSV - 1 -infected cell proteins harvested at various times postinfec- 85 tioD probed with anti-UL42

The fusion loops and membrane proximal region of Epstein-Barr virus glycoprotein B (gB) can function in the context of herpes simplex virus 1 gB when substituted individually but not in combination.

PubMed

Zago, Anna; Connolly, Sarah A; Spear, Patricia G; Longnecker, Richard

2013-01-01

Among the herpesvirus glycoprotein B (gB) fusion proteins, the hydrophobic content of fusion loops and membrane proximal regions (MPRs) are inversely correlated with each other. We examined the functional importance of the hydrophobicity of these regions by replacing them in herpes simplex virus type 1 gB with corresponding regions from Epstein-Barr virus gB. We show that fusion activity is dependent on the structural context in which the specific loops and MPR sequences exist, rather than a simple hydrophobic relationship. Copyright © 2012 Elsevier B.V. All rights reserved.

Genital herpes simplex.

PubMed

Tummon, I S; Dudley, D K; Walters, J H

1981-07-01

Genital herpes is a sexually transmitted disease caused by the herpes simplex virus. Following the initial infection the virus becomes latent in the sacral ganglia. Approximately 80% of patients are then subject to milder but unpredictable recurrences and may shed the virus even when they are asymptomatic. The disorder causes concern because genital herpes in the mother can result in rare but catastrophic neonatal infection and because of a possible association between genital herpes and cancer of the cervix. No effective treatment is as yet available. Weekly monitoring for virus by cervical culture from 32 weeks' gestation is recommended for women with a history of genital herpes and for those whose sexual partner has such a history.

The UL24 protein of herpes simplex virus 1 affects the sub-cellular distribution of viral glycoproteins involved in fusion

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ben Abdeljelil, Nawel; Rochette, Pierre-Alexandre; Pearson, Angela, E-mail: angela.pearson@iaf.inrs.ca

2013-09-15

Mutations in UL24 of herpes simplex virus type 1 can lead to a syncytial phenotype. We hypothesized that UL24 affects the sub-cellular distribution of viral glycoproteins involved in fusion. In non-immortalized human foreskin fibroblasts (HFFs) we detected viral glycoproteins B (gB), gD, gH and gL present in extended blotches throughout the cytoplasm with limited nuclear membrane staining; however, in HFFs infected with a UL24-deficient virus (UL24X), staining for the viral glycoproteins appeared as long, thin streaks running across the cell. Interestingly, there was a decrease in co-localized staining of gB and gD with F-actin at late times in UL24X-infected HFFs.more » Treatment with chemical agents that perturbed the actin cytoskeleton hindered the formation of UL24X-induced syncytia in these cells. These data support a model whereby the UL24 syncytial phenotype results from a mislocalization of viral glycoproteins late in infection. - Highlights: • UL24 affects the sub-cellular distribution of viral glycoproteins required for fusion. • Sub-cellular distribution of viral glycoproteins varies in cell-type dependent manner. • Drugs targeting actin microfilaments affect formation of UL24-related syncytia in HFFs.« less

Polyploidization on SK-N-MC human neuroblastoma cells infected with herpes simplex virus 1.

PubMed

Karalyan, Zaven; Izmailyan, Roza; Karalova, Elena; Abroyan, Liana; Hakobyan, Lina; Avetisyan, Aida; Semerjyan, Zara

2016-01-01

Polyploidization is one of the most dramatic changes occurring within cell genome owing to various reasons including under many viral infections. We examined the impact of herpes simplex virus-1 (HSV-1) on SK-N-MC human neuroblastoma cell line. The infected cells were followed from 6 hours up to 96 hours post infection (hpi). A large number of polyploid cells with giant nuclei was observed under the influence of HSV-1 at 24 hpi with the DNA content of 32c to 64c or more, in comparison with control SK-N-MC cells that were characterized by relatively moderate values of ploidy, i.e. 8с to 16с (where 1c is the haploid amount of nuclear DNA found in normal diploid populations in G0/G1). After 48-96 hpi, the population of polyploid cells with giant nuclei decreased to the benchmark level. The SK-NMC cells infected with HSV-1 for 24 hours were stained with gallocyanine and monitored for cytological features. The infected cells underwent virus induced cellcell and nuclei fusion with the formation of dense nuclei syncytium. The metabolic activity of HSV-1 infected cells was higher in both nuclei and nucleoli when compared to control cells.

Worldwide occurrence of virus-infections in filamentous marine brown algae

NASA Astrophysics Data System (ADS)

Müller, D. G.; Stache, B.

1992-03-01

Virus infections were detected in Ectocarpus siliculosus and Ectocarpus fasciculatus on the coasts of Ireland, California, Peru, southern South America, Australia and New Zealand; in three Feldmannia species on the coasts of Ireland, continental Chile and Archipelago Juan Fernandez (Chile); and in Leptonematella from Antarctica. Natural populations on the Irish coast contained 3% infected plants in E. fasciculatus, and less than 1% in Feldmannia simplex. On the Californian coast, 15 to 25% of Ectocarpus isolates were infected. Virus symptoms were absent in E. siliculosus from Peru, but appeared after meiosis in laboratory cultures. The virus particles in E. fasciculatus are identical in size and capsid structure to those reported for E. siliculosus, while the virus in F. simplex is smaller and has a different envelope. Our findings suggest that virus infections are a common and worldwide phenomenon in filamentous brown algae.

Isolation of pyropheophorbide a from the leaves of Atalantia monophylla (ROXB.) CORR. (Rutaceae) as a possible antiviral active principle against herpes simplex virus type 2.

PubMed

Chansakaow, S; Ruangrungsi, N; Ishikawa, T

1996-07-01

Antiviral activity-guided isolation studies on the leaves of Atalantia monophylla (ROXB.) CORR. (Rutaceae) led to the identification of pyropheophorbide a (1), a simple chlorin derivative, from the chloroform extract (fr. B) as a possible antiviral active principle against herpes simplex virus type 2 (HSV-2). Pyropheophorbide a methyl ester (2) was also isolated from the hexane extract (fr. A).

Activation of caspase-3 noninvolved in the bystander effect of the herpes simplex virus thymidine kinase gene/ganciclovir (HSV-tk/GCV) system.

PubMed

Zhang, Zhihong; Lin, Juqiang; Chu, Jun; Ma, Yan; Zeng, Shaoqun; Luo, Qingming

2008-01-01

Use of the herpes simplex virus thymidine kinase gene/ganciclovir (HSV-tk/GCV) system is one of the promising approaches in the rapidly growing area of gene therapy. The "bystander effect," a phenomenon in which HSV-tk+ cells exposed to GCV are toxic to adjacent HSV-tk- cells, was reported to play an important role in suicide gene therapy. However, the mechanism by which HSV-tk/GCV induces the bystander effect is poorly understood. We monitored the activation of caspase-3 in living cells induced by the HSV-tk/GCV system using a genetically encoded fluorescence resonance energy transfer (FRET) probe CD3, , a caspase-3 recognition site fused with a cyan fluorescent protien (CFP) and a red fluorescent protein (DsRed) which we reported and named in a previous paper. Fluorescence protein (FP)-based multicolor cellular labeling, combined with the multichannel fluorescence imaging and FRET imaging techniques, provides a novel and improved approach to directly determine whether the activation of caspase-3 involved in the HSV-tk/GCV system induces cell apoptosis in tk gene-expressing cells and their neighboring cells. FRET ratio images of CD3, and fluorescence images of the fusion protein of thymidine kinase linked with green fluorescent protein (TK-GFP), indicated that HSV-tk/GCV system-induced apoptosis in human adenoid cystic carcinoma (ACC-M) cells was via a caspase-3 pathway, and the activation of caspase-3 was not involved in the bystander effect of HSV-tk/GCV system.

The Herpes Simplex Virus Type 1 Latency-Associated Transcript Can Protect Neuron-Derived C1300 and Neuro2A Cells from Granzyme B-Induced Apoptosis and CD8 T-Cell Killing▿

PubMed Central

Jiang, Xianzhi; Alami Chentoufi, Aziz; Hsiang, Chinhui; Carpenter, Dale; Osorio, Nelson; BenMohamed, Lbachir; Fraser, Nigel W.; Jones, Clinton; Wechsler, Steven L.

2011-01-01

The herpes simplex virus type 1 (HSV-1) latency-associated transcript (LAT) is the only HSV-1 gene transcript abundantly expressed throughout latency. LAT null mutants have a significantly reduced reactivation phenotype. LAT's antiapoptosis activity is the major LAT factor involved in supporting the wild-type reactivation phenotype. During HSV-1 latency, some ganglionic neurons are surrounded by CD8 T cells, and it has been proposed that these CD8 T cells help maintain HSV-1 latency by suppressing viral reactivations. Surprisingly, despite injection of cytotoxic lytic granules by these CD8 T cells into latently infected neurons, neither apoptosis nor neuronal cell death appears to occur. We hypothesized that protection of latently infected neurons against cytotoxic CD8 T-cell killing is due to LAT's antiapoptosis activity. Since CD8 T-cell cytotoxic lytic granule-mediated apoptosis is critically dependent on granzyme B (GrB), we examined LAT's ability to block GrB-induced apoptosis. We report here that (i) LAT can interfere with GrB-induced apoptosis in cell cultures, (ii) LAT can block GrB-induced cleavage (activation) of caspase-3 both in cell culture and in a cell-free in vitro cell extract assay, and (iii) LAT can protect C1300 and Neuro2A cells from cytotoxic CD8 T-cell killing in vitro. These findings support the hypothesis that LAT's antiapoptosis activity can protect latently infected neurons from being killed by CD8 T-cell lytic granules in vivo. PMID:21177822

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.

Patient recognition of recrudescent herpes labialis: a clinical and virological assessment.

PubMed

Lamey, P J; Biagioni, P A

1996-09-01

The purpose of this study was to ascertain how accurate the general public was at diagnosing the condition of recrudescent herpes labialis. An advertisement was placed in a local newspaper inviting patients to attend the Oral Medicine Clinic as soon as they thought they developed the clinically evident stage of herpes labialis. At the clinic, patients were examined to confirm the clinical presence of herpes labialis and also had a swab of the lesion(s) taken for virus culture. Virus culture was by the HEP-2 culture technique capable of detecting both herpes simplex Type 1 and herpes simplex Type 2. Patients also completed a detailed questionnaire concerning their knowledge of herpes labialis. In total, 41 patients attended for screening. The findings were that all patients had clinical herpes labialis, and herpes simplex virus was isolated in 96% of cases. In contrast, in only about 50% of cases were patients aware that their herpes labialis was caused by a virus. The general public are very good at recognizing herpes labialis lesions but need to be given more information about their infectivity.

Herpetic keratoconjunctivitis: Therapy with synthetic double-stranded RNA

USGS Publications Warehouse

Friedman, I.; Evans, C.; Meighan, C.W.; Foote, L.J.; Aiello, P.V.; Park, J.H.; Baron, S.

1968-01-01

A study was undertaken in rabbits to determine how late in the course of keratoconjunctivitis caused by herpes simplex recovery could be effected by an inducer of interferon. Interferon was induced by means of synthetic double-stranded RNA copolymer formed with polynosinic acid : polycytidilic acid RNA. Therapy promotes recovery from severe and fully established keratoconjunctivitis for which treatment was begun as late as 3 days after virus inoculation. No drug toxicity was observed in the therapeutic dose range. These findings further support the proposed role of the interferon mechanism in the natural recovery of already established viral infection. They also suggest the usefulness of interferon inducers in viral infections of man.

The Herpes Simplex Virus 1 Latency-Associated Transcript Promotes Functional Exhaustion of Virus-Specific CD8+ T Cells in Latently Infected Trigeminal Ganglia: a Novel Immune Evasion Mechanism▿

PubMed Central

Chentoufi, Aziz A.; Kritzer, Elizabeth; Tran, Michael V.; Dasgupta, Gargi; Lim, Chang Hyun; Yu, David C.; Afifi, Rasha E.; Jiang, Xianzhi; Carpenter, Dale; Osorio, Nelson; Hsiang, Chinhui; Nesburn, Anthony B.; Wechsler, Steven L.; BenMohamed, Lbachir

2011-01-01

Following ocular herpes simplex virus 1 (HSV-1) infection of C57BL/6 mice, HSV-specific (HSV-gB498–505 tetramer+) CD8+ T cells are induced, selectively retained in latently infected trigeminal ganglia (TG), and appear to decrease HSV-1 reactivation. The HSV-1 latency-associated transcript (LAT) gene, the only viral gene that is abundantly transcribed during latency, increases reactivation. Previously we found that during latency with HSV-1 strain McKrae-derived viruses, more of the total TG resident CD8 T cells expressed markers of exhaustion with LAT+ virus compared to LAT− virus. Here we extend these findings to HSV-1 strain 17syn+-derived LAT+ and LAT− viruses and to a virus expressing just the first 20% of LAT. Thus, the previous findings were not an artifact of HSV-1 strain McKrae, and the LAT function involved mapped to the first 1.5 kb of LAT. Importantly, to our knowledge, we show here for the first time that during LAT+ virus latency, most of the HSV-1-specific TG resident CD8 T cells were functionally exhausted, as judged by low cytotoxic function and decreased gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) production. This resulted in LAT− TG having more functional HSV-gB498–505 tetramer+ CD8+ T cells compared to LAT+ TG. In addition, LAT expression, in the absence of other HSV-1 gene products, appeared to be able to directly or indirectly upregulate both PD-L1 and major histocompatibility complex class I (MHC-I) on mouse neuroblastoma cells (Neuro2A). These findings may constitute a novel immune evasion mechanism whereby the HSV-1 LAT directly or indirectly promotes functional exhaustion (i.e., dysfunction) of HSV-specific CD8+ T cells in latently infected TG, resulting in increased virus reactivation. PMID:21715478

Increased neurovirulence and reactivation of the herpes simplex virus type 1 latency associated transcript (LAT) negative mutant dLAT2903 with a disrupted LAT miR-H2

PubMed Central

Jiang, Xianzhi; Brown, Don; Osorio, Nelson; Hsiang, Chinhui; BenMohamed, Lbachir; Wechsler, Steven L.

2015-01-01

At least six microRNAs (miRNAs) appear to be encoded by the latency associated transcript (LAT) of herpes simplex virus type 1 (HSV-1). The gene for ICP0, an important immediate early (IE) viral protein, is antisense to, and overlaps with, the region of LAT from which miRNA H2 (miR-H2) is derived. We recently reported that a mutant (McK-ΔH2) disrupted for miR-H2 on the wild type HSV-1 strain McKrae genomic background has increased ICP0 expression, increased neurovirulence, and slightly more rapid reactivation. We report here that HSV-1 mutants deleted for the LAT promoter nonetheless make significant amounts of miR-H2 during lytic tissue culture infection, presumably via readthrough transcription from an upstream promoter. To determine if miR-H2 might also play a role in the HSV-1 latency-reactivation cycle of a LAT negative mutant, we constructed dLAT-ΔH2, in which miR-H2 is disrupted in dLAT2903 without altering the predicted amino acid sequence of the overlapping ICP0 open reading frame. Similar to McK-ΔH2, dLAT-ΔH2 expressed more ICP0, was more neurovirulent, and had increased reactivation in the mouse TG explant induced reactivation model of HSV-1 compared to its parental virus. Interestingly, although the increased reactivation of McK-ΔH2 compared to its parental wt virus was subtle and only detected at very early times after explant TG induced reactivation, the increased reactivation of dLAT-ΔH2 compared to its dLAT2903 parental virus appeared more robust and was significantly increased even at late times after induction. These results confirm that miR-H2 plays a role in modulating the HSV-1 reactivation phenotype. PMID:26069184

Amino acid substitutions in the thymidine kinase gene of induced acyclovir-resistant herpes simplex virus type 1

NASA Astrophysics Data System (ADS)

Hussin, Ainulkhir; Nor, Norefrina Shafinaz Md; Ibrahim, Nazlina

2013-11-01

Acyclovir (ACV) is an antiviral drug of choice in healthcare setting to treat infections caused by herpes viruses, including, but not limited to genital herpes, cold sores, shingles and chicken pox. Acyclovir resistance has emerged significantly due to extensive use and misuse of this antiviral in human, especially in immunocompromised patients. However, it remains unclear about the amino acid substitutions in thymidine (TK) gene, which specifically confer the resistance-associated mutation in herpes simplex virus. Hence, acyclovir-resistant HSV-1 was selected at high concentration (2.0 - 4.5 μg/mL), and the TK-gene was subjected to sequencing and genotypic characterization. Genotypic sequences comparison was done using HSV-1 17 (GenBank Accesion no. X14112) for resistance-associated mutation determination whereas HSV-1 KOS, HSV-1 473/08 and HSV clinical isolates sequences were used for polymorphism-associated mutation. The result showed that amino acid substitutions at the non-conserved region (UKM-1: Gln34Lys, UKM-2: Arg32Ser & UKM-5: Arg32Cys) and ATP-binding site (UKM-3: Tyr53End & UKM-4: Ile54Leu) of the TK-gene. These discoveries play an important role to extend another dimension to the evolution of acyclovir-resistant HSV-1 and suggest that selection at high ACV concentration induced ACV-resistant HSV-1 evolution. These findings also expand the knowledge on the type of mutations among acyclovir-resistant HSV-1. In conclusion, HSV-1 showed multiple strategies to exhibit acyclovir resistance, including amino acid substitutions in the TK gene.

Downregulation of Cellular c-Jun N-Terminal Protein Kinase and NF-κB Activation by Berberine May Result in Inhibition of Herpes Simplex Virus Replication

PubMed Central

Song, Siwei; Qiu, Min; Chu, Ying; Chen, Deyan; Wang, Xiaohui; Su, Airong

2014-01-01

Berberine is a quaternary ammonium salt from the protoberberine group of isoquinoline alkaloids. Some reports show that berberine exhibits anti-inflammatory, antitumor, and antiviral properties by modulating multiple cellular signaling pathways, including p53, nuclear factor κB (NF-κB), and mitogen-activated protein kinase. In the present study, we investigated the antiviral effect of berberine against herpes simplex virus (HSV) infection. Current antiherpes medicines such as acyclovir can lessen the recurring activation when used early at infection but are unable to prevent or cure infections where treatment has selected for resistant mutants. In searching for new antiviral agents against herpesvirus infection, we found that berberine reduced viral RNA transcription, protein synthesis, and virus titers in a dose-dependent manner. To elucidate the mechanism of its antiviral activity, the effect of berberine on the individual steps of viral replication cycle of HSV was investigated via time-of-drug addition assay. We found that berberine acted at the early stage of HSV replication cycle, between viral attachment/entry and genomic DNA replication, probably at the immediate-early gene expression stage. We further demonstrated that berberine significantly reduced HSV-induced NF-κB activation, as well as IκB-α degradation and p65 nuclear translocation. Moreover, we found that berberine also depressed HSV-induced c-Jun N-terminal kinase (JNK) phosphorylation but had little effect on p38 phosphorylation. Our results suggest that the berberine inhibition of HSV infection may be mediated through modulating cellular JNK and NF-κB pathways. PMID:24913175

Suppression of RIP3-dependent Necroptosis by Human Cytomegalovirus

PubMed Central

Omoto, Shinya; Guo, Hongyan; Talekar, Ganesh R.; Roback, Linda; Kaiser, William J.; Mocarski, Edward S.

2015-01-01

Necroptosis is an alternate programmed cell death pathway that is unleashed by caspase-8 compromise and mediated by receptor-interacting protein kinase 3 (RIP3). Murine cytomegalovirus (CMV) and herpes simplex virus (HSV) encode caspase-8 inhibitors that prevent apoptosis together with competitors of RIP homotypic interaction motif (RHIM)-dependent signal transduction to interrupt the necroptosis. Here, we show that pro-necrotic murine CMV M45 mutant virus drives virus-induced necroptosis during nonproductive infection of RIP3-expressing human fibroblasts, whereas WT virus does not. Thus, M45-encoded RHIM competitor, viral inhibitor of RIP activation, sustains viability of human cells like it is known to function in infected mouse cells. Importantly, human CMV is shown to block necroptosis induced by either TNF or M45 mutant murine CMV in RIP3-expressing human cells. Human CMV blocks TNF-induced necroptosis after RIP3 activation and phosphorylation of the mixed lineage kinase domain-like (MLKL) pseudokinase. An early, IE1-regulated viral gene product acts on a necroptosis step that follows MLKL phosphorylation prior to membrane leakage. This suppression strategy is distinct from RHIM signaling competition by murine CMV or HSV and interrupts an execution process that has not yet been fully elaborated. PMID:25778401

Antigenic Relationships Among Four Herpesviruses

PubMed Central

Blue, W. T.; Plummer, G.

1973-01-01

Common viral antigens were detected, by fluorescent-antibody studies, in cells infected with herpes simplex virus 1, squirrel monkey herpesvirus 1, bovine rhinotracheitis, and equine abortion viruses. The two primate viruses showed slight cross-neutralization. PMID:4351969

Herpes simplex virus-induced anti-N-methyl-d-aspartate receptor encephalitis: a systematic literature review with analysis of 43 cases.

PubMed

Nosadini, Margherita; Mohammad, Shekeeb S; Corazza, Francesco; Ruga, Ezia Maria; Kothur, Kavitha; Perilongo, Giorgio; Frigo, Anna Chiara; Toldo, Irene; Dale, Russell C; Sartori, Stefano

2017-08-01

To conduct a systematic literature review on patients with biphasic disease with herpes simplex virus (HSV) encephalitis followed by anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. We conducted a case report and systematic literature review (up to 10 December 2016), focused on differences between herpes simplex encephalitis (HSE) and anti-NMDAR encephalitis phases, age-related characteristics of HSV-induced anti-NMDAR encephalitis, and therapy. For statistical analyses, McNemar's test, Fisher's test, and Wilcoxon rank sum test were used (two-tailed significance level set at 5%). Forty-three patients with biphasic disease were identified (31 children). Latency between HSE and anti-NMDAR encephalitis was significantly shorter in children than adults (median 24 vs 40.5d; p=0.006). Compared with HSE, anti-NMDAR encephalitis was characterized by significantly higher frequency of movement disorder (2.5% vs 75% respectively; p<0.001), and significantly lower rate of seizures (70% vs 30% respectively; p=0.001). Compared with adults, during anti-NMDAR encephalitis children had significantly more movement disorders (86.7% children vs 40% adults; p=0.006), fewer psychiatric symptoms (41.9% children vs 90.0% adults; p=0.025), and a slightly higher median modified Rankin Scale score (5 in children vs 4 in adults; p=0.015). During anti-NMDAR encephalitis, 84.6 per cent of patients received aciclovir (for ≤7d in 22.7%; long-term antivirals in 18.0% only), and 92.7 per cent immune therapy, but none had recurrence of HSE clinically or using cerebrospinal fluid HSV polymerase chain reaction (median follow-up 7mo). Our review suggests that movement disorder may help differentiate clinically an episode of HSV-induced anti-NMDAR encephalitis from HSE relapse. Compared with adults, children have shorter latency between HSE and anti-NMDAR encephalitis and, during anti-NMDAR encephalitis, more movement disorder, fewer psychiatric symptoms, and slightly more severe disease. According to our results, immune therapy given for HSV-induced anti-NMDAR encephalitis does not predispose patients to HSE recurrence. © 2017 Mac Keith Press.

Burning mouth syndrome due to herpes simplex virus type 1.

PubMed

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

2015-04-01

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. 2015 BMJ Publishing Group Ltd.

Non-nucleosidic inhibition of Herpes simplex virus DNA polymerase: mechanistic insights into the anti-herpetic mode of action of herbal drug withaferin A.

PubMed

Grover, Abhinav; Agrawal, Vibhuti; Shandilya, Ashutosh; Bisaria, Virendra S; Sundar, Durai

2011-01-01

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. 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. 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 virus. Results of these studies will also guide the design of selective inhibitors of DNA POL with high specificity and potent activity in order to strengthen the therapeutic arsenal available today against the dangerous biological warfare agent represented by Herpes Simplex Virus.

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 virus. Results of these studies will also guide the design of selective inhibitors of DNA POL with high specificity and potent activity in order to strengthen the therapeutic arsenal available today against the dangerous biological warfare agent represented by Herpes Simplex Virus. PMID:22373101

Persistence in herpes simplex virus infections.

PubMed Central

Longson, M.

1978-01-01

Diseases of man caused by the virus of herpes simplex fall into two broad categories. The primary disease occurs only once in any individual's life and is caused by transmission of virus from an already infected human. Thereafter, the individual may be subject to recurrent herpetic disease, the manifestations of which are different from the primary disease. Recurrent disease varies in severity from trivial, to incapacitating and frankly lethal (as in diseases resulting from the virus's neurotropic and oncogenic properties). The source of the virus in recurrent herpetic disease has never been conclusively resolved, but is almost certainly endogenous to the patient. Theories, case reports and experiments exist to show that endogenous virus may, in periods of clinical quiescence, be latent (or persistent) at the site of the recurrent lesions itself, or more remotely in nerve tissues related to the site of recurrence. Images Fig. 1 PMID:214773

A herpes simplex virus type 1 mutant disrupted for microRNA H2 with increased neurovirulence and rate of reactivation

PubMed Central

Jiang, Xianzhi; Brown, Don; Osorio, Nelson; Hsiang, Chinhui; Li, Lily; Chan, Lucas; BenMohamed, Lbachir; Wechsler, Steven L.

2015-01-01

The herpes simplex virus type 1 (HSV-1) latency associated transcript (LAT) encodes several microRNAs. One of these, miR-H2, overlaps and is antisense to the ICP0 gene, and appears to decrease expression of the ICP0 protein. To determine if miR-H2 plays a role in the HSV-1 latency-reactivation cycle, we constructed a mutant, McK-ΔH2, in which this microRNA has been disrupted without altering the predicted amino acid sequence of ICP0. McK-ΔH2 produced increased amounts of ICP0. Although replication of McK-ΔH2 was similar to that of its wt McKrae parental virus in RS cells and mouse eyes, McK-ΔH2 was more neurovirulent in Swiss Webster mice than McKrae based on the percent of mice that died from herpes encephalitis following ocular infection. In addition, using a mouse TG explant model of induced reactivation, we show here for the first time that miR-H2 appears to play a role in modulating HSV-1 reactivation. Although the percent of TG from which virus reactivated by day 10 after explant was similar for McK-ΔH2, wt McKrae, and the marker rescued virus McK-ΔH2Res, at earlier times significantly more reactivation was seen with McK-ΔH2. Our results suggest that in the context of the virus, miR-H2 downregulates ICP0 and this moderates both HSV-1 neurovirulence and reactivation. PMID:25645379

Tanshinone IIA Increases the Bystander Effect of Herpes Simplex Virus Thymidine Kinase/Ganciclovir Gene Therapy via Enhanced Gap Junctional Intercellular Communication

PubMed Central

Liu, Xijuan; Wu, Yingya; Du, Biaoyan; Li, Jiefen; Zhou, Jing; Li, Jingjing; Tan, Yuhui

2013-01-01

The bystander effect is an intriguing phenomenon by which adjacent cells become sensitized to drug treatment during gene therapy with herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV). This effect is reported to be mediated by gap junctional intercellular communication (GJIC), and therefore, we postulated that upregulation of genes that facilitate GJIC may enhance the HSV-tk/GCV bystander effect. Previous findings have shown Tanshinone IIA (Tan IIA), a chemical substance derived from a Chinese medicine herb, promotes the upregulation of the connexins Cx26 and Cx43 in B16 cells. Because gap junctions are formed by connexins, we hypothesized that Tan IIA might increase GJIC. Our results show that Tan IIA increased GJIC in B16 melanoma cells, leading to more efficient GCV-induced bystander killing in cells stably expressing HSV-tk. Additionally, in vivo experiments demonstrated that tumors in mice with 10% HSV-tk positive B16 cells and 90% wild-type B16 cells became smaller following treatment with the combination of GCV and Tan IIA as compared to GCV or Tan IIA alone. These data demonstrate that Tan IIA can augment the bystander effect of HSV-tk/GCV system through increased gap junction coupling, which adds strength to the promising strategy that develops connexins inducer to potentiate the effects of suicide gene therapy. PMID:23861780

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

2016-06-09

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.

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

Medroxyprogesterone acetate inhibits CD8+ T cell viral specific effector function and induces herpes simplex virus type 1 reactivation

PubMed Central

Cherpes, Thomas L.; Busch, James L.; Sheridan, Brian S.; Harvey, Stephen A. K.; Hendricks, Robert L.

2008-01-01

Clinical research suggests hormonal contraceptive use is associated with increased frequencies of herpes simplex virus (HSV) reactivation and shedding. We examined the effects of medroxyprogesterone acetate (MPA), the compound most commonly used for injectable hormonal contraception, on HSV-1 reactivation and CD8+ T cell function in murine trigeminal ganglia (TG). In ex vivo TG cultures, MPA dramatically inhibited canonical CD8+ T cell effector functions, including IFN-γ production and lytic granule release, and increased HSV-1 reactivation from latency. In vivo, MPA treatment of latently infected ovariectomized mice inhibited IFN-γ production and lytic granule release by TG resident CD8+ T cells stimulated directly ex vivo. RNA specific for the essential immediate early viral gene ICP4 as well as viral genome DNA copy number were increased in mice that received MPA during latency, suggesting that treatment increased in vivo reactivation. The increase in HSV-1 copy number appeared to be the result of a two-tine effect, as MPA induced higher reactivation frequencies from latently infected explanted TG neurons in the presence or absence of CD45+ cells. Our data suggest hormonal contraceptives that contain MPA may promote increased frequency of HSV reactivation from latency through the combinatory effects of inhibiting protective CD8+ T cell responses and by a leukocyte-independent effect on infected neurons. PMID:18606648

The immunomodulator, ammonium trichloro[1,2-ethanediolato-O,O']-tellurate, suppresses the propagation of herpes simplex virus 2 by reducing the infectivity of the virus progeny.

PubMed

Sheinboim, D; Hindiyeh, M; Mendelson, E; Albeck, M; Sredni, B; Dovrat, S

2015-07-01

Persistent investigations for the identification of novel anti-herpetic drugs are being conducted worldwide, as current treatment options are sometimes insufficient. The immunomodulator, ammonium trichloro[1,2‑ethanediolato‑O,O']‑tellurate (AS101), a non‑toxic tellurium (Ⅳ) compound, has been shown to exhibit anti‑viral activity against a variety of viruses in cell cultures and in animal models. In the present study, the anti‑viral activity of AS101 against herpes simplex virus (HSV)‑1 and 2 was investigated in vitro. The results demonstrated that AS101 significantly restricted HSV‑2-induced plaque formation and reduced the infectivity of the HSV‑2 yield, while HSV‑1 was affected to a lesser extent. The incubation of mature HSV‑1 and HSV‑2 viruses with AS101 had no effect on viral infectivity, indicating that the compound interrupts de novo viral synthesis. The addition of AS101 at up to 9 h post‑infection had almost the same effect as did the addition of the drug together with the virus (it maintained 80% of its total anti‑viral capacity). Quantitative PCR and immunofluoresence staining of viral structural proteins revealed that the viral DNA and protein synthesis stages were not interrupted by the administration of AS101. By contrast, in the presence of the compound, significantly fewer viable viruses (≥2 log reduction) were recovered from the AS10‑treated cell cultures. Of note, when we determined the viability of the intracellular virus, formed in the presence of the compound, a less severe (≤1 log) effect was observed. Taken together, these data strongly suggest that AS101 primarily interferes with late stages of viral replication, such as viral particle envelopment or egress, leading to the production of a defective virus progeny.

Blocking herpes simplex virus 2 glycoprotein E immune evasion as an approach to enhance efficacy of a trivalent subunit antigen vaccine for genital herpes.

PubMed

Awasthi, Sita; Huang, Jialing; Shaw, Carolyn; Friedman, Harvey M

2014-08-01

Herpes simplex virus 2 (HSV-2) subunit antigen vaccines targeting virus entry molecules have failed to prevent genital herpes in human trials. Our approach is to include a virus entry molecule and add antigens that block HSV-2 immune evasion. HSV-2 glycoprotein C (gC2) is an immune evasion molecule that inhibits complement. We previously reported that adding gC2 to gD2 improved vaccine efficacy compared to the efficacy of either antigen alone in mice and guinea pigs. Here we demonstrate that HSV-2 glycoprotein E (gE2) functions as an immune evasion molecule by binding the IgG Fc domain. HSV-2 gE2 is synergistic with gC2 in protecting the virus from antibody and complement neutralization. Antibodies produced by immunization with gE2 blocked gE2-mediated IgG Fc binding and cell-to-cell spread. Mice immunized with gE2 were only partially protected against HSV-2 vaginal challenge in mice; however, when gE2 was added to gC2/gD2 to form a trivalent vaccine, neutralizing antibody titers with and without complement were significantly higher than those produced by gD2 alone. Importantly, the trivalent vaccine protected the dorsal root ganglia (DRG) of 32/33 (97%) mice between days 2 and 7 postchallenge, compared with 27/33 (82%) in the gD2 group. The HSV-2 DNA copy number was significantly lower in mice immunized with the trivalent vaccine than in those immunized with gD2 alone. The extent of DRG protection using the trivalent vaccine was better than what we previously reported for gC2/gD2 immunization. Therefore, gE2 is a candidate antigen for inclusion in a multivalent subunit vaccine that attempts to block HSV-2 immune evasion. Herpes simplex virus is the most common cause of genital ulcer disease worldwide. Infection results in emotional distress for infected individuals and their partners, is life threatening for infants exposed to herpes during childbirth, and greatly increases the risk of individuals acquiring and transmitting HIV infection. A vaccine that prevents genital herpes infection will have major public health benefits. Our vaccine approach includes strategies to prevent the virus from evading immune attack. Mice were immunized with a trivalent vaccine containing an antigen that induces antibodies to block virus entry and two antigens that induce antibodies that block immune evasion from antibody and complement. Immunized mice demonstrated no genital disease, and 32/33 (97%) animals had no evidence of infection of dorsal root ganglia, suggesting that the vaccine may prevent the establishment of latency and recurrent infections. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Social Stress and the Reactivation of Latent Herpes Simplex Virus Type 1

NASA Astrophysics Data System (ADS)

Padgett, David A.; Sheridan, John F.; Dorne, Julianne; Berntson, Gary G.; Candelora, Jessica; Glaser, Ronald

1998-06-01

Psychological stress is thought to contribute to reactivation of latent herpes simplex virus (HSV). Although several animal models have been developed in an effort to reproduce different pathogenic aspects of HSV keratitis or labialis, until now, no good animal model existed in which application of a psychological laboratory stressor results in reliable reactivation of the virus. Reported herein, disruption of the social hierarchy within colonies of mice increased aggression among cohorts, activated the hypothalamic-pituitary-adrenal axis, and caused reactivation of latent HSV type 1 in greater than 40% of latently infected animals. However, activation of the hypothalamic-pituitary-adrenal axis using restraint stress did not activate the latent virus. Thus, the use of social stress in mice provides a good model in which to investigate the neuroendocrine mechanisms that underlie behaviorally mediated reactivation of latent herpes-viruses.

Recombination Promoted by DNA Viruses: Phage λ to Herpes Simplex Virus

PubMed Central

Weller, Sandra K.; Sawitzke, James A.

2015-01-01

The purpose of this review is to explore recombination strategies in DNA viruses. Homologous recombination is a universal genetic process that plays multiple roles in the biology of all organisms, including viruses. Recombination and DNA replication are interconnected, with recombination being essential for repairing DNA damage and supporting replication of the viral genome. Recombination also creates genetic diversity, and viral recombination mechanisms have important implications for understanding viral origins as well as the dynamic nature of viral-host interactions. Both bacteriophage λ and herpes simplex virus (HSV) display high rates of recombination, both utilizing their own proteins and commandeering cellular proteins to promote recombination reactions. We focus primarily on λ and HSV, as they have proven amenable to both genetic and biochemical analysis and have recently been shown to exhibit some surprising similarities that will guide future studies. PMID:25002096

Prevalence of herpes simplex virus 1 and 2 antibodies in patients with autism spectrum disorders.

PubMed

Gentile, Ivan; Zappulo, Emanuela; Bonavolta, Raffaele; Maresca, Roberta; Riccio, Maria Pia; Buonomo, Antonio Riccardo; Portella, Giuseppe; Vallefuoco, Luca; Settimi, Alessandro; Pascotto, Antonio; Borgia, Guglielmo; Bravaccio, Carmela

2014-01-01

The etiology of autism spectrum disorder (ASD) is unknown, even though it is hypothesized that a viral infection could trigger this disorder. The aim of this study was to evaluate the seropositivity rate and antibody level of Herpes Simplex Virus 1 (HSV1) and Herpes Simplex Virus 2 (HSV2) in children with ASD compared to same-aged healthy controls. We compared seropositivity rate and levels of antibodies to HSV1/2 in 54 children with ASD (19 with autistic disorder and 35 with non-autistic ASD) and in 46 controls. Seropositivity rate and levels of anti-HSV1/2 were not dissimilar between cases and controls. Exposure to HSV2 was minimal. Rate of contact with HSV1 and HSV2 assessed by the mean of detection of specific antibodies was similar between children with ASD and healthy controls. Copyright © 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

[Neonatal facial palsy: identification of herpes simplex virus 1 in cerebrospinal fluid. Case report].

PubMed

Lubián López, Simón; Pérez Guerrero, Juan J; Salazar Oliva, Patricia; Benavente Fernández, Isabel

2018-06-01

Neonatal facial palsy is very uncommon and is generally diagnosed at birth. We present the first published case of neonatal facial palsy with identification of herpes simplex virus 1 in cerebrospinal fluid. A 35-day-old male was presented at the Emergency Department with mouth deviation to the left and impossibility of full closure of the right eye. There were no symptoms of infection or relevant medical history. Physical examination was compatible with peripheral facial palsy. Studies performed at admission were normal (blood count, biochemical analysis and coagulation blood tests and cerebrospinal fluid analysis). The patient was admitted on oral prednisolone and intravenous aciclovir. Cranial magnetic resonance was normal. Polymerase chain reaction test for herpes simplex virus 1 in cerebrospinal fluid was reported positive after 48 hours of admission. Patient followed good evolution and received prednisolone for 7 days and acyclovir for 21 days. At discharge, neurological examination was normal. Sociedad Argentina de Pediatría.

Identification of a Monocyte Receptor on Herpesvirus-Infected Endothelial Cells

NASA Astrophysics Data System (ADS)

Etingin, Orli R.; Silverstein, Roy L.; Hajjar, David P.

1991-08-01

The adhesion of circulating blood cells to vascular endothelium may be an initial step in atherosclerosis, inflammation, and wound healing. One mechanism for promoting cell-cell adhesion involves the expression of adhesion molecules on the surface of the target cell. Herpes simplex virus infection of endothelium induces arterial injury and has been implicated in the development of human atherosclerosis. We now demonstrate that HSV-infected endothelial cells express the adhesion molecule GMP140 and that this requires cell surface expression of HSV glycoprotein C and local thrombin generation. Monocyte adhesion to HSV-infected endothelial cells was completely inhibited by anti-GMP140 antibodies but not by antibodies to other adhesion molecules such as VCAM and ELAM-1. The induction of GMP140 expression on HSV-infected endothelium may be an important pathophysiological mechanism in virus-induced cell injury and inflammation.

Management of Developmentally Disabled Children with Chronic Infections.

ERIC Educational Resources Information Center

Andersen, Richard D.

1988-01-01

The nature of chronic infections in developmentally disabled children is reviewed, along with appropriate management strategies for care providers and implications for other children. Discussed are herpes simplex virus, cytomegalovirus, hepatitis B virus, and human immunodeficiency virus. (Author/JDD)

US9, a stable lysine-less herpes simplex virus 1 protein, is ubiquitinated before packaging into virions and associates with proteasomes

PubMed Central

Brandimarti, Renato; Roizman, Bernard

1997-01-01

The US9 gene of herpes simplex virus 1 encodes a virion tegument protein with a predicted Mr of 10,000. Earlier studies have shown that the gene is not essential for viral replication in cells in culture. We report that (i) US9 forms in denaturing polyacrylamide gels multiple overlapping bands ranging in Mr from 12,000 to 25,000; (ii) the protein recovered from infected cells or purified virions reacts with anti-ubiquitin antibodies; (iii) autoradiographic images of US9 protein immunoprecipitated from cells infected with [35S]methionine-labeled virus indicate that the protein is stable for at least 4 h after entry into cells (the protein was also stable for at least 4 h after a 1-h labeling interval 12 h after infection); (iv) antibody to subunit 12 of proteasomes pulls down US9 protein from herpes simplex virus-infected cell lysates; and (v) the US9 gene is highly conserved among the members of the alpha subfamily of herpes viruses, and the US9 gene product lacks lysines. We conclude that US9 is a lysine-less, ubiquitinated protein that interacts with the ubiquitin-dependent pathway for degradation of proteins and that this function may be initiated at the time of entry of the virus into the cell. PMID:9391137

Herpes Simplex Virus Suppressive Therapy in Herpes Simplex Virus-2/Human Immunodeficiency Virus-1 Coinfected Women Is Associated With Reduced Systemic CXCL10 But Not Genital Cytokines.

PubMed

Andersen-Nissen, Erica; Chang, Joanne T; Thomas, Katherine K; Adams, Devin; Celum, Connie; Sanchez, Jorge; Coombs, Robert W; McElrath, M Juliana; Baeten, Jared M

2016-12-01

Herpes simplex virus type-2 (HSV-2) may heighten immune activation and increase human immunodeficiency virus 1 (HIV-1) replication, resulting in greater infectivity and faster HIV-1 disease progression. An 18-week randomized, placebo-controlled crossover trial of 500 mg valacyclovir twice daily in 20 antiretroviral-naive women coinfected with HSV-2 and HIV-1 was conducted and HSV-2 suppression was found to significantly reduce both HSV-2 and HIV-1 viral loads both systemically and the endocervical compartment. To determine the effect of HSV-2 suppression on systemic and genital mucosal inflammation, plasma specimens, and endocervical swabs were collected weekly from volunteers in the trial and cryopreserved. Plasma was assessed for concentrations of 31 cytokines and chemokines; endocervical fluid was eluted from swabs and assayed for 14 cytokines and chemokines. Valacyclovir significantly reduced plasma CXCL10 but did not significantly alter other cytokine concentrations in either compartment. These data suggest genital tract inflammation in women persists despite HSV-2 suppression, supporting the lack of effect on transmission seen in large scale efficacy trials. Alternative therapies are needed to reduce persistent mucosal inflammation that may enhance transmission of HSV-2 and HIV-1.

Recurrent herpes simplex virus type 2 meningitis in elderly persons.

PubMed

Davis, Larry E; Guerre, Jenny; Gerstein, Wendy H

2010-06-01

To review the ages of patients with recurrent herpes simplex virus type 2 (HSV-2) meningitis. Case report and literature review back to 1970. Referral Veterans Affairs hospital. Our patient developed his first episode of recurrent HSV-2 meningitis at 78 years of age, 57 years after his only episode of genital herpes simplex infection. Of 223 patients in the literature with recurrent HSV-2 meningitis, 5% occurred in patients older than 60 years and 19% in patients older than 50 years. Although recurrent meningitis due to HSV is primarily seen in young, sexually active adults, a surprising number of episodes of HSV meningitis can develop in older age. Meningitis due to HSV-2 should be in the differential diagnosis of aseptic meningitis in older patients.

Recombinant Vaccinia Virus: Immunization against Multiple Pathogens

NASA Astrophysics Data System (ADS)

Perkus, Marion E.; Piccini, Antonia; Lipinskas, Bernard R.; Paoletti, Enzo

1985-09-01

The coding sequences for the hepatitis B virus surface antigen, the herpes simplex virus glycoprotein D, and the influenza virus hemagglutinin were inserted into a single vaccinia virus genome. Rabbits inoculated intravenously or intradermally with this polyvalent vaccinia virus recombinant produced antibodies reactive to all three authentic foreign antigens. In addition, the feasibility of multiple rounds of vaccination with recombinant vaccinia virus was demonstrated.

Mouse superkiller‐2‐like helicase DDX60 is dispensable for type I IFN induction and immunity to multiple viruses

PubMed Central

Goubau, Delphine; van der Veen, Annemarthe G.; Chakravarty, Probir; Lin, Rongtuan; Rogers, Neil; Rehwinkel, Jan; Deddouche, Safia; Rosewell, Ian; Hiscott, John

2015-01-01

Abstract IFN‐α/β allow cells to fight virus infection by inducing the expression of many genes that encode effectors of antiviral defense. One of these, the Ski2‐like DExH‐box helicase DDX60, was recently implicated in resistance of human cells to hepatitis C virus, as well as in induction of IFN‐α/β by retinoic acid inducible gene 1‐like receptors (RLRs) that detect the presence of RNA viruses in a cell‐intrinsic manner. Here, we sought to investigate the role of DDX60 in IFN‐α/β induction and in resistance to virus infection. Analysis of fibroblasts and myeloid cells from Ddx60‐deficient mice revealed no impairment in IFN‐α/β production in response to RLR agonists, RNA viruses, or other stimuli. Moreover, overexpression of DDX60 did not potentiate IFN induction and DDX60 did not interact with RLRs or capture RLR agonists from virally infected cells. We also failed to identify any impairment in Ddx60‐deficient murine cells or mice in resistance to infection with influenza A virus, encephalomyocarditis virus, Sindbis virus, vaccinia virus, or herpes simplex virus‐1. These results put in question the reported role of DDX60 as a broad‐acting positive regulator of RLR responses and hint at the possibility that it may function as a restriction factor highly specific for a particular virus or class of viruses. PMID:26457795

Friendly fire: redirecting herpes simplex virus-1 for therapeutic applications.

PubMed

Advani, S J; Weichselbaum, R R; Whitley, R J; Roizman, B

2002-09-01

Herpes simplex virus-1 (HSV-1) is a relatively large double-stranded DNA virus encoding at least 89 proteins with well characterized disease pathology. An understanding of the functions of viral proteins together with the ability to genetically engineer specific viral mutants has led to the development of attenuated HSV-1 for gene therapy. This review highlights the progress in creating attenuated genetically engineered HSV-1 mutants that are either replication competent (viral non-essential gene deleted) or replication defective (viral essential gene deleted). The choice between a replication-competent or -defective virus is based on the end-goal of the therapeutic intervention. Replication-competent HSV-1 mutants have primarily been employed as antitumor oncolytic viruses, with the lytic nature of the virus harnessed to destroy tumor cells selectively. In replacement gene therapy, replication-defective viruses have been utilized as delivery vectors. The advantages of HSV-1 vectors are that they infect quiescent and dividing cells efficiently and can encode for relatively large transgenes.

Epidermal Viral Immunity Induced by CD8α+ Dendritic Cells But Not by Langerhans Cells

NASA Astrophysics Data System (ADS)

Allan, Rhys S.; Smith, Chris M.; Belz, Gabrielle T.; van Lint, Allison L.; Wakim, Linda M.; Heath, William R.; Carbone, Francis R.

2003-09-01

The classical paradigm for dendritic cell function derives from the study of Langerhans cells, which predominate within skin epidermis. After an encounter with foreign agents, Langerhans cells are thought to migrate to draining lymph nodes, where they initiate T cell priming. Contrary to this, we show here that infection of murine epidermis by herpes simplex virus did not result in the priming of virus-specific cytotoxic T lymphocytes by Langerhans cells. Rather, the priming response required a distinct CD8α+ dendritic cell subset. Thus, the traditional view of Langerhans cells in epidermal immunity needs to be revisited to accommodate a requirement for other dendritic cells in this response.

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

Herpes simplex virus 2 VP22 phosphorylation induced by cellular and viral kinases does not influence intracellular localization

DOE Office of Scientific and Technical Information (OSTI.GOV)

Geiss, Brian J.; Cano, Gina L.; Tavis, John E.

2004-12-05

Phosphorylation of the herpes simplex virus (HSV) VP22 protein is regulated by cellular kinases and the UL13 viral kinase, but the sites at which these enzymes induce phosphorylation of HSV-2 VP22 are not known. Using serine-to-alanine mutants to map phosphorylation sites on HSV-2 VP22 in cells, we made three major observations. First, phosphorylation by a cellular kinase mapped to serines 70, 71, and/or 72 within CKII consensus sites analogous to previously identified phosphorylation sites in HSV-1 VP22. Second, we mapped UL13-mediated phosphorylation of HSV-2 VP22 to serines 28 and 34, describing for the first time UL13-dependent phosphorylation sites on VP22.more » Third, previously identified VP22-associated cellular kinase sites in HSV-1 VP22 (serines 292 and 294) were not phosphorylated in HSV-2 VP22 (serines 291 and 293). VP22 expressed alone accumulated in the cytoplasm and to a lesser extent in the nucleus. Phosphorylation by endogenous cellular kinase(s) did not alter the localization of VP22. Co-expression of HSV-2 VP22 with active UL13, but not with enzymatically inactive UL13, resulted in nuclear accumulation of VP22 and altered nuclear morphology. Surprisingly, redistribution of VP22 to the nucleus occurred independently of UL13-induced phosphorylation of VP22. The altered nuclear morphology of UL13-expressing cells was not due to apoptosis. These results demonstrate that phosphorylation of HSV-2 VP22 at multiple serine residues is induced by UL13 and cellular kinase(s), and that the nuclear/cytoplasmic distribution of VP22 is independent of its phosphorylation status but is controlled indirectly by UL13 kinase activity.« less

Herpes simplex virus serotype and entry receptor availability alter CNS disease in a mouse model of neonatal HSV.

PubMed

Kopp, Sarah J; Ranaivo, Hantamalala R; Wilcox, Douglas R; Karaba, Andrew H; Wainwright, Mark S; Muller, William J

2014-12-01

Outcomes of neonates with herpes simplex virus (HSV) encephalitis are worse after infection with HSV-2 when compared with HSV-1. The proteins herpes virus entry mediator (HVEM) and nectin-1 mediate HSV entry into susceptible cells. Prior studies have shown receptor-dependent differences in pathogenesis that depend on route of inoculation and host developmental age. We investigated serotype-related differences in HSV disease and their relationship to entry receptor availability in a mouse model of encephalitis. Mortality was attenuated in 7-d-old, wild-type (WT) mice inoculated with HSV-1(F) when compared with HSV-2(333). No serotype-specific differences were seen after inoculation of adult mice. HSV-1 pathogenesis was also attenuated relative to HSV-2 in newborn but not adult mice lacking HVEM or nectin-1. HSV-2 requires nectin-1 for encephalitis in adult but not newborn mice; in contrast, nectin-1 was important for HSV-1 pathogenesis in both age groups. Early viral replication was independent of age, viral serotype, or mouse genotype, suggesting host responses influence outcomes. In this regard, significantly greater amounts of inflammatory mediators were detected in brain homogenates from WT newborns 2 d after infection compared with adults and receptor-knockout newborns. Dysregulation of inflammatory responses induced by infection may influence the severity of HSV encephalitis.

Induction of Cervical Neoplasia in the Mouse by Herpes Simplex Virus Type 2 DNA

NASA Astrophysics Data System (ADS)

Anthony, Donald D.; Budd Wentz, W.; Reagan, James W.; Heggie, Alfred D.

1989-06-01

Induction of cervical neoplasia in the mouse cervix by herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) has been reported. The present study was done to determine if transfection with DNA of HSV-2 can induce carcinogenesis in this animal model. Genomic HSV-2 DNA was isolated from infected HEp-2 cells and separated from host cell DNA by cesium chloride density gradient centrifugation. The DNA was applied to mouse cervix for periods of 80-100 weeks. Experimental controls were treated with uninfected genomic HEp-2 cell DNA or with calf thymus DNA. Vaginal cytological preparations from all animals were examined monthly to detect epithelial abnormalities. Animals were sacrificed and histopathology studies were done when cellular changes indicative of premalignant or malignant lesions were seen on vaginal smears. Cytologic and histologic materials were coded and evaluated without knowledge of whether they were from animals treated with virus or control DNA. Premalignant and malignant cervical lesions similar to those that occur in women were detected in 61% of the histologic specimens obtained from animals exposed to HSV-2 DNA. The yield of invasive cancers was 21% in animals treated with HSV-2 DNA. No cancers were detected in mice treated with either HEp-2 or calf thymus DNA. Dysplasia was detected in only one of these control animals.

Neonatal herpes simplex virus infection: epidemiology and treatment.

PubMed

James, Scott H; Kimberlin, David W

2015-03-01

Herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) are highly prevalent viruses capable of establishing lifelong infection. Genital herpes in women of childbearing age represents a major risk for mother-to-child transmission (MTCT) of HSV infection, with primary and first-episode genital HSV infections posing the highest risk. The advent of antiviral therapy with parenteral acyclovir has led to significant improvement in neonatal HSV disease mortality. Further studies are needed to improve the clinician's ability to identify infants at increased risk for HSV infection and prevent MTCT, and to develop novel antiviral agents with increased efficacy in infants with HSV infection. Copyright © 2015 Elsevier Inc. All rights reserved.

Performance of the Epstein-Barr Virus and Herpes Simplex Virus Immunoglobulin M Assays on the Liaison Platform with Sera from Patients Displaying Acute Parvovirus B19 Infection▿

PubMed Central

Costa, Elisa; Tormo, Nuria; Clari, María Ángeles; Bravo, Dayana; Muñoz-Cobo, Beatriz; Navarro, David

2009-01-01

Acute parvovirus B19 infection has been reported to cause false-positive results frequently in the Epstein-Barr (EBV) and herpes simplex virus (HSV) immunoglobulin M (IgM) assays from DiaSorin performed on the Liaison platform. We tested 65 sera from patients with a presumptive or conclusive diagnosis of acute parvovirus B19 infection in both assays and obtained no false-positive results in the EBV IgM test and 10.4% nonspecific reactivities in the HSV IgM assay. Our data support the specificity of both assays in this clinical setting. PMID:19571110

Tolerance and immunity in mice infected with herpes simplex virus: studies on the mechanism of tolerance to delayed-type hypersensitivity.

PubMed

Nash, A A; Phelan, J; Gell, P G; Wildy, P

1981-06-01

Tolerance to delayed-type hypersensitivity is produced in mice following an intravenous injection of herpes simplex virus. This form of tolerance is produced early on, following simultaneous injections of virus subcutaneously and intravenously, and is long lasting (greater than 100 days). The early tolerance mechanism is resistant to high doses of cyclophosphamide and is not transferable by serum or spleen cells taken after 7 days. However, spleen cells taken at 14 days onwards inhibit the induction of delayed hypersensitivity when transferred to normal syngeneic recipients. These cells are T lymphocytes and are specific for the herpes type used in the induction.

Tolerance and immunity in mice infected with herpes simplex virus: studies on the mechanism of tolerance to delayed-type hypersensitivity.

PubMed Central

Nash, A A; Phelan, J; Gell, P G; Wildy, P

1981-01-01

Tolerance to delayed-type hypersensitivity is produced in mice following an intravenous injection of herpes simplex virus. This form of tolerance is produced early on, following simultaneous injections of virus subcutaneously and intravenously, and is long lasting (greater than 100 days). The early tolerance mechanism is resistant to high doses of cyclophosphamide and is not transferable by serum or spleen cells taken after 7 days. However, spleen cells taken at 14 days onwards inhibit the induction of delayed hypersensitivity when transferred to normal syngeneic recipients. These cells are T lymphocytes and are specific for the herpes type used in the induction. PMID:6265348

Quantitative autoradiographic mapping of focal herpes simplex virus encephalitis using a radiolabeled antiviral drug

DOE Office of Scientific and Technical Information (OSTI.GOV)

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.

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

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

Identification of a novel higher molecular weight isoform of USP7/HAUSP that interacts with the Herpes simplex virus type-1 immediate early protein ICP0.

PubMed

Antrobus, Robin; Boutell, Chris

2008-10-01

The Herpes simplex virus type-1 (HSV-1) regulatory protein ICP0, a RING-finger E3 ubiquitin ligase, stimulates the onset of viral lytic replication and the reactivation of quiescent viral genomes from latency. Like many ubiquitin ligases ICP0 induces its own ubiquitination, a process that can lead to its proteasome-dependent degradation. ICP0 counteracts this activity by recruiting the cellular ubiquitin-specific protease USP7/HAUSP. Here we show that ICP0 can also interact with a previously unidentified isoform of USP7 (termed here USP7(beta)). This isoform is not a predominantly ubiquitinated, SUMO-modified, or phosphorylated species of USP7 but is constitutively expressed in a number of different cell types. Like USP7, USP7(beta) binds specifically to an electrophilic ubiquitin probe, indicating that it contains an accessible catalytic core with potential ubiquitin-protease activity. The interaction formed between ICP0 and USP7(beta) requires ICP0 to have an intact USP7-binding domain and results in its susceptibility to ICP0-mediated degradation during HSV-1 infection.

Mediators and Mechanisms of Herpes Simplex Virus Entry into Ocular Cells

PubMed Central

Farooq, Asim V.; Valyi-Nagy, Tibor; Shukla, Deepak

2010-01-01

The entry of herpes simplex virus (HSV) into cells was once thought to be a general process. It is now understood that the virus is able to use multiple mechanisms for entry and spread, including the use of receptors and co-receptors that have been determined to be cell-type specific. This is certainly true for ocular cell types, which is important as the virus may use different mechanisms to gain access to multiple anatomic structures in close proximity, leading to various ocular diseases. There are some patterns that may be utilized by the virus in the eye and elsewhere, including surfing along filopodia in moving from cell to cell. There are common themes as well as intriguing differences in the entry mechanisms of HSV into ocular cells. We discuss these issues in the context of conjunctivitis, keratitis, acute retinal necrosis and other ocular diseases. PMID:20465436

Characterization of soluble glycoprotein D-mediated herpes simplex virus type 1 infection

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tsvitov, Marianna; Frampton, Arthur R.; Shah, Waris A.

2007-04-10

Herpes simplex virus type 1 (HSV-1) entry into permissive cells involves attachment to cell-surface glycosaminoglycans (GAGs) and fusion of the virus envelope with the cell membrane triggered by the binding of glycoprotein D (gD) to cognate receptors. In this study, we characterized the observation that soluble forms of the gD ectodomain (sgD) can mediate entry of gD-deficient HSV-1. We examined the efficiency and receptor specificity of this activity and used sequential incubation protocols to determine the order and stability of the initial interactions required for entry. Surprisingly, virus binding to GAGs did not increase the efficiency of sgD-mediated entry andmore » gD-deficient virus was capable of attaching to GAG-deficient cells in the absence of sgD. These observations suggested a novel binding interaction that may play a role in normal HSV infection.« less

Evaluation of an edible blue-green alga, Aphanothece sacrum, for its inhibitory effect on replication of herpes simplex virus type 2 and influenza virus type A.

PubMed

Ogura, Fumie; Hayashi, Kyoko; Lee, Jung-Bum; Kanekiyo, Kenji; Hayashi, Toshimitsu

2010-01-01

A hot-water extract of Aphanothece sacrum, an edible aquacultured blue-green alga, was found to show a remarkable inhibitory effect on the replication of enveloped viruses including herpes simplex virus type 2 (HSV-2) and influenza virus type A (IFV-A, H1N1) in vitro. The main active components were suggested to be sulfated polysaccharides in non-dialyzable portion (ASWPH). ASWPH was found to inhibit the viral adsorption to the receptor of the host cells involved in the replication process of HSV-2 and IFV-A. In addition, while the penetration stage of HSV-2 was also significantly suppressed with ASWPH, no such effect was observed in the replication of IFV-A. These results suggest that ASWPH might be useful in the prevention of infectious diseases caused by HSV-2 as well as IFV-A.

Immune mechanisms induced by an HSV-1 mutant strain: Discrepancy analysis of the immune system gene profile in comparison with a wild-type strain.

PubMed

Zhang, Xiaolong; Jiang, Quanlong; Xu, Xingli; Wang, Yongrong; Liu, Lei; Lian, Yaru; Li, Hao; Wang, Lichun; Zhang, Ying; Jiang, Guorun; Zeng, Jieyuan; Zhang, Han; Han, Jing-Dong Jackie; Li, Qihan

2018-04-25

Herpes simplex virus is a prevalent pathogen of humans of various age groups. The fact that no prophylactic or therapeutic vaccine is currently available suggests a significant need to further investigate the immune mechanisms induced by the virus and various vaccine candidates. We previously generated an HSV-1 mutant strain, M3, with partial deletions in ul7, ul41 and LAT that produced an attenuated phenotype in mice. In the present study, we performed a comparative analysis to characterize the immune responses induced by M3 versus wild-type HSV-1 in a mouse model. Infection with wild-type HSV-1 triggered an inflammatory-dominated response and adaptive immunity suppression and was accompanied by severe pathological damage. In contrast, infection with M3 induced a systematic immune response involving full activation of both innate and adaptive immunity and was accompanied by no obvious pathological changes. Furthermore, the immune response induced by M3 protected mice from lethal challenge with wild-type strains of HSV-1 and restrained virus proliferation and impaired latency. These data are useful for further HSV-1 vaccine development using a mutant strain construction strategy. Copyright © 2018 Elsevier Ltd. All rights reserved.

An Adjuvanted Herpes Simplex Virus 2 Subunit Vaccine Elicits a T Cell Response in Mice and Is an Effective Therapeutic Vaccine in Guinea Pigs

PubMed Central

Skoberne, Mojca; Cardin, Rhonda; Lee, Alexander; Kazimirova, Ana; Zielinski, Veronica; Garvie, Danielle; Lundberg, Amy; Larson, Shane; Bravo, Fernando J.; Bernstein, David I.; Flechtner, Jessica B.

2013-01-01

Immunotherapeutic herpes simplex virus 2 (HSV-2) vaccine efficacy depends upon the promotion of antigen-specific immune responses that inhibit reactivation or reactivated virus, thus controlling both recurrent lesions and viral shedding. In the present study, a candidate subunit vaccine, GEN-003/MM-2, was evaluated for its ability to induce a broad-spectrum immune response in mice and therapeutic efficacy in HSV-2-infected guinea pigs. GEN-003 is comprised of HSV-2 glycoprotein D2 (gD2ΔTMR340-363) and a truncated form of infected cell polypeptide 4 (ICP4383-766), formulated with Matrix M-2 (MM-2) adjuvant (GEN-003/MM-2). In addition to eliciting humoral immune responses, CD4+ and CD8+ T cells characterized by the secretion of multiple cytokines and cytolytic antigen-specific T cell responses that were able to be recalled at least 44 days after the last immunization were induced in immunized mice. Furthermore, vaccination with either GEN-003 or GEN-003/MM-2 led to significant reductions in both the prevalence and severity of lesions in HSV-2-infected guinea pigs compared to those of phosphate-buffered saline (PBS) control-vaccinated animals. While vaccination with MM-2 adjuvant alone decreased recurrent disease symptoms compared to the PBS control group, the difference was not statistically significant. Importantly, the frequency of recurrent viral shedding was considerably reduced in GEN-003/MM-2-vaccinated animals but not in GEN-003- or MM-2-vaccinated animals. These findings suggest a possible role for immunotherapeutic GEN-003/MM-2 vaccination as a viable alternative to chronic antiviral drugs in the treatment and control of genital herpes disease. PMID:23365421

Herpes Simplex Virus Type 1 Neuronal Infection Perturbs Golgi Apparatus Integrity through Activation of Src Tyrosine Kinase and Dyn-2 GTPase

PubMed Central

Martin, Carolina; Leyton, Luis; Hott, Melissa; Arancibia, Yennyfer; Spichiger, Carlos; McNiven, Mark A.; Court, Felipe A.; Concha, Margarita I.; Burgos, Patricia V.; Otth, Carola

2017-01-01

Herpes simplex virus type 1 (HSV-1) is a ubiquitous pathogen that establishes a latent persistent neuronal infection in humans. The pathogenic effects of repeated viral reactivation in infected neurons are still unknown. Several studies have reported that during HSV-1 epithelial infection, the virus could modulate diverse cell signaling pathways remodeling the Golgi apparatus (GA) membranes, but the molecular mechanisms implicated, and the functional consequences to neurons is currently unknown. Here we report that infection of primary neuronal cultures with HSV-1 triggers Src tyrosine kinase activation and subsequent phosphorylation of Dynamin 2 GTPase, two players with a role in GA integrity maintenance. Immunofluorescence analyses showed that HSV-1 productive neuronal infection caused a scattered and fragmented distribution of the GA through the cytoplasm, contrasting with the uniform perinuclear distribution pattern observed in control cells. In addition, transmission electron microscopy revealed swollen cisternae and disorganized stacks in HSV-1 infected neurons compared to control cells. Interestingly, PP2, a selective inhibitor for Src-family kinases markedly reduced these morphological alterations of the GA induced by HSV-1 infection strongly supporting the possible involvement of Src tyrosine kinase. Finally, we showed that HSV-1 tegument protein VP11/12 is necessary but not sufficient to induce Dyn2 phosphorylation. Altogether, these results show that HSV-1 neuronal infection triggers activation of Src tyrosine kinase, phosphorylation of Dynamin 2 GTPase, and perturbation of GA integrity. These findings suggest a possible neuropathogenic mechanism triggered by HSV-1 infection, which could involve dysfunction of the secretory system in neurons and central nervous system. PMID:28879169

Herpes Simplex Virus Type 1 Neuronal Infection Perturbs Golgi Apparatus Integrity through Activation of Src Tyrosine Kinase and Dyn-2 GTPase.

PubMed

Martin, Carolina; Leyton, Luis; Hott, Melissa; Arancibia, Yennyfer; Spichiger, Carlos; McNiven, Mark A; Court, Felipe A; Concha, Margarita I; Burgos, Patricia V; Otth, Carola

2017-01-01

Herpes simplex virus type 1 (HSV-1) is a ubiquitous pathogen that establishes a latent persistent neuronal infection in humans. The pathogenic effects of repeated viral reactivation in infected neurons are still unknown. Several studies have reported that during HSV-1 epithelial infection, the virus could modulate diverse cell signaling pathways remodeling the Golgi apparatus (GA) membranes, but the molecular mechanisms implicated, and the functional consequences to neurons is currently unknown. Here we report that infection of primary neuronal cultures with HSV-1 triggers Src tyrosine kinase activation and subsequent phosphorylation of Dynamin 2 GTPase, two players with a role in GA integrity maintenance. Immunofluorescence analyses showed that HSV-1 productive neuronal infection caused a scattered and fragmented distribution of the GA through the cytoplasm, contrasting with the uniform perinuclear distribution pattern observed in control cells. In addition, transmission electron microscopy revealed swollen cisternae and disorganized stacks in HSV-1 infected neurons compared to control cells. Interestingly, PP2, a selective inhibitor for Src-family kinases markedly reduced these morphological alterations of the GA induced by HSV-1 infection strongly supporting the possible involvement of Src tyrosine kinase. Finally, we showed that HSV-1 tegument protein VP11/12 is necessary but not sufficient to induce Dyn2 phosphorylation. Altogether, these results show that HSV-1 neuronal infection triggers activation of Src tyrosine kinase, phosphorylation of Dynamin 2 GTPase, and perturbation of GA integrity. These findings suggest a possible neuropathogenic mechanism triggered by HSV-1 infection, which could involve dysfunction of the secretory system in neurons and central nervous system.

Elimination of mitochondrial DNA is not required for herpes simplex virus 1 replication.

PubMed

Duguay, Brett A; Saffran, Holly A; Ponomarev, Alina; Duley, Shayla A; Eaton, Heather E; Smiley, James R

2014-03-01

Infection with herpes simplex virus type 1 (HSV-1) results in the rapid elimination of mitochondrial DNA (mtDNA) from host cells. It is known that a mitochondrial isoform of the viral alkaline nuclease (UL12) called UL12.5 triggers this process. However, very little is known about the impact of mtDNA depletion on viral replication or the biology of HSV-1 infections. These questions have been difficult to address because UL12.5 and UL12 are encoded by overlapping transcripts that share the same open reading frame. As a result, mutations that alter UL12.5 also affect UL12, and UL12 null mutations severely impair viral growth by interfering with the intranuclear processing of progeny viral genomes. Therefore, to specifically assess the impact of mtDNA depletion on viral replication, it is necessary to eliminate the activity of UL12.5 while preserving the nuclear functions of UL12. Previous work has shown that the human cytomegalovirus alkaline nuclease UL98 can functionally substitute for UL12 during HSV-1 replication. We found that UL98 is unable to deplete mtDNA in transfected cells and therefore generated an HSV-1 variant in which UL98 coding sequences replace the UL12/UL12.5 open reading frame. The resulting virus was severely impaired in its ability to trigger mtDNA loss but reached titers comparable to those of wild-type HSV-1 in one-step and multistep growth experiments. Together, these observations demonstrate that the elimination of mtDNA is not required for HSV-1 replication in cell culture. Herpes simplex virus types 1 and 2 destroy the DNA of host cell mitochondria, the powerhouses of cells. Epstein-Barr virus, a distantly related herpesvirus, has a similar effect, indicating that mitochondrial DNA destruction is under positive selection and thus confers a benefit to the virus. The present work shows that mitochondrial DNA destruction is not required for efficient replication of herpes simplex virus type 1 in cultured Vero kidney epithelial cells, suggesting that this activity likely benefits the virus in other cell types or in the intact human host.

The nervous system in genital herpes simplex virus type 2 infections in mice. Lethal panmyelitis or nonlethal demyelinative myelitis or meningitis.

PubMed

Martin, J R; Stoner, G L

1984-11-01

Female mice were inoculated vaginally with the MS strain of herpes simplex virus type 2, and serially positive vaginal cultures were used to confirm infection. The proportion of mice infected and the mortality rate in infected mice decreased with increasing age. In mice 12 weeks old, clinical, neuropathologic, and virologic criteria defined four patterns of disease. Moribund mice had severe genital lesions, hindleg paralysis, and urinary and fecal retention, and most died during the second week of infection. These mice had a panmyelitis with a decreasing gradient of both viral antigen and lesions extending rostrally from the lumbosacral cord into the brain stem. Lesions were about equally distributed in gray and white matter and were characterized by neuronal loss and axonal demyelination, respectively. By contrast, mice with nonfatal infections had mild or no evident genital lesions and a small proportion had mild hindleg weakness. Of these, some mice had demyelinative lesions, particularly in the lower spinal cord but also at higher cord and brain stem levels, whereas others had leptomeningitis. Both of these groups had sacral sensory root abnormalities. A third group of survivors lacked both sensory root and central nervous system abnormalities. This report defines a broader spectrum of disease patterns following infection by a natural route than has been previously appreciated. It provides the first evidence that nonfatal herpes simplex virus type 2 infection by a peripheral route can produce central nervous system demyelination. It indicates that in aseptic meningitis with this agent, the route of virus spread to the central nervous system is neural and not hematogenous. Finally, the antigenic and pathologic observations presented here complement and confirm the virus isolation data and pathologic findings of others that genital herpes simplex virus type 2 infection causes ascending infection in the peripheral and central nervous system.

Topical SMIP-7.7, a toll-like receptor 7 agonist, protects against genital herpes simplex virus type-2 disease in the guinea pig model of genital herpes.

PubMed

Bernstein, David I; Cardin, Rhonda D; Bravo, Fernando J; Earwood, Julie; Clark, Jennifer R; Li, Yongkai; Mishra, Pranab; Li, Chun; Nayak, Bishnu P; Miller, Andrew T; Wu, Tom Y-H; Cooke, Michael P; Valiante, Nicholas M

2014-04-11

Development of more effective therapies for genital herpes simplex virus type-2 (HSV-2) infections remains a priority. The toll-like receptors (TLR) are attractive targets for the immunomodulation of primary and recurrent genital herpes infection. The guinea pig model of genital HSV-2 disease was therefore used to evaluate the efficacy of a new TLR-7 agonist, SMIP-7.7. The effects of SMIP-7.7 at concentrations between 0.90% and 0.09% were compared to the vehicle control or Aldara(®) (3M Health Care Limited, Northridge, CA, USA) as treatment for genital HSV-2 infections. Following intravaginal inoculation of Hartley guinea pigs with 10(6) pfu HSV-2 (MS strain), animals were treated intravaginally beginning at 36 h post-infection. Animals were evaluated for acute disease, acute virus replication, recurrent disease and shedding, as well as infection of the dorsal root ganglia. Treatment with SMIP-7.7 significantly decreased mean total lesion scores during primary infection (all doses, P<0.01 compared with vehicle control, and similar to Aldara(®)). Vaginal virus titres were reduced in treated animals compared with vehicle control (P<0.001 for each treatment versus vehicle control on day 4). Treatment with SMIP-7.7 also significantly decreased the number of recurrent lesion days, the number of days with recurrent virus shedding and the infection of the dorsal root ganglia compared to the vehicle control, and was similar to Aldara(®). As opposed to Aldara(®), SMIP-7.7 did not induce fever or weight loss during treatment. SMIP-7.7 improves the outcome of primary and recurrent HSV-2 disease comparable to Aldara(®) but without some of the side effects associated with Aldara(®).

Bovine Herpes Virus 1 (BHV-1) and Herpes Simplex Virus Type 1 (HSV-1) Promote Survival of Latently Infected Sensory Neurons, in Part by Inhibiting Apoptosis

PubMed Central

Jones, Clinton

2013-01-01

α-Herpesvirinae subfamily members, including herpes simplex virus type 1 (HSV-1) and bovine herpes virus 1 (BHV-1), initiate infection in mucosal surfaces. BHV-1 and HSV-1 enter sensory neurons by cell-cell spread where a burst of viral gene expression occurs. When compared to non-neuronal cells, viral gene expression is quickly extinguished in sensory neurons resulting in neuronal survival and latency. The HSV-1 latency associated transcript (LAT), which is abundantly expressed in latently infected neurons, inhibits apoptosis, viral transcription, and productive infection, and directly or indirectly enhances reactivation from latency in small animal models. Three anti-apoptosis genes can be substituted for LAT, which will restore wild type levels of reactivation from latency to a LAT null mutant virus. Two small non-coding RNAs encoded by LAT possess anti-apoptosis functions in transfected cells. The BHV-1 latency related RNA (LR-RNA), like LAT, is abundantly expressed during latency. The LR-RNA encodes a protein (ORF2) and two microRNAs that are expressed in certain latently infected neurons. Wild-type expression of LR gene products is required for stress-induced reactivation from latency in cattle. ORF2 has anti-apoptosis functions and interacts with certain cellular transcription factors that stimulate viral transcription and productive infection. ORF2 is predicted to promote survival of infected neurons by inhibiting apoptosis and sequestering cellular transcription factors which stimulate productive infection. In addition, the LR encoded microRNAs inhibit viral transcription and apoptosis. In summary, the ability of BHV-1 and HSV-1 to interfere with apoptosis and productive infection in sensory neurons is crucial for the life-long latency-reactivation cycle in their respective hosts. PMID:25278776

Herpes simplex virus amplicon delivery of a hypoxia-inducible soluble vascular endothelial growth factor receptor (sFlk-1) inhibits angiogenesis and tumor growth in pancreatic adenocarcinoma.

PubMed

Reinblatt, Maura; Pin, Richard H; Bowers, William J; Federoff, Howard J; Fong, Yuman

2005-12-01

Tumor hypoxia induces vascular endothelial growth factor (VEGF) expression, which stimulates angiogenesis and tumor proliferation. The VEGF signaling pathway is inhibited by soluble VEGF receptors (soluble fetal liver kinase 1; sFlk-1), which bind VEGF and block its interaction with endothelial cells. Herpes simplex virus (HSV) amplicons are replication-incompetent viruses used for gene delivery. We attempted to attenuate angiogenesis and inhibit pancreatic tumor growth through HSV amplicon-mediated expression of sFlk-1 under hypoxic control. A multimerized hypoxia-responsive enhancer (10 x HRE) was cloned upstream of the sFlk-1 gene (10 x HRE/sFlk-1). A novel HSV amplicon expressing 10 x HRE/sFlk-1 was genetically engineered (HSV10 x HRE/sFlk-1).Human pancreatic adenocarcinoma cells (AsPC1) were transduced with HSV10 x HRE/sFlk-1 and incubated in normoxia (21% oxygen) or hypoxia (1% oxygen). Capillary inhibition was evaluated by human umbilical vein endothelial cell assay. Western blot assessed sFlk-1 expression. AsPC1 flank tumor xenografts (n = 24) were transduced with HSV10 x HRE/sFlk-1. Media from normoxic AsPC1 transduced with HSV10 x HRE/sFlk-1 yielded a 36% reduction in capillary formation versus controls (P < .05), whereas hypoxic AsPC1 yielded a 76% reduction (P < .005). Western blot of AsPC1 transduced with HSV10 x HRE/sFlk-1 demonstrated greater sFlk-1 expression in hypoxia versus normoxia. AsPC1 flank tumors treated with HSV10 x HRE/sFlk-1 exhibited a 59% reduction in volume versus controls (P < .000001). HSV amplicon delivery of a hypoxia-inducible soluble VEGF receptor significantly reduces new vessel formation and tumor growth. Tumor hypoxia can thus be used to direct antiangiogenic therapy to pancreatic adenocarcinoma.

Alphaherpesvirus Proteins Related to Herpes Simplex Virus Type 1 ICP0 Affect Cellular Structures and Proteins

PubMed Central

Parkinson, Jane; Everett, Roger D.

2000-01-01

The herpes simplex virus type 1 (HSV-1) immediate-early protein ICP0 interacts with several cellular proteins and induces the proteasome-dependent degradation of others during infection. In this study we show that ICP0 is required for the proteasome-dependent degradation of the ND10 protein Sp100 and, as with the other target proteins, the ICP0 RING finger domain is essential. Further, comparison of the kinetics and ICP0 domain requirements for the degradation of PMI and Sp100 suggests that a common mechanism is involved. Homologues of ICP0 are encoded by other members of the alphaherpesvirus family. These proteins show strong sequence homology to ICP0 within the RING finger domain but limited similarity elsewhere. Using transfection assays, we have shown that all the ICP0 homologues that we tested have significant effects on the immunofluorescence staining character of at least one of the proteins destabilized by ICP0, and by using a recombinant virus, we found that the equine herpesvirus ICP0 homologue induced the proteasome-dependent degradation of endogenous CENP-C and modified forms of PML and Sp100. However, in contrast to ICP0, the homologue proteins had no effect on the distribution of the ubiquitin-specific protease USP7 within the cell, consistent with their lack of a USP7 binding domain. We also found that ICP0 by itself could induce the abrogation of SUMO-1 conjugation and then the proteasome-dependent degradation of unmodified exogenous PML in transfected cells, thus demonstrating that other HSV-1 proteins are not required. Surprisingly, the ICP0 homologues were unable to cause these effects. Overall, these data suggest that the members of the ICP0 family of proteins may act via a similar mechanism or pathway involving their RING finger domain but that their intrinsic activities and effects on endogenous and exogenous proteins differ in detail. PMID:11024129

Virus inactivation under the photodynamic effect of phthalocyanine zinc(II) complexes.

PubMed

Remichkova, Mimi; Mukova, Luchia; Nikolaeva-Glomb, Lubomira; Nikolova, Nadya; Doumanova, Lubka; Mantareva, Vanya; Angelov, Ivan; Kussovski, Veselin; Galabov, Angel S

2017-03-01

Various metal phthalocyanines have been studied for their capacity for photodynamic effects on viruses. Two newly synthesized water-soluble phthalocyanine Zn(II) complexes with different charges, cationic methylpyridyloxy-substituted Zn(II)- phthalocyanine (ZnPcMe) and anionic sulfophenoxy-substituted Zn(II)-phthalocyanine (ZnPcS), were used for photoinactivation of two DNA-containing enveloped viruses (herpes simplex virus type 1 and vaccinia virus), two RNA-containing enveloped viruses (bovine viral diarrhea virus and Newcastle disease virus) and two nude viruses (the enterovirus Coxsackie B1, a RNA-containing virus, and human adenovirus 5, a DNA virus). These two differently charged phthalocyanine complexes showed an identical marked virucidal effect against herpes simplex virus type 1, which was one and the same at an irradiation lasting 5 or 20 min (Δlog=3.0 and 4.0, respectively). Towards vaccinia virus this effect was lower, Δlog=1.8 under the effect of ZnPcMe and 2.0 for ZnPcS. Bovine viral diarrhea virus manifested a moderate sensitivity to ZnPcMe (Δlog=1.8) and a pronounced one to ZnPcS at 5- and 20-min irradiation (Δlog=5.8 and 5.3, respectively). The complexes were unable to inactivate Newcastle disease virus, Coxsackievirus B1 and human adenovirus type 5.

Infection of Polarized MDCK Cells with Herpes Simplex Virus 1: Two Asymmetrically Distributed Cell Receptors Interact with Different Viral Proteins

NASA Astrophysics Data System (ADS)

Sears, Amy E.; McGwire, Bradford S.; Roizman, Bernard

1991-06-01

Herpes simplex virus 1 attaches to at least two cell surface receptors. In polarized epithelial (Madin-Darby canine kidney; MDCK) cells one receptor is located in the apical surface and attachment to the cells requires the presence of glycoprotein C in the virus. The second receptor is located in the basal surface and does not require the presence of glycoprotein C. Exposure of MDCK cells at either the apical or basal surface to wild-type virus yields plaques and viral products whereas infection by a glycoprotein C-negative mutant yields identical results only after exposure of MDCK cells to virus at the basal surface. Multiple receptors for viral entry into cells expand the host range of the virus. The observation that glycoprotein C-negative mutants are infectious in many nonpolarized cell lines suggests that cells in culture may express more than one receptor and explains why genes that specify the viral proteins that recognize redundant receptors, like glycoprotein C, are expendable.

Synergism of herpes simplex virus and tobacco-specific N'-nitrosamines in cell transformation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Park, N.H.; Dokko, H.; Li, S.L.

1991-03-01

Previous studies indicate that herpes simplex virus (HSV) enhances the carcinogenic activity of smokeless tobacco and tobacco-related chemical carcinogens in animals. Since tobacco-specific N'-nitrosamines (TSNAs) such as N'-nitrosonornicotine (NNN) and 4-(N-methyl-N'-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are major chemical carcinogens of smokeless tobacco and are known to be responsible for the development of oral cancers in smokeless tobacco users, the combined effects of TSNAs and HSV in cell transformation were investigated. Exposure of cells to NNN or NNK followed by virus infection resulted in a significant enhancement of transformation frequency when compared with that observed with chemical carcinogens or virus alone. This study suggestsmore » that TSNAs and HSV can interact together and show synergism in cell transformation.« less

Neurons versus herpes simplex virus: the innate immune interactions that contribute to a host–pathogen standoff

PubMed Central

Rosato, Pamela C; Leib, David A

2015-01-01

Herpes simplex virus (HSV) is a prevalent neurotropic virus, which establishes lifelong latent infections in the neurons of sensory ganglia. Despite our long-standing knowledge that HSV predominately infects sensory neurons during its life cycle, little is known about the neuronal antiviral response to HSV infection. Recent studies show that while sensory neurons have impaired intrinsic immunity to HSV infection, paracrine IFN signaling can potentiate a potent antiviral response. Additionally, antiviral autophagy plays an important role in neuronal control of HSV infection. Here we review the literature of antiviral signaling and autophagy in neurons, the mechanisms by which HSV can counteract these responses, and postulate how these two pathways may synergize to mediate neuronal control of HSV infection and yet result in lifelong persistence of the virus. PMID:26213562

Inhibition of herpes simplex virus multiplication by activated macrophages: a role for arginase?

PubMed Central

Wildy, P; Gell, P G; Rhodes, J; Newton, A

1982-01-01

Proteose-peptone-activated mouse macrophages can prevent productive infection by herpes simplex virus in neighboring cells in vitro whether or not those cells belong to the same animal species. The effect does not require contact between the macrophages and the infected cells, may be prevented by adding extra arginine to the medium, and may be reversed when extra arginine is added 24 h after the macrophages. Arginase activity was found both intracellularly and released from the macrophages. The extracellular enzyme is quite stable; 64% activity was found after 48 h of incubation at 37 degrees C in tissue culture medium. No evidence was found that the inefficiency of virus replication in macrophages was due to self-starvation by arginase. As might be predicted macrophages can, by the same mechanism, limit productive infection by vaccinia virus. PMID:6286497

Inhibition of herpes simplex virus multiplication by activated macrophages: a role for arginase?

PubMed

Wildy, P; Gell, P G; Rhodes, J; Newton, A

1982-07-01

Proteose-peptone-activated mouse macrophages can prevent productive infection by herpes simplex virus in neighboring cells in vitro whether or not those cells belong to the same animal species. The effect does not require contact between the macrophages and the infected cells, may be prevented by adding extra arginine to the medium, and may be reversed when extra arginine is added 24 h after the macrophages. Arginase activity was found both intracellularly and released from the macrophages. The extracellular enzyme is quite stable; 64% activity was found after 48 h of incubation at 37 degrees C in tissue culture medium. No evidence was found that the inefficiency of virus replication in macrophages was due to self-starvation by arginase. As might be predicted macrophages can, by the same mechanism, limit productive infection by vaccinia virus.

Primate Neural Retina Upregulates IL-6 and IL-10 in Response to a Herpes Simplex Vector Suggesting the Presence of a Pro-/Anti-inflammatory Axis

PubMed Central

Sauter, Monica M.; Brandt, Curtis R.

2016-01-01

Injection of herpes simplex virus vectors into the vitreous of primate eyes induces an acute, transient uveitis. The purpose of this study was to characterize innate immune responses of macaque neural retina tissue to the herpes simplex virus type 1-based gene delivery vector hrR3. PCR array analysis demonstrated the induction of the pro-inflammatory cytokine IL-6, as well as the anti-inflammatory cytokine IL-10, following hrR3 exposure. Secretion of IL-6 was detected by ELISA and cone photoreceptors and Muller cells were the predominant IL-6 positive cell types. RNA in situ hybridization confirmed that IL-6 was expressed in photoreceptor and Muller cells. The IL-10 positive cells in the inner nuclear layer were identified as amacrine cells by immunofluorescence staining with calretinin antibody. hrR3 challenge resulted in activation of NFκB (p65) in Muller glial cells, but not in cone photoreceptors, suggesting a novel regulatory mechanism for IL-6 expression in cone cells. hrR3 replication was not required for IL-6 induction or NFκB (p65) activation. These data suggest a pro-inflammatory (IL-6)/anti-inflammatory (IL-10) axis exists in neural retina and the severity of acute posterior uveitis may be determined by this interaction. Further studies are needed to identify the trigger for IL-6 and IL-10 induction and the mechanism of IL-6 induction in cone cells. PMID:27170050

Mouse superkiller-2-like helicase DDX60 is dispensable for type I IFN induction and immunity to multiple viruses.

PubMed

Goubau, Delphine; van der Veen, Annemarthe G; Chakravarty, Probir; Lin, Rongtuan; Rogers, Neil; Rehwinkel, Jan; Deddouche, Safia; Rosewell, Ian; Hiscott, John; Reis E Sousa, Caetano

2015-12-01

IFN-α/β allow cells to fight virus infection by inducing the expression of many genes that encode effectors of antiviral defense. One of these, the Ski2-like DExH-box helicase DDX60, was recently implicated in resistance of human cells to hepatitis C virus, as well as in induction of IFN-α/β by retinoic acid inducible gene 1-like receptors (RLRs) that detect the presence of RNA viruses in a cell-intrinsic manner. Here, we sought to investigate the role of DDX60 in IFN-α/β induction and in resistance to virus infection. Analysis of fibroblasts and myeloid cells from Ddx60-deficient mice revealed no impairment in IFN-α/β production in response to RLR agonists, RNA viruses, or other stimuli. Moreover, overexpression of DDX60 did not potentiate IFN induction and DDX60 did not interact with RLRs or capture RLR agonists from virally infected cells. We also failed to identify any impairment in Ddx60-deficient murine cells or mice in resistance to infection with influenza A virus, encephalomyocarditis virus, Sindbis virus, vaccinia virus, or herpes simplex virus-1. These results put in question the reported role of DDX60 as a broad-acting positive regulator of RLR responses and hint at the possibility that it may function as a restriction factor highly specific for a particular virus or class of viruses. © 2015 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Improving immunogenicity and efficacy of vaccines for genital herpes containing herpes simplex virus glycoprotein D.

PubMed

Awasthi, Sita; Shaw, Carolyn; Friedman, Harvey

2014-12-01

No vaccines are approved for prevention or treatment of genital herpes. The focus of genital herpes vaccine trials has been on prevention using herpes simplex virus type 2 (HSV-2) glycoprotein D (gD2) alone or combined with glycoprotein B. These prevention trials did not achieve their primary end points. However, subset analyses reported some positive outcomes in each study. The most recent trial was the Herpevac Trial for Women that used gD2 with monophosphoryl lipid A and alum as adjuvants in herpes simplex virus type 1 (HSV-1) and HSV-2 seronegative women. Unexpectedly, the vaccine prevented genital disease by HSV-1 but not HSV-2. Currently, HSV-1 causes more first episodes of genital herpes than HSV-2, highlighting the importance of protecting against HSV-1. The scientific community is conflicted between abandoning vaccine efforts that include gD2 and building upon the partial successes of previous trials. We favor building upon success and present approaches to improve outcomes of gD2-based subunit antigen vaccines.

Hydroxyurea enhances the activity of acyclovir and cidofovir against herpes simplex virus type 1 resistant strains harboring mutations in the thymidine kinase and/or the DNA polymerase genes.

PubMed

Sergerie, Yan; Boivin, Guy

2008-01-01

Drug-resistant herpes simplex virus type 1 (HSV-1) recombinant strains harboring mutations in the thymidine kinase and/or the DNA polymerase genes were evaluated for their susceptibility to various antivirals in the presence of 25 microg/ml of hydroxyurea (HyU). The latter compound decreased the 50% inhibitory concentrations of acyclovir by 1.5-3.8-fold and that of cidofovir by 2.7-14.4-fold. However, HyU did not affect the susceptibilities of the various recombinant mutants to foscarnet. Hydroxyurea, a ribonucleotide reductase inhibitor, can increase the activity of nucleoside/nucleotide analogues against drug-resistant viruses.

Identification of a novel NLS of herpes simplex virus type 1 (HSV-1) VP19C and its nuclear localization is required for efficient production of HSV-1.

PubMed

Li, You; Zhao, Lei; Wang, Shuai; Xing, Junji; Zheng, Chunfu

2012-09-01

Herpes simplex virus type 1 (HSV-1) triplex is a complex of three protein subunits, consisting of two copies of VP23 and one copy of VP19C. Here, we identified a non-classical NLS of VP19C between aa 50 and 61, and the nuclear import of VP19C was mediated by RanGTP and importin β1-, but not importin α5-, dependent pathway. Additionally, recombinant virus harbouring this NLS mutation (NLSm) replicates less efficiently as wild-type. These data strongly suggested that the nuclear import of VP19C is required for efficient HSV-1 production.

Identification of herpes simplex virus type 1 proteins encoded within the first 1.5 kb of the latency-associated transcript.

PubMed

Henderson, Gail; Jaber, Tareq; Carpenter, Dale; Wechsler, Steven L; Jones, Clinton

2009-09-01

Expression of the first 1.5 kb of the latency-associated transcript (LAT) that is encoded by herpes simplex virus type 1 (HSV-1) is sufficient for wild-type (wt) levels of reactivation from latency in small animal models. Peptide-specific immunoglobulin G (IgG) was generated against open reading frames (ORFs) that are located within the first 1.5 kb of LAT coding sequences. Cells stably transfected with LAT or trigeminal ganglionic neurons of mice infected with a LAT expressing virus appeared to express the L2 or L8 ORF. Only L2 ORF expression was readily detected in trigeminal ganglionic neurons of latently infected mice.

A herpes simplex virus type 2-encoded microRNA promotes tumor cell metastasis by targeting suppressor of cytokine signaling 2 in lung cancer.

PubMed

Wang, Xudong; Liu, Shupeng; Zhou, Zhenhua; Yan, Hongli; Xiao, Jianru

2017-05-01

Certain viruses use microRNAs to regulate the expression of their own genes, host genes, or both. A number of microRNAs expressed by herpes simplex virus type 2 have been confirmed by previous studies. However, whether these microRNAs play a role in the metastasis of lung cancers and how these viral microRNAs precisely regulated the tumor biological process in lung cancer bone metastasis remain obscure. We recently identified the high expression of an acutely and latently expressed viral microRNA, Hsv2-miR-H9-5p, encoded by herpes simplex virus type 2 latency-associated transcript through microarray and quantitative polymerase chain reaction analyses which compared the expression of microRNAs in bone metastasis from lung cancer with primary lung cancers. We now reported that Hsv2-miR-H9-5p was highly expressed in bone metastasis and closely associated with pathological and metastatic processes of lung cancers. The functions of Hsv2-miR-H9-5p were determined by overexpression which results in an increase in survival, migration, and invasion of lung cancer cells in vitro. We determined that Hsv2-miR-H9-5p directly targeted SOCS2 mechanistically by dual-luciferase reporter assay. Then, we investigated the functions of SOCS2 in the progress of lung cancers. Reduction of SOCS2 dosage by hsv2-miR-H9-5p induced increased migration and invasion of lung cancer cells. Overexpression of SOCS2 inverted these phenotypes generated by hsv2-miR-H9-5p, indicating the potential roles of SOCS2 in Hsv2-miR-H9-5p-driven metastasis in lung cancers. The results highlighted that Hsv2-miR-H9-5p regulated and contributed to bone metastasis of lung cancers. We proposed that Hsv2-miR-H9-5p could be used as a potential target in lung cancer therapy.

Vaccination with the Secreted Glycoprotein G of Herpes Simplex Virus 2 Induces Protective Immunity after Genital Infection.

PubMed

Önnheim, Karin; Ekblad, Maria; Görander, Staffan; Bergström, Tomas; Liljeqvist, Jan-Åke

2016-04-22

Herpes simplex virus 2 (HSV-2) infects the genital mucosa and establishes a life-long infection in sensory ganglia. After primary infection HSV-2 may reactivate causing recurrent genital ulcerations. HSV-2 infection is prevalent, and globally more than 400 million individuals are infected. As clinical trials have failed to show protection against HSV-2 infection, new vaccine candidates are warranted. The secreted glycoprotein G (sgG-2) of HSV-2 was evaluated as a prophylactic vaccine in mice using two different immunization and adjuvant protocols. The protocol with three intramuscular immunizations combining sgG-2 with cytosine-phosphate-guanine dinucleotide (CpG) motifs and alum induced almost complete protection from genital and systemic disease after intra-vaginal challenge with HSV-2. Robust immunoglobulin G (IgG) antibody titers were detected with no neutralization activity. Purified splenic CD4+ T cells proliferated and produced interferon-γ (IFN-γ) when re-stimulated with the antigen in vitro. sgG-2 + adjuvant intra-muscularly immunized mice showed a significant reduction of infectious HSV-2 and increased IFN-γ levels in vaginal washes. The HSV-2 DNA copy numbers were significantly reduced in dorsal root ganglia, spinal cord, and in serum at day six or day 21 post challenge. We show that a sgG-2 based vaccine is highly effective and can be considered as a novel candidate in the development of a prophylactic vaccine against HSV-2 infection.

Cofilin 1-Mediated Biphasic F-Actin Dynamics of Neuronal Cells Affect Herpes Simplex Virus 1 Infection and Replication

PubMed Central

Xiang, Yangfei; Zheng, Kai; Ju, Huaiqiang; Wang, Shaoxiang; Pei, Ying; Ding, Weichao; Chen, Zhenping; Wang, Qiaoli; Qiu, Xianxiu; Zhong, Meigong; Zeng, Fanli; Ren, Zhe; Qian, Chuiwen; Liu, Ge

2012-01-01

Herpes simplex virus 1 (HSV-1) invades the nervous system and causes pathological changes. In this study, we defined the remodeling of F-actin and its possible mechanisms during HSV-1 infection of neuronal cells. HSV-1 infection enhanced the formation of F-actin-based structures in the early stage of infection, which was followed by a continuous decrease in F-actin during the later stages of infection. The disruption of F-actin dynamics by chemical inhibitors significantly reduced the efficiency of viral infection and intracellular HSV-1 replication. The active form of the actin-depolymerizing factor cofilin 1 was found to increase at an early stage of infection and then to continuously decrease in a manner that corresponded to the remodeling pattern of F-actin, suggesting that cofilin 1 may be involved in the biphasic F-actin dynamics induced by HSV-1 infection. Knockdown of cofilin 1 impaired HSV-1-induced F-actin assembly during early infection and inhibited viral entry; however, overexpression of cofilin 1 did not affect F-actin assembly or viral entry during early infection but decreased intracellular viral reproduction efficiently. Our results, for the first time, demonstrated the biphasic F-actin dynamics in HSV-1 neuronal infection and confirmed the association of F-actin with the changes in the expression and activity of cofilin 1. These results may provide insight into the mechanism by which HSV-1 productively infects neuronal cells and causes pathogenesis. PMID:22623803

Herpes simplex keratitis in South India: clinico-virological correlation.

PubMed

Pramod, N P; Rajendran, P; Kannan, K A; Thyagarajan, S P

1999-01-01

A retrospective cross-section study to analyze the prevalence of herpes simplex virus-induced keratitis (HSK) among 3,000 patients attending a corneal clinic in South India between 1995 and 1997, and to evaluate laboratory techniques for detecting HSK. The clinico-virological correlation was studied using herpes simplex virus (HSV) isolation on the Vero cell line, HSV-specific antigen detection by indirect immunofluorescence (IF) microscopy, and serum anti-HSV IgG quantitation, IgM estimation, and tear secretory IgA (sIgA) detection by ELISA. HSK had a prevalence of 7.8% (234 patients) in this study. A virological correlation could be obtained in 44.4% of the cases that had epithelial manifestations and in 14.8% of the cases that had only stromal disease. In 161 cases where both culture and IF microscopy were used, IF detected 27 cases (26.8%) more than cell culture. The difference in sensitivity between cell culture and IF was found to be statistically significant (McNemar's test, P < .05). An elevation in IgG titer was seen in 17 (30.4%) cases. IgM was detected in only 2 cases of the 62 (3.2%) analyzed. Of the 138 cases analyzed, sIgA was positive in 28 (20.3%) cases. A proved diagnosis could be made in 58% of cases when the specimen was collected during the first week after disease onset, and in only 5% when the time interval increased to 4 weeks. HSV antigen detection by indirect IF is a rapid and sensitive diagnostic tool for HSK. Tear secretory IgA (sIgA) is a specific marker for acute herpetic keratitis, and the detection of HSV-specific tear sIgA is a valuable adjunct to virus isolation and antigen detection in the laboratory diagnosis of HSK. For a successful diagnosis, the specimen should be collected as soon as possible after HSK onset.

Herpes simplex virus type 1 encephalitis and unusual retinitis in a patient with systemic lupus erythematosus.

PubMed

Zhang, L; Liu, J J; Li, M T

2013-11-01

In this report we discuss a case of a patient with systemic lupus erythematosus who developed herpes simplex virus type 1(HSV-1) infection presenting with encephalitis as well as necrotic and non-necrotic retinitis. The patient presented with typical clinical symptoms and radiologic abnormalities consistent with HSV-1 encephalitis and HSV-1 retinitis in patients with HIV infection, but lacked cerebrospinal fluid pleocytosis and had bilateral retinitis with poor visual acuity. To the best of our knowledge, this is the first such case reported in the literature.

Powassan virus encephalitis resembling herpes simplex encephalitis.

PubMed

Embil, J A; Camfield, P; Artsob, H; Chase, D P

1983-02-01

A boy from New York traveling in Nova Scotia had olfactory hallucinations and other signs of temporal lobe involvement, leading to a diagnosis of herpes simplex encephalitis. The patient was treated with vidarabine and made a complete recovery. However, hemagglutination inhibition, complement fixation, and neutralization tests identified Powassan virus (POW) as the pathogen. Shortly before his trip to Nova Scotia, the patient had traveled in an area where POW encephalitis had occurred in humans (the eastern part of the state of New York), and he also came in contact with a known reservoir of POW infection (a groundhog) at home.

Preventing herpes simplex virus in the newborn.

PubMed

Pinninti, Swetha G; Kimberlin, David W

2014-12-01

Genital herpes simplex virus (HSV) infections are very common worldwide. Approximately 22% of pregnant women are infected genitally with HSV, and most of them are unaware of this. The most devastating consequence of maternal genital herpes is HSV disease in the newborn. Although neonatal HSV infections remain uncommon, due to the significant morbidity and mortality associated with the infection, HSV infection in the newborn is often considered in the differential diagnosis of ill neonates. This review summarizes the epidemiology and management of neonatal HSV infections and discusses strategies to prevent HSV infection in the newborn. Copyright © 2014 Elsevier Inc. All rights reserved.

Neonatal Herpes Simplex Virus Infection.

PubMed

James, Scott H; Kimberlin, David W

2015-09-01

Herpes simplex virus (HSV) 1 and HSV-2 infections are highly prevalent worldwide and are characterized by establishing lifelong infection with periods of latency interspersed with periodic episodes of reactivation. Acquisition of HSV by an infant during the peripartum or postpartum period results in neonatal HSV disease, a rare but significant infection that can be associated with severe morbidity and mortality, especially if there is dissemination or central nervous system involvement. Diagnostic and therapeutic advances have led to improvements in mortality and, to a lesser extent, neurodevelopmental outcomes, but room exists for further improvement. Copyright © 2015 Elsevier Inc. All rights reserved.

Acute Liver Failure from Herpes Simplex Virus in an Immunocompetent Patient Due to Direct Inoculation of the Peritoneum.

PubMed

Chaudhary, Dhruv; Ahmed, Shifat; Liu, Nanlong; Marsano-Obando, Luis

2017-01-01

Herpes simplex virus (HSV) hepatitis is a rare cause of acute liver failure (ALF). It carries a mortality rate of 80% if untreated, thus early identification and treatment are critical. Without high clinical suspicion, HSV hepatitis is difficult to diagnose. A 48-year-old Hispanic female presented with a 4-day history of abdominal pain and a vaginal cuff tear requiring laparoscopic repair. She subsequently developed postsurgical disseminated HSV, resulting in ALF. Acyclovir was initiated, but she was resistant to treatment. She was given additional foscarnet and responded without requiring a liver transplant.

Management of Herpes Simplex Virus Keratitis in the Pediatric Population.

PubMed

Vadoothker, Saujanya; Andrews, Laura; Jeng, Bennie H; Levin, Moran Roni

2018-05-14

Herpes simplex virus (HSV) keratitis is a highly prevalent and visually-disabling disease in both the pediatric and adult population. While many studies have investigated the treatment of HSV keratitis in adult patients, few have focused on managing this condition in children. Children are at particularly high risk for visual morbidity due to unique challenges in diagnosis and treatment, and the often more aggressive disease course that results in corneal scarring, and subsequently amblyopia. This review presents the pathogenesis and most current recommendations for the medical and surgical management of HSV keratitis in the pediatric population.

Acute retinal necrosis results in low vision in a young patient with a history of herpes simplex virus encephalitis.

PubMed

Shahi, Sanjeet K

2017-05-01

Acute retinal necrosis (ARN), secondary to herpes simplex encephalitis, is a rare syndrome that can present in healthy individuals, as well as immuno-compromised patients. Most cases are caused by a secondary infection from the herpes virus family, with varicella zoster virus being the leading cause of this syndrome. Potential symptoms include blurry vision, floaters, ocular pain and photophobia. Ocular findings may consist of severe uveitis, retinal vasculitis, retinal necrosis, papillitis and retinal detachment. Clinical manifestations of this disease may include increased intraocular pressure, optic disc oedema, optic neuropathy and sheathed retinal arterioles. A complete work up is essential to rule out cytomegalovirus retinitis, herpes simplex encephalitis, herpes virus, syphilis, posterior uveitis and other conditions. Depending on the severity of the disease, the treatment options consist of anticoagulation therapy, cycloplegia, intravenous acyclovir, systemic steroids, prophylactic laser photocoagulation and pars plana vitrectomy with silicon oil for retinal detachment. An extensive history and clinical examination is crucial in making the correct diagnosis. Also, it is very important to be aware of low vision needs and refer the patients, if expressing any sort of functional issues with completing daily living skills, especially reading. In this article, we report one case of unilateral ARN 20 years after herpetic encephalitis. © 2016 Optometry Australia.

2'-fluoro-5-iodo-aracytosine, a potent and selective anti-herpesvirus agent.

PubMed

Lopez, C; Watanabe, K A; Fox, J J

1980-05-01

A newly synthesized pyrimidine analog, 2'-fluoro-5-iodo-aracytosine (FIAC), suppressed by 90% the replication of various strains of herpes simplex virus types 1 and 2 at concentrations of 0.0025 to 0.0126 microM. Cytotoxicity was minimal, as determined by trypan blue dye exclusion with norman Vero, WI-38, and NC-37 cell proliferation; the 50% inhibitory dose was 4 to 10 microM in a 4-day assay. When compared with other antiviral drugs, FIAC was active at much lower concentrations than arabinosylcytosine, iododeoxyuridine, and arabinosyladenine. It was slightly more active against herpes simplex virus type 1 than acycloquanosine and slightly more toxic to normal cells. FIAC was about 8,000 times more active against the replication of wild-type herpes simplex virus type 1 than against a mutant strain lacking the expression of virus-specified thymidine kinase. Since FIAC appears to be preferentially phosphorylated by the viral enzyme, this is probably responsible, at least in part, for the selectivity of its antiviral actions. Although FIAC appears to be an arabinosylcytosine analog, its antiviral activity was not reversed by deoxycytidine. The minimal cytotoxicity exhibited by FIAC for normal cells, however, was reversed by equimolar concentrations of deoxycytidine. Thymidine, which reversed the antiviral activity, was effective only when used in great excess.

2'-fluoro-5-iodo-aracytosine, a potent and selective anti-herpesvirus agent.

PubMed Central

Lopez, C; Watanabe, K A; Fox, J J

1980-01-01

A newly synthesized pyrimidine analog, 2'-fluoro-5-iodo-aracytosine (FIAC), suppressed by 90% the replication of various strains of herpes simplex virus types 1 and 2 at concentrations of 0.0025 to 0.0126 microM. Cytotoxicity was minimal, as determined by trypan blue dye exclusion with norman Vero, WI-38, and NC-37 cell proliferation; the 50% inhibitory dose was 4 to 10 microM in a 4-day assay. When compared with other antiviral drugs, FIAC was active at much lower concentrations than arabinosylcytosine, iododeoxyuridine, and arabinosyladenine. It was slightly more active against herpes simplex virus type 1 than acycloquanosine and slightly more toxic to normal cells. FIAC was about 8,000 times more active against the replication of wild-type herpes simplex virus type 1 than against a mutant strain lacking the expression of virus-specified thymidine kinase. Since FIAC appears to be preferentially phosphorylated by the viral enzyme, this is probably responsible, at least in part, for the selectivity of its antiviral actions. Although FIAC appears to be an arabinosylcytosine analog, its antiviral activity was not reversed by deoxycytidine. The minimal cytotoxicity exhibited by FIAC for normal cells, however, was reversed by equimolar concentrations of deoxycytidine. Thymidine, which reversed the antiviral activity, was effective only when used in great excess. PMID:6249196

Specific Inhibition of Herpes Simplex Virus DNA Polymerase by Helical Peptides Corresponding to the Subunit Interface

NASA Astrophysics Data System (ADS)

Digard, Paul; Williams, Kevin P.; Hensley, Preston; Brooks, Ian S.; Dahl, Charles E.; Coen, Donald M.

1995-02-01

The herpes simplex virus DNA polymerase consists of two subunits-a catalytic subunit and an accessory subunit, UL42, that increases processivity. Mutations affecting the extreme C terminus of the catalytic subunit specifically disrupt subunit interactions and ablate virus replication, suggesting that new antiviral drugs could be rationally designed to interfere with polymerase heterodimerization. To aid design, we performed circular dichroism (CD) spectroscopy and analytical ultracentrifugation studies, which revealed that a 36-residue peptide corresponding to the C terminus of the catalytic subunit folds into a monomeric structure with partial α-helical character. CD studies of shorter peptides were consistent with a model where two separate regions of α-helix interact to form a hairpin-like structure. The 36-residue peptide and a shorter peptide corresponding to the C-terminal 18 residues blocked UL42-dependent long-chain DNA synthesis at concentrations that had no effect on synthesis by the catalytic subunit alone or by calf thymus DNA polymerase δ and its processivity factor. These peptides, therefore, represent a class of specific inhibitors of herpes simplex virus DNA polymerase that act by blocking accessory-subunit-dependent synthesis. These peptides or their structures may form the basis for the synthesis of clinically effective drugs.

Production of recombinant gG-1 protein of herpes simplex virus type 1 in a prokaryotic system in order to develop a type-specific enzyme-linked immunosorbent assay kit.

PubMed

Zandi, Keivan; Roostaee, Mohammad Hassan; Sadeghizadeh, Majid; Rasaee, Mohammad Javad; Sajedi, Reza Hassan; Soleimanjahi, Hoorieh

2007-08-01

The herpes simplex viruses are important causes of disease worldwide. Herpes simplex virus type 1 (HSV-1) is the primary cause of oral-facial and pharyngeal infections and may cause herpetic whitlow, eye infections as well as severe and sometimes dangerous infections of the eyes and brain. HSV-1 also accounts for 10-15% of all genital herpetic infections. Therefore, laboratory diagnosis of this virus and development of diagnostic serological techniques for HSV-1 is of particular importance. In the present study, pTrc His2A-gG1 plasmid, containing the full-length glycoprotein G (gG) protein, was produced in a prokaryotic system for the first time. Upon confirmation of a 37-kDa gG-1 protein production in a prokaryotic system based on western blotting and monoclonal antibodies, the protein was produced at a large scale and purified by ion-exchange chromatography using DEAE-sepharose. An HSV-1 type-specific diagnostic kit was designed and developed and the specificity and sensitivity of this kit were demonstrated to be 89.5% and 100%, respectively, as compared with a commercially available kit. A significant correlation was shown between the developed kit and the commercial kit.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Americo, Jeffrey L.; Sood, Cindy L.; Cotter, Catherine A.

Classical inbred mice are extensively used for virus research. However, we recently found that some wild-derived inbred mouse strains are more susceptible than classical strains to monkeypox virus. Experiments described here indicated that the 50% lethal dose of vaccinia virus (VACV) and cowpox virus (CPXV) were two logs lower in wild-derived inbred CAST/Ei mice than classical inbred BALB/c mice, whereas there was little difference in the susceptibility of the mouse strains to herpes simplex virus. Live bioluminescence imaging was used to follow spread of pathogenic and attenuated VACV strains and CPXV virus from nasal passages to organs in the chestmore » and abdomen of CAST/Ei mice. Luminescence increased first in the head and then simultaneously in the chest and abdomen in a dose-dependent manner. The spreading kinetics was more rapid with VACV than CPXV although the peak photon flux was similar. These data suggest advantages of CAST/Ei mice for orthopoxvirus studies. - Highlights: • Wild-derived inbred CAST/Ei mice are susceptible to vaccinia virus and cowpox virus. • Morbidity and mortality from orthopoxviruses are greater in CAST/Ei than BALB/c mice. • Morbidity and mortality from herpes simplex virus type 1 are similar in both mice. • Imaging shows virus spread from nose to lungs, abdominal organs and brain. • Vaccinia virus spreads more rapidly than cowpox virus.« less

NLRC3, a member of the NLR family of proteins, is a negative regulator of innate immune signaling induced by the DNA sensor STING

PubMed Central

Zhang, Lu; Mo, Jinyao; Swanson, Karen V.; Wen, Haitao; Petrucelli, Alex; Gregory, Sean M.; Zhang, Zhigang; Schneider, Monika; Jiang, Yan; Fitzgerald, Katherine A.; Ouyang, Songying; Liu, Zhi-Jie; Damania, Blossom A; Shu, Hong-Bing; Duncan, Joseph A.; Ting, Jenny P-Y.

2014-01-01

SUMMARY Stimulator of interferon genes (STING, also named MITA, MYPS or ERIS) is an intracellular DNA sensor that induces type I interferon through its interaction with TANK-binding kinase 1 (TBK1). Here we found that the nucleotide-binding, leucine-rich repeat containing protein, NLRC3, reduced STING-dependent innate immune activation in response to cytosolic DNA, cyclic di-GMP (c-di-GMP) and DNA viruses. NLRC3 associated with both STING and TBK1, and impeded STING-TBK1 interaction and downstream type I interferon production. Using purified recombinant proteins NLRC3 was found to interact directly with STING. Furthermore, NLRC3 prevented proper trafficking of STING to perinuclear and punctated region, known to be important for its activation. In animals, herpes simplex virus 1 (HSV-1)-infected Nlrc3−/− mice exhibited enhanced innate immunity, reduced morbidity and viral load. This demonstrates the intersection of two key pathways of innate immune regulation, NLR and STING, to fine tune host response to intracellular DNA, DNA virus and c-di-GMP PMID:24560620

Recurrent herpetic keratitis: failure to detect herpes simplex virus infection using the Syva MicroTrak HSV1/HSV2 direct specimen identification/typing test.

PubMed

Kumano, Y; Yamamoto, M; Inomata, H; Sakuma, S; Hidaka, Y; Minagawa, H; Mori, R

1990-01-01

A 35-year-old man had developed recurrent herpetic keratitis characterized by dendritic keratitis at intervals of a year. We were able to culture cytopathic agents repeatedly from his lesions by inoculating Vero cells. The cultures yielded definitive evidence of a virus that caused a cytopathic effect within 3 days. However, these virus strains could not be identified as herpes simplex virus (HSV) in immunofluorescence assays using the Syva MicroTrak HSV1/HSV2 direct specimen identification/typing test. Rather they were identified as strains of HSV type 1 (HSV-1) on the basis of plaque morphology, neutralization tests, electron-microscopic examination and DNA restriction endonuclease analysis. Our results allow us to assume the existence of HSV-1 strains isolated clinically that are negative to analysis using the Syva Micro-Trak HSV1/HSV2 direct specimen identification/typing test.

Bovine lactoferrin and lactoferricin interfere with intracellular trafficking of Herpes simplex virus-1.

PubMed

Marr, A K; Jenssen, H; Moniri, M Roshan; Hancock, R E W; Panté, N

2009-01-01

Although both lactoferrin (Lf), a component of the innate immune system of living organisms, and its N-terminal pepsin cleavage product lactoferricin (Lfcin) have anti-herpes activity, the precise mechanisms by which Lf and Lfcin bring about inhibition of herpes infections are not fully understood. In the present study, experiments were carried out to characterize the activity of bovine Lf and Lfcin (BLf and BLfcin) against the Herpes simplex virus-1 (HSV-1). HSV-1 cellular uptake and intracellular trafficking were studied by immunofluorescence microscopy. In comparison to the untreated infected control cells, both the BLf- and BLfcin-treated cells showed a significant reduction in HSV-1 cellular uptake. The few virus particles that were internalized appeared to have a delayed intracellular trafficking. Thus, in addition to their interference with the uptake of the virus into host cells, Lf and Lfcin also exert their antiviral effect intracellularly.

[Clinical, epidemiological, and etiological studies of adult aseptic meningitis: a report of 12 cases of herpes simplex meningitis, and a comparison with cases of herpes simplex encephalitis].

PubMed

Himeno, Takahiro; Shiga, Yuji; Takeshima, Shinichi; Tachiyama, Keisuke; Kamimura, Teppei; Kono, Ryuhei; Takemaru, Makoto; Takeshita, Jun; Shimoe, Yutaka; Kuriyama, Masaru

2018-01-26

We treated 437 cases of adult aseptic meningitis and 12 cases (including 2 recurrent patients; age, 31.8 ± 8.9 years; 7 females) of herpes simplex meningitis from 2004 to 2016. The incidence rate of adult herpes simplex meningitis in the cases with aseptic meningitis was 2.7%. One patient was admitted during treatment of genital herpes, but no association was observed between genital herpes and herpes simplex meningitis in the other cases. The diagnoses were confirmed in all cases as the cerebrospinal fluid (CSF) was positive for herpes simplex virus (HSV)-DNA. For diagnosis confirmation, the DNA test was useful after 2-7 days following initial disease onset. Among other types of aseptic meningitis, the patients with herpes simplex meningitis showed relatively high white blood cell counts and relatively high CSF protein and high CSF cell counts. CSF cells showed mononuclear cell dominance from the initial stage of the disease. During same period, we also experienced 12 cases of herpes simplex encephalitis and 21 cases of non-hepatic acute limbic encephalitis. Notably, the patients with herpes simplex meningitis were younger and their CSF protein and cells counts were higher than those of the patients with herpes simplex encephalitis.

Human TRAF3 adaptor molecule deficiency leads to impaired Toll-like receptor 3 response and susceptibility to herpes simplex encephalitis

PubMed Central

de Diego, Rebeca Pérez; Sancho-Shimizu, Vanessa; Lorenzo, Lazaro; Puel, Anne; Plancoulaine, Sabine; Picard, Capucine; Herman, Melina; Cardon, Annabelle; Durandy, Anne; Bustamante, Jacinta; Vallabhapurapu, Sivakumar; Bravo, Jerónimo; Warnatz, Klaus; Chaix, Yves; Cascarrigny, Françoise; Lebon, Pierre; Rozenberg, Flore; Karin, Michael; Tardieu, Marc; Al-Muhsen, Saleh; Jouanguy, Emmanuelle; Zhang, Shen-Ying; Abel, Laurent; Casanova, Jean-Laurent

2010-01-01

Tumor necrosis factor (TNF) receptor-associated factor 3 (TRAF3) functions downstream of multiple receptors that induce interferon-α (IFN-α), IFN–β and IFN-λ production, including Toll-like receptor 3 (TLR3), which is deficient in some patients with herpes simplex virus-1 encephalitis (HSE). Mice lacking TRAF3 die in the neonatal period, preventing direct investigation of the role of TRAF3 in immune responses and host defenses in vivo. Here we reported the autosomal dominant, human TRAF3 deficiency in a young adult with a history of HSE in childhood. The TRAF3 mutant allele was a loss-of-expression, loss-of-function, dominant-negative phenotype, and was associated with impaired, but not abolished TRAF3-dependent responses upon stimulation of both TNF receptors and receptors that induce IFN production. TRAF3 deficiency was associated with a clinical phenotype limited to HSE resulting from the impairment of TLR3-dependent induction of IFN. Thus, TLR3-mediated immunity against primary infection by HSV-1 in the central nervous system is critically dependent on TRAF3. Highlight sentence Autosomal dominant TRAF3 deficiency is a genetic etiology of herpes simplex encephalitis. Highlight sentence R118W TRAF3 allele is loss-of-function, loss-of-expression, and dominant-negative. Highlight sentence Human TRAF3 deficiency impairs the TLR3-dependent induction of anti-viral interferons. PMID:20832341

Regulation of Herpes Simplex Virus Glycoprotein-Induced Cascade of Events Governing Cell-Cell Fusion

PubMed Central

Saw, Wan Ting; Eisenberg, Roselyn J.; Cohen, Gary H.

2016-01-01

ABSTRACT Receptor-dependent herpes simplex virus (HSV)-induced cell-cell fusion requires glycoproteins gD, gH/gL, and gB. Our current model posits that during fusion, receptor-activated conformational changes in gD activate gH/gL, which subsequently triggers the transformation of the prefusion form of gB into a fusogenic state. To examine the role of each glycoprotein in receptor-dependent cell-cell fusion, we took advantage of our discovery that fusion by wild-type herpes simplex virus 2 (HSV-2) glycoproteins occurs twice as fast as that achieved by HSV-1 glycoproteins. By sequentially swapping each glycoprotein between the two serotypes, we established that fusion speed was governed by gH/gL, with gH being the main contributor. While the mutant forms of gB fuse at distinct rates that are dictated by their molecular structure, these restrictions can be overcome by gH/gL of HSV-2 (gH2/gL2), thereby enhancing their activity. We also found that deregulated forms of gD of HSV-1 (gD1) and gH2/gL2 can alter the fusogenic potential of gB, promoting cell fusion in the absence of a cellular receptor, and that deregulated forms of gB can drive the fusion machinery to even higher levels. Low pH enhanced fusion by affecting the structure of both gB and gH/gL mutants. Together, our data highlight the complexity of the fusion machinery, the impact of the activation state of each glycoprotein on the fusion process, and the critical role of gH/gL in regulating HSV-induced fusion. IMPORTANCE Cell-cell fusion mediated by HSV glycoproteins requires gD, gH/gL, gB, and a gD receptor. Here, we show that fusion by wild-type HSV-2 glycoproteins occurs twice as fast as that achieved by HSV-1 glycoproteins. By sequentially swapping each glycoprotein between the two serotypes, we found that the fusion process was controlled by gH/gL. Restrictions imposed on the gB structure by mutations could be overcome by gH2/gL2, enhancing the activity of the mutants. Under low-pH conditions or when using deregulated forms of gD1 and gH2/gL2, the fusogenic potential of gB could only be increased in the absence of receptor, underlining the exquisite regulation that occurs in the presence of receptor. Our data highlight the complexity of the fusion machinery, the impact of the activation state of each glycoprotein on the fusion process, and the critical role of gH/gL in regulating HSV-induced fusion. PMID:27630245

Herpes simplex virus type 1 (HSV-1)-derived recombinant vectors for gene transfer and gene therapy.

PubMed

Marconi, Peggy; Fraefel, Cornel; Epstein, Alberto L

2015-01-01

Herpes simplex virus type 1 (HSV-1 ) is a human pathogen whose lifestyle is based on a long-term dual interaction with the infected host, being able to establish both lytic and latent infections. The virus genome is a 153-kilobase pair (kbp) double-stranded DNA molecule encoding more than 80 genes. The interest of HSV-1 as gene transfer vector stems from its ability to infect many different cell types, both quiescent and proliferating cells, the very high packaging capacity of the virus capsid, the outstanding neurotropic adaptations that this virus has evolved, and the fact that it never integrates into the cellular chromosomes, thus avoiding the risk of insertional mutagenesis. Two types of vectors can be derived from HSV-1, recombinant vectors and amplicon vectors, and different methodologies have been developed to prepare large stocks of each type of vector. This chapter summarizes the approach most commonly used to prepare recombinant HSV-1 vectors through homologous recombination, either in eukaryotic cells or in bacteria.

The challenge of developing a herpes simplex virus 2 vaccine

PubMed Central

Dropulic, Lesia K; Cohen, Jeffrey I

2013-01-01

HSV infections are prevalent worldwide. A vaccine to prevent genital herpes would have a significant impact on this disease. Several vaccines have shown promise in animal models; however, so far these have not been successful in human clinical studies. Prophylactic HSV vaccines to prevent HSV infection or disease have focused primarily on eliciting antibody responses. Potent antibody responses are needed to result in sufficiently high levels of virus-specific antibody in the genital tract. Therapeutic vaccines that reduce recurrences need to induce potent T-cell responses at the site of infection. With the increasing incidence of HSV-1 genital herpes, an effective herpes vaccine should protect against both HSV-1 and HSV-2. Novel HSV vaccines, such as replication-defective or attenuated viruses, have elicited humoral and cellular immune responses in preclinical studies. These vaccines and others hold promise in future clinical studies. PMID:23252387

Herpes Simplex Virus Type 1 and Other Pathogens are Key Causative Factors in Sporadic Alzheimer’s Disease

PubMed Central

Harris, Steven A.; Harris, Elizabeth A.

2015-01-01

Abstract This review focuses on research in epidemiology, neuropathology, molecular biology, and genetics regarding the hypothesis that pathogens interact with susceptibility genes and are causative in sporadic Alzheimer’s disease (AD). Sporadic AD is a complex multifactorial neurodegenerative disease with evidence indicating coexisting multi-pathogen and inflammatory etiologies. There are significant associations between AD and various pathogens, including Herpes simplex virus type 1 (HSV-1), Cytomegalovirus, and other Herpesviridae, Chlamydophila pneumoniae, spirochetes, Helicobacter pylori, and various periodontal pathogens. These pathogens are able to evade destruction by the host immune system, leading to persistent infection. Bacterial and viral DNA and RNA and bacterial ligands increase the expression of pro-inflammatory molecules and activate the innate and adaptive immune systems. Evidence demonstrates that pathogens directly and indirectly induce AD pathology, including amyloid-β (Aβ) accumulation, phosphorylation of tau protein, neuronal injury, and apoptosis. Chronic brain infection with HSV-1, Chlamydophila pneumoniae, and spirochetes results in complex processes that interact to cause a vicious cycle of uncontrolled neuroinflammation and neurodegeneration. Infections such as Cytomegalovirus, Helicobacter pylori, and periodontal pathogens induce production of systemic pro-inflammatory cytokines that may cross the blood-brain barrier to promote neurodegeneration. Pathogen-induced inflammation and central nervous system accumulation of Aβ damages the blood-brain barrier, which contributes to the pathophysiology of AD. Apolipoprotein E4 (ApoE4) enhances brain infiltration by pathogens including HSV-1 and Chlamydophila pneumoniae. ApoE4 is also associated with an increased pro-inflammatory response by the immune system. Potential antimicrobial treatments for AD are discussed, including the rationale for antiviral and antibiotic clinical trials. PMID:26401998

A Herpes Simplex Virus-Derived Replicative Vector Expressing LIF Limits Experimental Demyelinating Disease and Modulates Autoimmunity

PubMed Central

Nygårdas, Michaela; Paavilainen, Henrik; Müther, Nadine; Nagel, Claus-Henning; Röyttä, Matias; Sodeik, Beate; Hukkanen, Veijo

2013-01-01

Herpes simplex virus type 1 (HSV-1) has properties that can be exploited for the development of gene therapy vectors. The neurotropism of HSV enables delivery of therapeutic genes to the nervous system. Using a bacterial artificial chromosome (BAC), we constructed an HSV-1(17+)-based replicative vector deleted of the neurovirulence gene γ134.5, and expressing leukemia inhibitory factor (LIF) as a transgene for treatment of experimental autoimmune encephalomyelitis (EAE). EAE is an inducible T-cell mediated autoimmune disease of the central nervous system (CNS) and is used as an animal model for multiple sclerosis. Demyelination and inflammation are hallmarks of both diseases. LIF is a cytokine that has the potential to limit demyelination and oligodendrocyte loss in CNS autoimmune diseases and to affect the T-cell mediated autoimmune response. In this study SJL/J mice, induced for EAE, were treated with a HSV-LIF vector intracranially and the subsequent changes in disease parameters and immune responses during the acute disease were investigated. Replicating HSV-LIF and its DNA were detected in the CNS during the acute infection, and the vector spread to the spinal cord but was non-virulent. The HSV-LIF significantly ameliorated the EAE and contributed to a higher number of oligodendrocytes in the brains when compared to untreated mice. The HSV-LIF therapy also induced favorable changes in the expression of immunoregulatory cytokines and T-cell population markers in the CNS during the acute disease. These data suggest that BAC-derived HSV vectors are suitable for gene therapy of CNS disease and can be used to test the therapeutic potential of immunomodulatory factors for treatment of EAE. PMID:23700462

Molecular mechanism and species specificity of TAP inhibition by herpes simplex virus ICP47.

PubMed Central

Ahn, K; Meyer, T H; Uebel, S; Sempé, P; Djaballah, H; Yang, Y; Peterson, P A; Früh, K; Tampé, R

1996-01-01

The immediate early protein ICP47 of herpes simplex virus (HSV) inhibits the transporter for antigen processing (TAP)-mediated translocation of antigen-derived peptides across the endoplasmic reticulum (ER) membrane. This interference prevents assembly of peptides with class I MHC molecules in the ER and ultimately recognition of HSV-infected cells by cytotoxic T-lymphocytes, potentially leading to immune evasion of the virus. Here, we demonstrate that recombinant, purified ICP47 containing a hexahistidine tag inhibits peptide import into microsomes of insect cells expressing human TAP, whereas inhibition of peptide transport by murine TAP was much less effective. This finding indicates an intrinsic species-specificity of ICP47 and suggests that no additional proteins interacting specifically with either ICP47 or TAP are required for inhibition of peptide transport. Since neither purified nor induced ICP47 inhibited photocrosslinking of 8-azido-ATP to TAP1 and TAP2 it seems that ICP47 does not prevent ATP from binding to TAP. By contrast, peptide binding was completely blocked by ICP47 as shown both by photoaffinity crosslinking of peptides to TAP and peptide binding to microsomes from TAP-transfected insect cells. Competition experiments indicated that ICP47 binds to human TAP with a higher affinity (50 nM) than peptides whereas the affinity to murine TAP was 100-fold lower. Our data suggest that ICP47 prevents peptides from being translocated by blocking their binding to the substrate-binding site of TAP. Images PMID:8670825

Nuclear envelope breakdown induced by herpes simplex virus type 1 involves the activity of viral fusion proteins.

PubMed

Maric, Martina; Haugo, Alison C; Dauer, William; Johnson, David; Roller, Richard J

2014-07-01

Herpesvirus infection reorganizes components of the nuclear lamina usually without loss of integrity of the nuclear membranes. We report that wild-type HSV infection can cause dissolution of the nuclear envelope in transformed mouse embryonic fibroblasts that do not express torsinA. Nuclear envelope breakdown is accompanied by an eight-fold inhibition of virus replication. Breakdown of the membrane is much more limited during infection with viruses that lack the gB and gH genes, suggesting that breakdown involves factors that promote fusion at the nuclear membrane. Nuclear envelope breakdown is also inhibited during infection with virus that does not express UL34, but is enhanced when the US3 gene is deleted, suggesting that envelope breakdown may be enhanced by nuclear lamina disruption. Nuclear envelope breakdown cannot compensate for deletion of the UL34 gene suggesting that mixing of nuclear and cytoplasmic contents is insufficient to bypass loss of the normal nuclear egress pathway. Copyright © 2014 Elsevier Inc. All rights reserved.

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.

Mapping of herpes simplex virus-1 neurovirulence to. gamma. sub 1 34. 5, a gene nonessential for growth in culture

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chou, J.; Roizman, B.; Kern, E.R.

1990-11-30

The gene designated {gamma}{sub 1}34.5 maps in the inverted repeats flanking the long unique sequence of herpes simplex virus-1 (HSV-1) DNA, and therefore it is present in two copies per genome. This gene is not essential for viral growth in cell culture. Four recombinant viruses were genetically engineered to test the function of this gene. These were (i) a virus from which both copies of the gene were deleted, (ii) a virus containing a stop codon in both copies of the gene, (iii) a virus containing after the first codon an insert encoding a 16-amino acid epitope known to reactmore » with a specific monoclonal antibody, and (iv) a virus in which the deleted sequences were restored. The viruses from which the gene was deleted or which carried stop codons were avirulent on intracerebral inoculation of mice. The virus with the gene tagged by the sequence encoding the epitope was moderately virulent, whereas the restored virus reacquired the phenotype of the parent virus. Significant amounts of virus were recovered only from brains of animals inoculated with virulent viruses. Inasmuch as the product of the {gamma}{sub 1}34.5 gene extended the host range of the virus by enabling it to replicate and destroy brain cells, it is a viral neurovirulence factor.« less

Monoclonal Antibodies, Derived from Humans Vaccinated with the RV144 HIV Vaccine Containing the HVEM Binding Domain of Herpes Simplex Virus (HSV) Glycoprotein D, Neutralize HSV Infection, Mediate Antibody-Dependent Cellular Cytotoxicity, and Protect Mice from Ocular Challenge with HSV-1.

PubMed

Wang, Kening; Tomaras, Georgia D; Jegaskanda, Sinthujan; Moody, M Anthony; Liao, Hua-Xin; Goodman, Kyle N; Berman, Phillip W; Rerks-Ngarm, Supachai; Pitisuttithum, Punnee; Nitayapan, Sorachai; Kaewkungwal, Jaranit; Haynes, Barton F; Cohen, Jeffrey I

2017-10-01

The RV144 HIV vaccine trial included a recombinant HIV glycoprotein 120 (gp120) construct fused to a small portion of herpes simplex virus 1 (HSV-1) glycoprotein D (gD) so that the first 40 amino acids of gp120 were replaced by the signal sequence and the first 27 amino acids of the mature form of gD. This region of gD contains most of the binding site for HVEM, an HSV receptor important for virus infection of epithelial cells and lymphocytes. RV144 induced antibodies to HIV that were partially protective against infection, as well as antibodies to HSV. We derived monoclonal antibodies (MAbs) from peripheral blood B cells of recipients of the RV144 HIV vaccine and showed that these antibodies neutralized HSV-1 infection in cells expressing HVEM, but not the other major virus receptor, nectin-1. The MAbs mediated antibody-dependent cellular cytotoxicity (ADCC), and mice that received the MAbs and were then challenged by corneal inoculation with HSV-1 had reduced eye disease, shedding, and latent infection. To our knowledge, this is the first description of MAbs derived from human recipients of a vaccine that specifically target the HVEM binding site of gD. In summary, we found that monoclonal antibodies derived from humans vaccinated with the HVEM binding domain of HSV-1 gD (i) neutralized HSV-1 infection in a cell receptor-specific manner, (ii) mediated ADCC, and (iii) reduced ocular disease in virus-infected mice. IMPORTANCE Herpes simplex virus 1 (HSV-1) causes cold sores and neonatal herpes and is a leading cause of blindness. Despite many trials, no HSV vaccine has been approved. Nectin-1 and HVEM are the two major cellular receptors for HSV. These receptors are expressed at different levels in various tissues, and the role of each receptor in HSV pathogenesis is not well understood. We derived human monoclonal antibodies from persons who received the HIV RV144 vaccine that contained the HVEM binding domain of HSV-1 gD fused to HIV gp120. These antibodies were able to specifically neutralize HSV-1 infection in vitro via HVEM. Furthermore, we showed for the first time that HVEM-specific HSV-1 neutralizing antibodies protect mice from HSV-1 eye disease, indicating the critical role of HVEM in HSV-1 ocular infection. Copyright © 2017 American Society for Microbiology.

Antiviral Effect of Pyran Against Systemic Infection of Mice with Herpes Simplex Virus Type 2

PubMed Central

McCord, Ronald S.; Breinig, Mary K.; Morahan, Page S.

1976-01-01

The immunomodulator pyran markedly protected 5-week-old mice from lethal intravenous infection with herpes simplex virus type 2. The 50% lethal dose was increased almost 100-fold in pyran-treated mice as compared with controls. Although the protection was not as marked in older mice (10 and 16 weeks old), there was a significant increase in mean survival time. When the pathogenesis of herpesvirus disease was monitored in control and drug-treated mice, the effect of pyran was most evident in the spinal cord, where virus was recovered from 20 of 25 control mice and from only 6 of 25 pyran-treated mice. There was also a significant reduction in the titer of virus present, and virus appeared later in the spinal cord of pyran-treated mice than in control mice. The protective effect of pyran was observed only when the drug was administered 24 h before viral challenge, was seen after both intraperitoneal and intravenous injection, and was not due to direct inactivation of the virus. PMID:185945

Antiviral Effects of Blackberry Extract Against Herpes Simplex Virus Type 1

PubMed Central

Danaher, Robert J.; Wang, Chunmei; Dai, Jin; Mumper, Russell J.; Miller, Craig S.

2011-01-01

Objective To evaluate antiviral properties of blackberry extract against herpes simplex virus type 1 (HSV-1) in vitro. Methods HSV-infected oral epithelial (OKF6) cells and cell-free virus suspensions were treated with blackberry extract (2.24 to 1400 μg/mL) and virus yield and infectivity were quantified by direct plaque assay. Results Blackberry extract ≥ 56 μg/ml inhibited HSV-1 replication in oral epithelial cells by > 99% (p < 0.005). Concentrations ≥ 280 μg/ml were antiviral when the extract was added after virus adsorption and entry. Exposure of cell-free virus to ≥ 280 μg/ml blackberry extract for 15 minutes at room temperature was virucidal (p = 0.0002). The virucidal effects were not due to pH changes at concentrations up to 1500 μg/ml. Conclusions Blackberry extract inhibited the early stages of HSV-1 replication and had potent virucidal activity. These properties suggest that this natural fruit extract could provide advantage as a topical prophylactic/therapeutic agent for HSV infections. PMID:21827957

Association of anti-herpes simplex virus IgG in tears and serum with clinical presentation in patients with presumed herpetic simplex keratitis.

PubMed

Borderie, Vincent M; Gineys, Raquel; Goldschmidt, Pablo; Batellier, Laurence; Laroche, Laurent; Chaumeil, Christine

2012-11-01

To assess the clinical relevance of tear anti-herpes simplex virus (HSV) antibody measurement for the diagnosis of herpes simplex keratitis. Records of 364 patients clinically suspect of HSV-related keratitis who had tear anti-HSV IgG assessment (tear-quantified anti-HSV IgG/filtrated IgG ratio) in our institution between January 2000 and August 2008 were retrospectively analyzed. Patients were classified into 4 groups as follows: group 1, anti-HSV IgG negative in serum and tears; group 2, anti-HSV IgG negative in tears and positive in serum; group 3, anti-HSV IgG nonsignificantly positive in tears and positive in serum; and group 4, anti-HSV IgG significantly positive in serum and tears. Randomly selected patient charts from each group were reviewed for clinical data. The prevalence of anti-HSV IgG in blood increased with age from >70% before 20 years to 95% after 70 years. The prevalence of anti-HSV IgG in tears increased with age from 20% before 20 years to >50% after 70 years. The presence (either significant or not) of anti-HSV IgG in tears was significantly associated with decreased corneal sensation, presence of stromal opacities, and with neurotrophic keratitis. Logistic regression showed no significant association between age and clinical signs except for herpetic ulcers and herpetic necrotizing keratitis. Tear production of anti-HSV IgG increases with age, and it is associated with sequelae of herpes simplex keratitis. Conversely, it is poorly associated with clinical signs of acute herpes simplex keratitis.

Topical Administration Is a Promising Inoculating Route versus Intramuscular Inoculation for the Nanoparticle-Carried DNA Vaccine to Prevent Corneal Infections.

PubMed

Hu, Kai; Malla, Tejsu; Zhai, Yujia; Dong, Lili; Tang, Ru

2015-01-01

To evaluate the comparative effect of topical versus intramuscular administration of nanoparticle-carried DNA vaccine in preventing corneal herpes simplex virus type 1 (HSV-1) infection. Nanoparticle [polyethylenimine (PEI)-Fe3O4]-carried DNA vaccine (PEI-Fe3O4-pRSC-gD-IL-21) or DNA vaccine (pRSC-gD-IL-21) alone were topically versus intramuscularly inoculated into one eye each of mice on days 0, 14 and 28. Three weeks after the final immunization, the specific immune responses and clinical degrees of primary herpes simplex keratitis were evaluated. Topical inoculation of nanoparticle-carried DNA vaccine induced mice to generate similar levels of specific HSV-1-neutralizing antibody, IFN-γ and IL-4 in serum and specific killing (cytotoxicity) and proliferative activities of the splenic lymphocytes, but a significantly higher level of secretory IgA in tears compared to those of intramuscular inoculation. More importantly, the mice inoculated topically showed a significantly decreased herpes simplex keratitis severity than the mice inoculated intramuscularly after HSV-1 challenge on the corneas of the mice. Topical inoculation of nanoparticle-carried DNA vaccine elicits a stronger specific local immune response and more effectively inhibits herpes simplex keratitis as compared to intramuscular inoculation in an HSV-1 ocular challenge mouse model. Thus, topical administration may be a promising inoculating route for the nanoparticle-carried DNA vaccine to prevent corneal infections. © 2015 S. Karger AG, Basel.

Identification of a herpes simplex labialis susceptibility region on human chromosome 21.

PubMed

Hobbs, Maurine R; Jones, Brandt B; Otterud, Brith E; Leppert, Mark; Kriesel, John D

2008-02-01

Most of the United States population is infected with either herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2, or both. Reactivations of HSV-1 infection cause herpes simplex labialis (HSL; cold sores or fever blisters), which is the most common recurring viral infection in humans. To investigate the possibility of a human genetic component conferring resistance or susceptibility to cold sores (i.e., a HSL susceptibility gene), we conducted a genetic linkage analysis that included serotyping and phenotyping 421 individuals from 39 families enrolled in the Utah Genetic Reference Project. Linkage analysis identified a 2.5-Mb nonrecombinant region of interest on the long arm of human chromosome 21, with a multipoint logarithm of odds score of 3.9 noted near marker abmc65 (D21S409). Nonparametric linkage analysis of the data also provided strong evidence for linkage (P = .0005). This region of human chromosome 21 contains 6 candidate genes for herpes susceptibility. The development of frequent cold sores is associated with a region on the long arm of human chromosome 21. This region contains several candidate genes that could influence the frequency of outbreaks of HSL.

In vivo production of cytokines and beta (C-C) chemokines in human recurrent herpes simplex lesions--do herpes simplex virus-infected keratinocytes contribute to their production?

PubMed

Mikloska, Z; Danis, V A; Adams, S; Lloyd, A R; Adrian, D L; Cunningham, A L

1998-04-01

Recurrent human herpes simplex lesions are infiltrated by macrophages and CD4 and CD8 lymphocytes, which secrete cytokines and chemokines. Vesicle fluid was examined by ELISA for the presence of cytokines and beta (C-C) chemokines. On the first day of the lesion, high concentrations of interleukin (IL)-1beta, and IL-6, moderate concentrations of IL-1alpha and IL-10, and low concentrations of IL-12 and beta chemokines were found; levels of macrophage inflammatory protein (MIP)-1beta were significantly higher than levels of MIP-1alpha and RANTES. At day 3, the concentrations of IL-1beta, IL-6, and MIP-1beta were lower, whereas the levels of IL-10, IL-12, and MIP-1alpha remained similar, and the level of tumor necrosis factor-alpha was now detectable. Herpes simplex virus infection of keratinocytes in vitro stimulated production of beta chemokines followed by IL-12 and then IL-10, IL-1alpha, IL-1beta, and IL-6, indicating a potential role for these events in early recruitment, activation, and interferon-gamma production of CD4 cells in herpetic lesions.

Comparison of the Host Immune Response to Herpes Simplex Virus 1 (HSV-1) and HSV-2 at Two Different Mucosal Sites

PubMed Central

Zheng, Min; Conrady, Christopher D.; Ward, Julie M.; Bryant-Hudson, Katie M.

2012-01-01

A study was undertaken to compare the host immune responses to herpes simplex virus 1 (HSV-1) and HSV-2 infection by the ocular or genital route in mice. Titers of HSV-2 from tissue samples were elevated regardless of the route of infection. The elevation in titers of HSV-2, including cell infiltration and cytokine/chemokine levels in the central nervous system relative to those found following HSV-1 infection, was correlative with inflammation. These results underscore a dichotomy between the host immune responses to closely related alphaherpesviruses. PMID:22532684

Prospects and perspectives for development of a vaccine against herpes simplex virus infections.

PubMed

McAllister, Shane C; Schleiss, Mark R

2014-11-01

Herpes simplex viruses 1 and 2 are human pathogens that lead to significant morbidity and mortality in certain clinical settings. The development of effective antiviral medications, however, has had little discernible impact on the epidemiology of these pathogens, largely because the majority of infections are clinically silent. Decades of work have gone into various candidate HSV vaccines, but to date none has demonstrated sufficient efficacy to warrant licensure. This review examines developments in HSV immunology and vaccine development published since 2010, and assesses the prospects for improved immunization strategies that may result in an effective, licensed vaccine in the near future.

Prospects and Perspectives for Development of a Vaccine Against Herpes Simplex Virus Infections

PubMed Central

McAllister, Shane C.; Schleiss, Mark R.

2014-01-01

Herpes simplex viruses 1 and -2 are human pathogens that lead to significant morbidity and mortality in certain clinical settings. The development of effective antiviral medications, however, has had little discernible impact on the epidemiology of these pathogens, largely because the majority of infections are clinically silent. Decades of work have gone into various candidate HSV vaccines, but to date none has demonstrated sufficient efficacy to warrant licensure. This review examines developments in HSV immunology and vaccine development published since 2010, and assesses the prospects for improved immunization strategies that may result in an effective, licensed vaccine in the near future. PMID:25077372

Neonatal herpes simplex virus infections.

PubMed

Pinninti, Swetha G; Kimberlin, David W

2018-04-01

Neonatal herpes simplex virus (HSV) is an uncommon but devastating infection in the newborn, associated with significant morbidity and mortality. The use of PCR for identification of infected infants and acyclovir for treatment has significantly improved the prognosis for affected infants. The subsequent use of suppressive therapy with oral acyclovir following completion of parenteral treatment of acute disease has further enhanced the long-term prognosis for these infants. This review article will discuss the epidemiology, risk factors and routes of acquisition, clinical presentation, and evaluation of an infant suspected to have the infection, and treatment of proven neonatal HSV disease. Copyright © 2018 Elsevier Inc. All rights reserved.

Different Mechanisms Regulate Productive Herpes Simplex Virus 1 (HSV-1) and HSV-2 Infections in Adult Trigeminal Neurons

PubMed Central

Ma, AyeAye; Margolis, Mathew S.

2013-01-01

Herpes simplex virus 1 (HSV-1) and HSV-2 establish latency in different neuronal subtypes (A5+ and KH10+) in murine trigeminal ganglia, results which correlate with restricted productive infection in these neurons in vitro. HSV-2 latency-associated transcript (LAT) contains a cis-acting regulatory element near the transcription start site that promotes productive infection in A5+ neurons and a second element in exon 1 that inhibits productive infection in KH10+ neurons. HSV-1 contains no such regulatory sequences, demonstrating different mechanisms for regulating productive HSV infection in neurons. PMID:23514893

Prevalence of HIV, human papillomavirus type 16 and herpes simplex virus type 2 among female sex workers in Guinea and associated factors.

PubMed

Aho, Joséphine; Koushik, Anita; Coutlée, François; Diakité, Soumaïla Laye; Rashed, Sélim

2014-03-01

Female sex workers are at high risk for HIV infection. Sexually transmitted infections are known to be co-factors for HIV infection. Our aims were (1) to assess the prevalence of HIV and other sexually transmitted infections in this population; (2) to determine the association between sociodemographic characteristics, behavioural variables, and variables related to HIV prevention and HIV infection. A cross-sectional study was conducted in Conakry, Guinea, among a convenience sample of 223 female sex workers. A questionnaire on sociodemographic characteristics, risk factors, and exposure to prevention was administered. Screening for HIV, herpes simplex virus type 2, human papillomavirus type 16, Neisseria gonorrhoeae, and Chlamydia trachomatis was performed. Prevalences of HIV, herpes simplex virus type 2, human papillomavirus type 16, N. gonorrhoeae, and C. trachomatis were 35.3%, 84.1%, 12.2%, 9.0%, and 13.6%, respectively. Having a child, lubricant use, and human papillomavirus type 16 infection were associated with HIV infection. Interventions that promote screening and treatment of sexually transmitted infections are needed in order to achieve successful interventions to prevent HIV among female sex workers in resource-limited settings.

Mechanism of ribonucleotide reductase from Herpes simplex virus type 1. Evidence for 3' carbon-hydrogen bond cleavage and inactivation by nucleotide analogs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ator, M.A.; Stubbe, J.; Spector, T.

1986-03-15

Isotope effects of 2.5, 2.1, and 1.0 were measured on the conversion of (3'-3H)ADP, (3'-H)UDP, and (5-3H) UDP to the corresponding 2'-deoxynucleotides by herpes simplex virus type 1 ribonucleotide reductase. These results indicate that the reduction of either purine or pyrimidine nucleotides requires cleavage of the 3' carbon-hydrogen bond of the substrate. The substrate analogs 2'-chloro-2'-deoxyuridine 5'-diphosphate (ClUDP), 2'-deoxy-2'-fluorouridine 5'-diphosphate, and 2'-azido-2'-deoxyuridine 5'-diphosphate were time-dependent inactivators of the herpes simplex virus type 1 ribonucleotide reductase. Incubation of (3'-3H)ClUDP with the enzyme was accompanied by time-dependent release of 3H to the solvent. Reaction of (beta-32P)ClUDP with the reductase resulted in themore » production of inorganic pyrophosphate. These results are consistent with the enzyme-mediated cleavage of the 3' carbon-hydrogen bond of ClUDP and the subsequent conversion of the nucleotide to 2-methylene-3(2H)furanone, as previously reported with the Escherichia coli ribonucleotide reductase.« less

An immunoassay for the study of DNA-binding activities of herpes simplex virus protein ICP8.

PubMed

Lee, C K; Knipe, D M

1985-06-01

An immunoassay was used to examine the interaction between a herpes simplex virus protein, ICP8, and various types of DNA. The advantage of this assay is that the protein is not subjected to harsh purification procedures. We characterized the binding of ICP8 to both single-stranded (ss) and double-stranded (ds) DNA. ICP8 bound ss DNA fivefold more efficiently than ds DNA, and both binding activities were most efficient in 150 mM NaCl. Two lines of evidence indicate that the binding activities were not identical: (i) ds DNA failed to complete with ss DNA binding even with a large excess of ds DNA; (ii) Scatchard plots of DNA binding with various amounts of DNA were fundamentally different for ss DNA and ds DNA. However, the two activities were related in that ss DNA efficiently competed with the binding of ds DNA. We conclude that the ds DNA-binding activity of ICP8 is probably distinct from the ss DNA-binding activity. No evidence for sequence-specific ds DNA binding was obtained for either the entire herpes simplex virus genome or cloned viral sequences.

Identification of structural protein-protein interactions of herpes simplex virus type 1.

PubMed

Lee, Jin H; Vittone, Valerio; Diefenbach, Eve; Cunningham, Anthony L; Diefenbach, Russell J

2008-09-01

In this study we have defined protein-protein interactions between the structural proteins of herpes simplex virus type 1 (HSV-1) using a LexA yeast two-hybrid system. The majority of the capsid, tegument and envelope proteins of HSV-1 were screened in a matrix approach. A total of 40 binary interactions were detected including 9 out of 10 previously identified tegument-tegument interactions (Vittone, V., Diefenbach, E., Triffett, D., Douglas, M.W., Cunningham, A.L., and Diefenbach, R.J., 2005. Determination of interactions between tegument proteins of herpes simplex virus type 1. J. Virol. 79, 9566-9571). A total of 12 interactions involving the capsid protein pUL35 (VP26) and 11 interactions involving the tegument protein pUL46 (VP11/12) were identified. The most significant novel interactions detected in this study, which are likely to play a role in viral assembly, include pUL35-pUL37 (capsid-tegument), pUL46-pUL37 (tegument-tegument) and pUL49 (VP22)-pUS9 (tegument-envelope). This information will provide further insights into the pathways of HSV-1 assembly and the identified interactions are potential targets for new antiviral drugs.

Treatment of colon cancer with oncolytic herpes simplex virus in preclinical models.

PubMed

Yang, H; Peng, T; Li, J; Wang, Y; Zhang, W; Zhang, P; Peng, S; Du, T; Li, Y; Yan, Q; Liu, B

2016-05-01

Cancer stem cells (CSCs), which are a rare population in any type of cancer, including colon cancer, are tumorigenic and responsible for cancer recurrence and metastasis. CSCs have been isolated from a number of different solid tumors recently, although the isolation of CSCs in colon cancer is still challenging. We cultured colon cancer cells in stem cell medium to obtain colonosphere cells. These cells possessed the characteristics of CSCs, with a high capacity of tumorigenicity, migration and invasion in vitro and in vivo. The isolation and identification of CSCs have provided new targets for the therapeutics. Oncolytic herpes simplex viruses (oHSV) are an effective strategy for killing colon cancer cells in preclinical models. Here, we examined the efficacy of an oncolytic herpes simplex virus type 2 (oHSV2) in killing colon cancer cells and colon cancer stem-like cells (CSLCs). oHSV2 was found to be highly cytotoxic to the adherent and sphere cells in vitro, and oHSV2 treatment in vivo significantly inhibited tumor growth. This study demonstrates that oHSV2 is effective against colon cancer cells and colon CSLCs and could be a promising strategy for treating colon cancer patients.

Herpes simplex virus: 'to disclose or not to disclose.' An exploration of the multi-disciplinary team's role in advising patients about disclosure when diagnosed with genital herpes simplex virus.

PubMed

Caulfield, Pauline; Willis, Diane

2017-07-01

The first UK prosecution for genital herpes simplex virus (HSV) transmission in 2011 attracted strong criticism from medical experts. To address the dearth of research on the topic, this study aimed to explore the nature of advice given to patients by the multidisciplinary team (MDT) in the West of Scotland on HSV disclosure to partners. Ten semi-structured interviews with members of the MDT were conducted and the interviews were analysed using Burnard's Thematic Content Analysis. Four themes emerged which explored practitioners' knowledge of HSV and their feelings regarding the emotional aspects of the diagnosis on clients including the challenges of discussing disclosure. Within this framework, participants' attitudes to the legal prosecution were also surveyed. This study revealed that participants had good knowledge about HSV. Furthermore, participants believed disclosure to be the patient's choice and had not altered their practice to advise disclosure to all partners in accordance with local protocol. However, there was a general consensus that disclosure was not required due to the prevalence of HSV and prevalence was used to dissipate emotional reactions to HSV diagnosis.

Lack of evidence for intertypic recombinants in the pathogenesis of recurrent genital infections with herpes simplex virus type 1.

PubMed

Fife, K H; Boggs, D

1986-01-01

Clinical observations indicate that herpes simplex virus type 1 (HSV-1) is significantly less likely than herpes simplex virus type 2 (HSV-2) to establish latency in (or reactivate from) sacral ganglionic tissue. In an effort to identify viral functions associated with latency, we analyzed HSV-1 isolates from three patients with established recurrent genital herpes and sought evidence of DNA sequences and proteins similar to those found in HSV-2. By restriction endonuclease cleavage patterns and by DNA hybridization analysis using either whole HSV-2 DNA or several cloned segments of HSV-2 DNA as probes, we found that the three HSV-1 isolates from patients with recurrent genital herpes showed no unusual homology to HSV-2 as compared with other HSV-1 isolates. Similarly, the proteins of these isolates could not be distinguished from those of other HSV-1 isolates and were distinct from those of HSV-2. At this level of resolution, there was no evidence to suggest that these recurrent genital HSV-1 isolates were intertypic recombinants, nor did they show any other unusual similarity to HSV-2.

Immunoglobulin G, Plasma Cells, and Lymphocytes in the Murine Vagina after Vaginal or Parenteral Immunization with Attenuated Herpes Simplex Virus Type 2

PubMed Central

Parr, Earl L.; Parr, Margaret B.

1998-01-01

This investigation evaluated immunity to vaginal herpes simplex virus type 2 (HSV-2) infection after local or parenteral immunization with attenuated HSV-2. Vaginal immunization induced sterilizing immunity against challenge with a high dose of wild-type virus, whereas parenteral immunizations protected against neurologic disease but did not entirely prevent infection of the vagina. Vaginal immunization caused 86- and 31-fold increases in the numbers of immunoglobulin G (IgG) plasma cells in the vagina at 6 weeks and 10 months after immunization, whereas parenteral immunizations did not increase plasma cell numbers in the vagina. Vaginal secretion/serum titer ratios and specific antibody activities in vaginal secretions and serum indicated that IgG viral antibody was produced in the vagina and released into vaginal secretions at 6 weeks and 10 months after vaginal immunization but not after parenteral immunizations. In contrast to the case for plasma cells, the numbers of T and B lymphocytes in the vagina were similar in vaginally and parenterally immunized mice. Also, lymphocyte numbers in the vagina were markedly but similarly increased by vaginal challenge with HSV-2 in both vaginally and parenterally immunized mice. Lymphocyte recruitment to the vagina after virus challenge appeared to involve memory lymphocytes, because it was not observed in nonimmunized mice. Thus, local vaginal immunization with attenuated HSV-2 increased the number of IgG plasma cells in the vagina and increased vaginal secretion/serum titer ratios to 3.0- to 4.7-fold higher than in parenterally immunized groups but caused little if any selective homing of T and B lymphocytes to the vagina. PMID:9573285

Herpes Simplex Virus 1 Tropism for Human Sensory Ganglion Neurons in the Severe Combined Immunodeficiency Mouse Model of Neuropathogenesis

PubMed Central

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

2013-01-01

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

Comparative Study of Mechanisms of Herpes Simplex Virus Inactivation by Sodium Lauryl Sulfate and n-Lauroylsarcosine

PubMed Central

Piret, Jocelyne; Roy, Sylvie; Gagnon, Mylène; Landry, Sébastien; Désormeaux, André; Omar, Rabeea F.; Bergeron, Michel G.

2002-01-01

The mechanisms of herpes simplex virus (HSV) inactivation by sodium lauryl sulfate (SLS) and n-lauroylsarcosine (LS), two anionic surfactants with protein denaturant potency, have been evaluated in cultured cells. Results showed that pretreatment of HSV type 1 (HSV-1) strain F and HSV-2 strain 333 with either surfactant inhibited, in a concentration- and time-dependent manner, their infectivities on Vero cells. SLS was a more potent inhibitor of HSV-2 strain 333 infectivity than LS with respect to the concentration (4.8-fold lower) and time (2.4-fold shorter) required to completely inactivate the virus. No inhibition of both herpesvirus strains infectivities was observed when Vero cells were pretreated with either surfactant. LS prevented the binding of HSV-2 strain 333 to cells without affecting the stable attachment and the rate of penetration into cells, whereas SLS exerted the opposite effect. Both SLS and LS inhibited, in a concentration-dependent manner, the HSV-2 strain 333-induced cytopathic effect, probably by affecting newly synthesized virions that come into contact with surfactant molecules present in culture medium. The pretreatment of HSV-2 strain 333 with specific combinations of SLS and LS concentrations inhibited the viral infectivity in a synergistic manner and resulted in only a small increase in their toxicities for exponentially growing Vero cells compared with that caused by each compound alone. Taken together, these results suggest that SLS and LS, alone or combined, could represent potent candidates as microbicides in topical vaginal formulations to prevent the transmission of herpes and possibly other pathogens that cause sexually transmitted diseases, including human immunodeficiency virus type 1. PMID:12183250

The use of FTIR microscopy for evaluation of herpes viruses infection development kinetics

NASA Astrophysics Data System (ADS)

Erukhimovitch, Vitaly; Mukmanov, Igor; Talyshinsky, Marina; Souprun, Yelena; Huleihel, Mahmoud

2004-08-01

The kinetics of Herpes simplex infection development was studied using an FTIR microscopy (FTIR-M) method. The family of herpes viruses includes several members like H. simplex types I and II (HSV I, II), Varicella zoster (VZV) viruses which are involved in various human and animal infections of different parts of the body. In our previous study, we found significant spectral differences between normal uninfected cells in cultures and cells infected with herpes viruses at early stages of the infection. In the present study, cells in cultures were infected with either HSV-I or VZV and at various times post-infection they were examined either by optical microscopy or by advanced FTIR-M. Spectroscopic measurements show a consistent decrease in the intensity of the carbohydrate peak in correlation with the viral infection development, observed by optical microscopy. This decrease in cellular carbohydrate level was used as indicator for herpes viruses infection kinetics. This parameter could be used as a basis for applying a spectroscopic method for the evaluation of herpes virus infection development. Our results show also that the development kinetics of viral infection has an exponential character for these viruses.

Future of an “Asymptomatic” T-cell Epitope-Based Therapeutic Herpes Simplex Vaccine

PubMed Central

Dervillez, Xavier; Gottimukkala, Chetan; Kabbara, Khaled W.; Nguyen, Chelsea; Badakhshan, Tina; Kim, Sarah M.; Nesburn, Anthony B.; Wechsler, Steven L.; BenMohamed, Lbachir

2012-01-01

Summary Considering the limited success of the recent herpes clinical vaccine trial [1], new vaccine strategies are needed. Infections with herpes simplex virus type 1 and type 2 (HSV-1 & HSV-2) in the majority of men and women are usually asymptomatic and results in lifelong viral latency in neurons of sensory ganglia (SG). However, in a minority of men and women HSV spontaneous reactivation can cause recurrent disease (i.e., symptomatic individuals). Our recent findings show that T cells from symptomatic and asymptomatic men and women (i.e. those with and without recurrences, respectively) recognize different herpes epitopes. This finding breaks new ground and opens new doors to assess a new vaccine strategy: mucosal immunization with HSV-1 & HSV-2 epitopes that induce strong in vitro CD4 and CD8 T cell responses from PBMC derived from asymptomatic men and women (designated here as “asymptomatic” protective epitopes”) could boost local and systemic “natural” protective immunity, induced by wild-type infection. Here we highlight the rationale and the future of our emerging “asymptomatic” T cell epitope-based mucosal vaccine strategy to decrease recurrent herpetic disease. PMID:22701511

Mechanical allodynia induced by nucleoside reverse transcriptase inhibitor is suppressed by p55TNFSR mediated by herpes simplex virus vector through the SDF1α/CXCR4 system in rats.

PubMed

Huang, Wan; Zheng, Wenwen; Ouyang, Handong; Yi, Hyun; Liu, Shue; Zeng, Weian; Levitt, Roy C; Candiotti, Keith A; Lubarsky, David A; Hao, Shuanglin

2014-03-01

In the human immunodeficiency virus (HIV)-associated sensory neuropathy, neuropathic pain associated with the use of nucleoside reverse transcriptase inhibitors (NRTIs) in patients with HIV/acquired immunodeficiency syndrome is clinically common. While evidence demonstrates that neuropathic pain is influenced by neuroinflammatory events that include the proinflammatory molecules, tumor necrosis factor-α (TNF-α), stromal cell-derived factor 1-α (SDF1-α), and C-X-C chemokine receptor type 4 (CXCR4), the detailed mechanisms by which NRTIs contribute to the development of neuropathic pain are not known. In this study, we investigated the role of these proinflammatory molecules in the dorsal root ganglion (DRG) and the spinal dorsal horn in NRTIs-mediated neuropathic pain state. Neuropathic pain was induced by intraperitoneal administration of 2',3'-dideoxycytidine (ddC, one of the NRTIs). Mechanical threshold was tested using von Frey filament fibers. Nonreplicating herpes simplex virus (HSV) vectors expressing p55 TNF soluble receptor (p55TNFSR) were inoculated into hindpaw of rats. The expression of TNF-α, SDF1-α, and CXCR4 in both the lumbar spinal cord and the L4/5 DRG was examined using Western blots. Intrathecal CXCR4 antagonist was administered. The present study demonstrated that (1) systemic ddC induced upregulation of TNF-α, SDF1-α, and CXCR4 in both the lumbar spinal cord and the L4/5 DRG; (2) p55TNFSR mediated by a nonreplicating HSV vector reversed mechanical allodynia induced by systemic ddC; (3) intrathecal administration of the CXCR4 antagonist AMD3100 increased mechanical threshold; and (4) HSV vector expressing p55TNFSR reversed upregulation of TNF-α, SDF1-α, and CXCR4 induced by ddC in the lumbar spinal dorsal horn and the DRG. Our studies demonstrate that TNF-α through the SDF1/CXCR4 system is involved in the NRTIs-related neuropathic pain state and that blocking the signaling of these proinflammatory molecules is able to reduce NRTIs-related neuropathic pain. These results provide a novel mechanism-based approach (gene therapy) to treating HIV-associated neuropathic pain.

Antiviral activity of an extract of Cordia salicifolia on herpes simplex virus type 1.

PubMed

Hayashi, K; Hayashi, T; Morita, N; Niwayama, S

1990-10-01

A partially purified extract (COL 1-6) from whole plant of Cordia salicifolia showed an inhibitory effect on herpes simplex virus type 1 (HSV-1). The activity of COL 1-6 on different steps of HSV-1 replication in HeLa cells was investigated. Under single-cycle replication conditions, COL 1-6 exerted a greater than 99.9% inhibition in virus yield when added to the cells 3 h or 1.5 h before infection, and even when added 8 h after infection the extract still caused a greater than 99% inhibition. The extract has been shown to have a direct virucidal activity. And also, analysis of early events following infection showed that COL 1-6 affected viral penetration in HeLa cells but did not interfere with adsorption to the cells.

Infection and Transport of Herpes Simplex Virus Type 1 in Neurons: Role of the Cytoskeleton

PubMed Central

2018-01-01

Herpes simplex virus type 1 (HSV-1) is a neuroinvasive human pathogen that has the ability to infect and replicate within epithelial cells and neurons and establish a life-long latent infection in sensory neurons. HSV-1 depends on the host cellular cytoskeleton for entry, replication, and exit. Therefore, HSV-1 has adapted mechanisms to promote its survival by exploiting the microtubule and actin cytoskeletons to direct its active transport, infection, and spread between neurons and epithelial cells during primary and recurrent infections. This review will focus on the currently known mechanisms utilized by HSV-1 to harness the neuronal cytoskeleton, molecular motors, and the secretory and exocytic pathways for efficient virus entry, axonal transport, replication, assembly, and exit from the distinct functional compartments (cell body and axon) of the highly polarized sensory neurons. PMID:29473915

Herpes Simplex Virus: Beyond the Basics.

PubMed

Kobty, Magidah

2015-01-01

One of the most common sexually transmitted infections is the herpes simplex virus (HSV) Type 2. Although the incidence of newborn infection is not as common as in adults, approximately 1,500 neonates are diagnosed annually with HSV infection. HSV can be detrimental to the life of a newborn, with morbidity and mortality rates of up to 65 percent. This article addresses the maternal and fetal complications of HSV and the impact of HSV on the newborn along with diagnostic evaluation methods. In addition, treatment options and evidence-based practices regarding HSV are defined. Despite growing technology and medical treatment for early identification of HSV, this virus remains challenging and can deeply impact the life of an infant and his or her family. Early diagnosis, treatment, and intervention of an infant with HSV are crucial to ensure the livelihood of the newborn.

Cross-reactive antibodies against GM2 and CMV-infected fibroblasts in Guillain-Barré syndrome.

PubMed

Ang, C W; Jacobs, B C; Brandenburg, A H; Laman, J D; van der Meché, F G; Osterhaus, A D; van Doorn, P A

2000-04-11

To investigate whether anti-GM2 antibodies in patients with Guillain-Barré syndrome (GBS) are induced by molecular mimicry with cytomegalovirus (CMV). Antibodies against ganglioside GM2 are frequently present in the serum from GBS patients with an antecedent infection with CMV. The authors detected inhibition of anti-GM2 reactivity after incubation of GM2-reactive serum samples with fibroblasts infected with a GBS-associated CMV strain. Control sera consisted of GQ1b-reactive samples, and control antigens included uninfected fibroblasts and fibroblasts that were infected with other herpes viruses. Serum immunoglobulin M reactivity with GM2 was decreased in a dose-dependent manner after incubation with CMV-infected fibroblasts. Incubation of anti-GM2-positive serum samples with uninfected fibroblasts and fibroblasts infected with varicella zoster virus did not inhibit anti-GM2 reactivity, whereas this reactivity was slightly decreased after incubation with herpes simplex virus type 1 in one patient. Antibodies against ganglioside GQ1b did not react with CMV-infected fibroblasts. CMV-infected fibroblasts express gangliosidelike epitopes that recognize specifically anti-GM2 antibodies. These results support the hypothesis that antiganglioside antibodies in CMV-infected GBS patients are induced by molecular mimicry between GM2 and antigens that are induced by a CMV infection.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Saito, Y.; Rubenstein, R.; Price, R.W.

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 ofmore » 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.« less

Chronic herpes simplex type-1 encephalitis with intractable epilepsy in an immunosuppressed patient.

PubMed

Laohathai, Christopher; Weber, Daniel J; Hayat, Ghazala; Thomas, Florian P

2016-02-01

Chronic herpes simplex virus type-1 encephalitis (HSE-1) is uncommon. Past reports focused on its association with prior documented acute infection. Here, we describe a patient with increasingly intractable epilepsy from chronic HSE-1 reactivation without history of acute central nervous system infection. A 49-year-old liver transplant patient with 4-year history of epilepsy after initiation of cyclosporine developed increasingly frequent seizures over 3 months. Serial brain magnetic resonance imaging showed left temporoparietal cortical edema that gradually improved despite clinical decline. Herpes simplex virus type-1 (HSV-1) DNA was detected in cerebrospinal fluid by polymerase chain reaction. Cerebrospinal fluid HSV-1&2 IgM was negative. Seizures were controlled after acyclovir treatment, and the patient remained seizure free at 1-year follow-up. Chronic HSE is a cause of intractable epilepsy, can occur without a recognized preceding acute phase, and the clinical course of infection may not directly correlate with neuroimaging changes.

Triple retinal infection with human immunodeficiency virus type 1, cytomegalovirus, and herpes simplex virus type 1. Light and electron microscopy, immunohistochemistry, and in situ hybridization.

PubMed

Rummelt, V; Rummelt, C; Jahn, G; Wenkel, H; Sinzger, C; Mayer, U M; Naumann, G O

1994-02-01

This report describes the histopathologic and virologic findings of the retina from a 55-year-old bisexual patient with the acquired immune deficiency syndrome (AIDS), who had concurrent human immunodeficiency virus type 1 (HIV-1), cytomegalovirus (CMV), and herpes simplex virus type 1 (HSV-1) retinitis, and was treated with ganciclovir. The eyes were obtained at autopsy and processed for light microscopy and transmission electron microscopy. Immunohistochemical stains for HSV-1, CMV, HIV-1, varicella zoster virus, and glial fibrillary acidic protein were carried out using the peroxidase-antiperoxidase and streptavidin-biotin-alkaline phosphatase techniques. For in situ hybridization, a radiolabeled CMV DNA probe (Eco-RI-Y fragment of strain AD 169) was used. Results of histopathologic examination showed a full-thickness necrotizing retinitis with cytomegalic and herpes viral intranuclear inclusions in cells of the neurosensory retina, retinal vascular endothelium, and the retinal pigment epithelium. Some areas of the retina were replaced by glial tissue. The choroid contained only a few chronic inflammatory cells. Immunoperoxidase studies disclosed CMV antigens diffusely distributed throughout all layers of the retina and the retinal pigment epithelium. Herpes simplex virus type 1 antigens were present in retinal cells and the retinal vascular endothelium. Human immunodeficiency virus type 1 antigens were found in mononuclear cells in all layers of the sensory retina. Dual infections with HIV-1 and CMV of individual multinucleated giant cells of glial origin were demonstrated immunohistochemically. Transmission electron microscopy showed herpes viral particles in the vascular endothelium of the retinal vessels and the choriocapillaris. Human immunodeficiency virus particles were identified in the endothelium of the choriocapillaris. The possibility of multiple viral infections of the retina, mimicking classic CMV retinitis, should be considered in the clinical and histologic differential diagnosis of necrotizing retinitis in patients with AIDS.

Nuclear envelope breakdown induced by herpes simplex virus type 1 involves the activity of viral fusion proteins

DOE Office of Scientific and Technical Information (OSTI.GOV)

Maric, Martina; Haugo, Alison C.; Dauer, William

2014-07-15

Herpesvirus infection reorganizes components of the nuclear lamina usually without loss of integrity of the nuclear membranes. We report that wild-type HSV infection can cause dissolution of the nuclear envelope in transformed mouse embryonic fibroblasts that do not express torsinA. Nuclear envelope breakdown is accompanied by an eight-fold inhibition of virus replication. Breakdown of the membrane is much more limited during infection with viruses that lack the gB and gH genes, suggesting that breakdown involves factors that promote fusion at the nuclear membrane. Nuclear envelope breakdown is also inhibited during infection with virus that does not express UL34, but ismore » enhanced when the US3 gene is deleted, suggesting that envelope breakdown may be enhanced by nuclear lamina disruption. Nuclear envelope breakdown cannot compensate for deletion of the UL34 gene suggesting that mixing of nuclear and cytoplasmic contents is insufficient to bypass loss of the normal nuclear egress pathway. - Highlights: • We show that wild-type HSV can induce breakdown of the nuclear envelope in a specific cell system. • The viral fusion proteins gB and gH are required for induction of nuclear envelope breakdown. • Nuclear envelope breakdown cannot compensate for deletion of the HSV UL34 gene.« less

Interleukin 10 mediated by herpes simplex virus vectors suppresses neuropathic pain induced by human immunodeficiency virus gp120 in rats.

PubMed

Zheng, Wenwen; Huang, Wan; Liu, Shue; Levitt, Roy C; Candiotti, Keith A; Lubarsky, David A; Hao, Shuanglin

2014-09-01

Human immunodeficiency virus (HIV)-associated sensory neuropathy is a common neurological complication of HIV infection affecting up to 30% of HIV-positive individuals. However, the exact neuropathological mechanisms remain unknown, which hinders our ability to develop effective treatments for HIV-related neuropathic pain (NP). In this study, we tested the hypothesis that inhibition of proinflammatory factors with overexpression of interleukin (IL)-10 reduces HIV-related NP in a rat model. NP was induced by the application of recombinant HIV-1 envelope protein gp120 into the sciatic nerve. The hindpaws of rats were inoculated with nonreplicating herpes simplex virus (HSV) vectors expressing anti-inflammatory cytokine IL-10 or control vector. Mechanical threshold was tested using von Frey filaments before and after treatments with the vectors. The mechanical threshold response was assessed over time using the area under curves. The expression of phosphorylated p38 mitogen-activated kinase, tumor necrosis factor-α, stromal cell-derived factor-1α, and C-X-C chemokine receptor type 4 in both the lumbar spinal cord and the L4/5 dorsal root ganglia (DRG), was examined at 14 and 28 days after vector inoculation using Western blots. We found that in the gp120-induced NP model, IL-10 overexpression mediated by the HSV vector resulted in a significant elevation of the mechanical threshold that was apparent on day 3 after vector inoculation compared with the control vector (P < 0.001). The antiallodynic effect of the single HSV vector inoculation expressing IL-10 lasted >28 days. The area under curve in the HSV vector expressing IL-10 was increased compared with that in the control vector (P < 0.0001). HSV vectors expressing IL-10 reversed the upregulation of phosphorylated p38 mitogen-activated kinase, tumor necrosis factor-α, stromal cell-derived factor-1α, and C-X-C chemokine receptor type 4 expression at 14 and/or 28 days in the DRG and/or the spinal dorsal horn. Our studies demonstrate that blocking the signaling of these proinflammatory molecules in the DRG and/or the spinal cord using the HSV vector expressing IL-10 is able to reduce HIV-related NP. These results provide new insights on the potential mechanisms of HIV-associated NP and a proof of concept for treating painful HIV sensory neuropathy with this type of gene therapy.

Antiviral Activities of Honey, Royal Jelly, and Acyclovir Against HSV-1.

PubMed

Hashemipour, Maryam Alsadat; Tavakolineghad, Zahra; Arabzadeh, Sayed Ali Mohammad; Iranmanesh, Zahra; Nassab, Sayed Amir Hossein Gandjalikhan

2014-02-01

Herpes simplex virus type 1 (HSV-1) belongs to the Herpesviridae family and genus simplex virus. This virus is usually acquired during childhood and is transmitted through direct mucocutaneous contact or droplet infection from infected secretions. The aim of the present study was to compare antiviral effects of honey, royal jelly, and acyclovir on herpes simplex virus-1 in an extra-somatic environment. Vero cells were cultured in the Dulbecco's Modified Eagle's Medium (DMEM) along with 10% fetal bovine serum (FBS) in 12-welled microplates. Various dilutions of honey, royal jelly, and acyclovir (5, 10, 50, 100, 2500, 500, and 800 μg/mL) were added to the Vero cells along with a 100-virus concentration of TCID50. The plaque assay technique was used to evaluate the antiviral activities. The results showed that honey, royal jelly, and acyclovir have the highest inhibitory effects on HSV-1 at concentrations of 500, 250, and 100 μg/mL, respectively. In addition, honey, royal jelly, and acyclovir decreased the viral load from 70 795 to 43.3, 30, and 0 PFU/mL at a concentration of 100 μg/mL, respectively. The results of the present study showed that honey and royal jelly, which are natural products with no reports about their deleterious effect at least in laboratory conditions, can be considered alternatives to acyclovir in the treatment of herpetic lesions. However, it should be pointed out that further studies are necessary to substantiate their efficacy because hard evidence on their effectiveness is not available at present.

Exposure to herpes simplex virus type 1 and cognitive impairments in individuals with schizophrenia.

PubMed

Prasad, Konasale M; Watson, Annie M M; Dickerson, Faith B; Yolken, Robert H; Nimgaonkar, Vishwajit L

2012-11-01

Latent infection with neurotropic herpes viruses, such as herpes simplex virus, type 1 (HSV1), has been generally considered benign in most immunocompetent individuals except for rare cases of encephalitis. However, several recent studies have shown impaired cognitive functions among individuals with schizophrenia exposed to HSV1 compared with schizophrenia patients not exposed to HSV1. Such impairments are robust and are prominently observed in working memory, verbal memory, and executive functions. Brain regions that play a key role in the regulation of these domains have shown smaller volumes, along with correlation between these morphometric changes and cognitive impairments in schizophrenia. One study noted temporal decline in executive function and gray matter loss among HSV1-exposed first-episode antipsychotic-naïve schizophrenia patients. Furthermore, a proof-of-concept double-blind placebo-controlled trial indicated improvement in cognitive performance following supplemental anti-herpes-specific medication among HSV1 seropositive schizophrenia patients. Cross-sectional studies have also identified an association between HSV1 exposure and lesser degrees of cognitive impairment among healthy control individuals and patients with bipolar disorder. These studies fulfill several Bradford-Hill criteria, suggesting etiological links between HSV1 exposure and cognitive impairment. Exposure to other human herpes viruses such as cytomegalovirus and herpes simplex virus type 2 (HSV2) may also be associated with cognitive impairment, but the data are less consistent. These studies are reviewed critically and further lines of enquiry recommended. The results are important from a public health perspective, as HSV1 exposure is highly prevalent in many populations.

Exposure to Herpes Simplex Virus Type 1 and Cognitive Impairments in Individuals With Schizophrenia

PubMed Central

Prasad, Konasale M.; Watson, Annie M. M.; Dickerson, Faith B.; Yolken, Robert H.; Nimgaonkar, Vishwajit L.

2012-01-01

Latent infection with neurotropic herpes viruses, such as herpes simplex virus, type 1 (HSV1), has been generally considered benign in most immunocompetent individuals except for rare cases of encephalitis. However, several recent studies have shown impaired cognitive functions among individuals with schizophrenia exposed to HSV1 compared with schizophrenia patients not exposed to HSV1. Such impairments are robust and are prominently observed in working memory, verbal memory, and executive functions. Brain regions that play a key role in the regulation of these domains have shown smaller volumes, along with correlation between these morphometric changes and cognitive impairments in schizophrenia. One study noted temporal decline in executive function and gray matter loss among HSV1-exposed first-episode antipsychotic-naïve schizophrenia patients. Furthermore, a proof-of-concept double-blind placebo-controlled trial indicated improvement in cognitive performance following supplemental anti-herpes–specific medication among HSV1 seropositive schizophrenia patients. Cross-sectional studies have also identified an association between HSV1 exposure and lesser degrees of cognitive impairment among healthy control individuals and patients with bipolar disorder. These studies fulfill several Bradford-Hill criteria, suggesting etiological links between HSV1 exposure and cognitive impairment. Exposure to other human herpes viruses such as cytomegalovirus and herpes simplex virus type 2 (HSV2) may also be associated with cognitive impairment, but the data are less consistent. These studies are reviewed critically and further lines of enquiry recommended. The results are important from a public health perspective, as HSV1 exposure is highly prevalent in many populations. PMID:22490995

Inactivation of Viruses by Benzalkonium Chloride

PubMed Central

Armstrong, J. A.; Froelich, E. J.

1964-01-01

Benzalkonium chloride (as Roccal or Zephiran) was found to inactivate influenza, measles, canine distemper, rabies, fowl laryngotracheitis, vaccinia, Semliki Forest, feline pneumonitis, meningopneumonitis, and herpes simplex viruses after 10 min of exposure at 30 C or at room temperature. Poliovirus and encephalomyocarditis virus were not inactivated under the same conditions. It was concluded that all viruses tested were sensitive except members of the picorna group. The literature was reviewed. PMID:4288740

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.

Ancient Recombination Events between Human Herpes Simplex Viruses

PubMed Central

Burrel, Sonia; Boutolleau, David; Ryu, Diane; Agut, Henri; Merkel, Kevin; Leendertz, Fabian H.

2017-01-01

Abstract Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) are seen as close relatives but also unambiguously considered as evolutionary independent units. Here, we sequenced the genomes of 18 HSV-2 isolates characterized by divergent UL30 gene sequences to further elucidate the evolutionary history of this virus. Surprisingly, genome-wide recombination analyses showed that all HSV-2 genomes sequenced to date contain HSV-1 fragments. Using phylogenomic analyses, we could also show that two main HSV-2 lineages exist. One lineage is mostly restricted to subSaharan Africa whereas the other has reached a global distribution. Interestingly, only the worldwide lineage is characterized by ancient recombination events with HSV-1. Our findings highlight the complexity of HSV-2 evolution, a virus of putative zoonotic origin which later recombined with its human-adapted relative. They also suggest that coinfections with HSV-1 and 2 may have genomic and potentially functional consequences and should therefore be monitored more closely. PMID:28369565

Glycoprotein Targeted Therapeutics: A New Era of Anti-Herpes Simplex Virus-1 Therapeutics

PubMed Central

Antoine, Thessicar; Park, Paul J.; Shukla, Deepak

2013-01-01

Herpes simplex virus type-1 (HSV-1) is among the most common human pathogens worldwide. Its entry into host cells is an intricate process that relies heavily on the ability of the viral glycoproteins to bind host cellular proteins and to efficiently mediate fusion of the virus envelope with the cell membrane. Acquisition of HSV-1 results in a lifelong latent infection. Due to the cycles of reactivation from a latent state, much emphasis has been placed on the management of infection through the use of DNA synthesis inhibitors. However, new methods are needed to provide more effective treatment at earlier phases of the viral infection and to prevent the development of drug resistance by the virus. This review outlines the infection process and the common therapeutics currently used against the fundamental stages of HSV-1 replication and fusion. The remainder of this article will focus on a new approach for HSV-1 infection control and management, the concept of glycoprotein-receptor targeting. PMID:23440920

Sulfated polysaccharide of Caesalpinia ferrea inhibits herpes simplex virus and poliovirus.

PubMed

Lopes, Nayara; Faccin-Galhardi, Lígia Carla; Espada, Samantha Fernandes; Pacheco, Arcelina Cunha; Ricardo, Nágila Maria Pontes Silva; Linhares, Rosa Elisa Carvalho; Nozawa, Carlos

2013-09-01

Herpes simplex virus (HSV) is one of the most regular human pathogens, being a public health problem, and causal agent of several diseases. Poliovirus (PV) is an enteric virus and about 1% of infected individuals develop paralytic poliomyelitis due to viral invasion of the central nervous system and destruction of motor neurons. This work evaluated the activity of a sulfated polysaccharide of Caesalpinia ferrea (SPLCf) in HSV and PV replication. The antiviral effect of SPLCf at varying concentrations was tested by plaque assay under several protocols, such as time-of-addition, adsorption and penetration inhibition and virucidal. Syntheses of viral protein and nucleic acid were also monitored by the immunofluorescence assay and PCR. The SPLCf inhibited virus adsorption and steps after penetration, and inhibited the synthesis of viral protein. Virucidal effect was also shown and nucleic acid synthesis was concurrent with positive results. Our findings suggested that the substance with low toxicity represent a potential viral inhibitor. Copyright © 2013 Elsevier B.V. All rights reserved.

Detection of herpes simplex virus and varicella-zoster virus in clinical swabs: frequent inhibition of PCR as determined by internal controls.

PubMed

Bezold, G; Volkenandt, M; Gottlöber, P; Peter, R U

2000-12-01

PCR-based detection of microorganisms is widely used for diagnostic purposes. Most routine PCR applications do not control for inhibition of PCR, thus leading to false-negative results. One hundred eighteen swab samples obtained from skin and mucosa were investigated for the presence of herpes simplex virus (HSV), varicella-zoster virus (VZV), and the control gene betaglobin by internally controlled PCR with purified and unpurified DNA in parallel. With unpurified DNA, inhibition of PCR was detected in 23% of betaglobin PCRs, 25% of VZV PCRs, and 16% of HSV PCRs versus 3% each for purified DNA. Approximately 20% of the samples with positive results for HSV or VZV had negative or inhibited results using unpurified DNA. These results indicate that PCR from clinical swab specimens should be performed exclusively with internal controls because the positive control alone cannot exclude PCR inhibition in individual samples. Purification of DNA will decrease, but not exclude, PCR inhibition.

Current Concepts for Genital Herpes Simplex Virus Infection: Diagnostics and Pathogenesis of Genital Tract Shedding

PubMed Central

Corey, Lawrence

2015-01-01

SUMMARY Herpes simplex virus 2 (HSV-2) is a DNA virus that is efficiently transmitted through intimate genital tract contact and causes persistent infection that cannot be eliminated. HSV-2 may cause frequent, symptomatic self-limited genital ulcers, but in most persons infection is subclinical. However, recent studies have demonstrated that the virus is frequently shed from genital surfaces even in the absence of signs or symptoms of clinical disease and that the virus can be transmitted during these periods of shedding. Furthermore, HSV-2 shedding is detected throughout the genital tract and may be associated with genital tract inflammation, which likely contributes to increased risk of HIV acquisition. This review focuses on HSV diagnostics, as well as what we have learned about the importance of frequent genital HSV shedding for (i) HSV transmission and (ii) genital tract inflammation, as well as (iii) the impact of HSV-2 infection on HIV acquisition and transmission. We conclude with discussion of future areas of research to push the field forward. PMID:26561565

Current Concepts for Genital Herpes Simplex Virus Infection: Diagnostics and Pathogenesis of Genital Tract Shedding.

PubMed

Johnston, Christine; Corey, Lawrence

2016-01-01

Herpes simplex virus 2 (HSV-2) is a DNA virus that is efficiently transmitted through intimate genital tract contact and causes persistent infection that cannot be eliminated. HSV-2 may cause frequent, symptomatic self-limited genital ulcers, but in most persons infection is subclinical. However, recent studies have demonstrated that the virus is frequently shed from genital surfaces even in the absence of signs or symptoms of clinical disease and that the virus can be transmitted during these periods of shedding. Furthermore, HSV-2 shedding is detected throughout the genital tract and may be associated with genital tract inflammation, which likely contributes to increased risk of HIV acquisition. This review focuses on HSV diagnostics, as well as what we have learned about the importance of frequent genital HSV shedding for (i) HSV transmission and (ii) genital tract inflammation, as well as (iii) the impact of HSV-2 infection on HIV acquisition and transmission. We conclude with discussion of future areas of research to push the field forward. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

The Quantity of Latent Viral DNA Correlates with the Relative Rates at Which Herpes Simplex Virus Types 1 and 2 Cause Recurrent Genital Herpes Outbreaks

PubMed Central

Lekstrom-Himes, Julie A.; Pesnicak, Lesley; Straus, Stephen E.

1998-01-01

Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) have evolved specific anatomic tropisms and site-dependent rates of reactivation. To determine whether reactivation rates depend on distinct abilities of HSV-1 and -2 to establish latency and to express latency-associated transcripts (LATs), virulent strains of each virus were studied in the guinea pig genital model. Following infection with equivalent titers of virus, the quantities of latent HSV-2 genomes and LATs were higher in lumbosacral ganglia, and HSV-2 infections recurred more frequently and lasted longer than HSV-1 infections. In contrast, if the inoculum of HSV-1 was 10 times that of HSV-2, the quantity of HSV-1 DNA and LATs increased correspondingly and HSV-1 infections were as likely to recur as those with HSV-2. The quantity of latent virus DNA correlates with and may be a major determinant of the site-specific patterns and rates of reactivation of HSV-1 and -2. PMID:9525595

Phytochemical screening and antiviral activity of some medicinal plants from the island Soqotra.

PubMed

Mothana, Ramzi A A; Mentel, Renate; Reiss, Christiane; Lindequist, Ulrike

2006-04-01

Methanol and hot-aqueous extracts of 25 different plant species, used in Yemeni traditional medicine and growing, partly as endemic plants, on the island Soqotra have been investigated for their antiviral activity. In addition, the phytochemical identification of the main chemical constituents was performed. The extracts were assayed in two in vitro viral systems, which used influenza virus type A/MDCK cells and herpes simplex virus type 1/Vero cells, at non-cytotoxic concentrations. The herpes simplex virus type 1 showed more sensitivity than the influenza virus type A against the extracts investigated. The methanol extracts of Boswellia ameero, Boswellia elongata, Buxus hildebrandtii, Cissus hamaderohensis, Cleome socotrana, Dracaena cinnabari, Exacum affine, Jatropha unicostata and Kalanchoe farinacea showed anti-influenza virus type A activity with 50% inhibition (IC50) concentrations ranging from 0.7 to 12.5 microg/mL. In addition, 17 plants of the 25 investigated exhibited anti-HSV-1 activity. The antiviral activity of some active extracts was also observed on a molecular level. Copyright 2006 John Wiley & Sons, Ltd.

Diagnosis of herpes simplex virus infection by immunofluorescence.

PubMed Central

Taber, L H; Brasier, F; Couch, R B; Greenberg, S B; Jones, D; Knight, V

1976-01-01

The utility of the indirect immunofluorescent antibody (IFA) technique for diagnosis of herpes simplex virus (HSV) infection was examined by testing specimens for this agent from 31 patients with encephalitis or meningitis, 17 with conjunctivitis, 19 with genital disease, and 1 with genital disease and meningitis. Brain biopsy tissue from four patients with encephalitis was positive by IFA and virus culture for HSV. Leukocytes in cerebrospinal fluid from these four patients and one with HSV meningitis were also positive by IFA, but virus isolation attempts on the fluid were all negative. Conjunctival scrapings from two patients with conjunctivitis were positive for HSV by both IFA and virus culture. Eleven of 12 culture-positive lesions of herpes progenitalis were positive by IFA, and 1 dark field-positive syphilitic chancre was also positive for HSV by both IFA and culture. Evidence for specificity of the results was provided by internal controls in each test and negative results from patients with other diagnoses. Thus, the IFA technique constituted a rapid, sensitive, and specific diagnostic method for the diagnosis of HSV infections. PMID:178689

Identification of an immunodominant epitope in glycoproteins B and G of herpes simplex viruses (HSVs) using synthetic peptides as antigens in assay of antibodies to HSV in herpes simplex encephalitis patients.

PubMed

Bhullar, S S; Chandak, N H; Baheti, N N; Purohit, H J; Taori, G M; Daginawala, H F; Kashyap, R S

2014-01-01

Herpes simplex encephalitis (HSE) is a severe viral infection of the central nervous system (CNS). Assay of antibody response is widely used in diagnostics of HSE. The aim of this study was to identify an immunodominant epitope determining the antibody response to herpes simplex viruses (HSVs) in cerebrospinal fluid (CSF) of HSE patients. The synthetic peptides that resembled type-common as well as type-specific domains of glycoproteins B (gB) and G (gG) of these viruses were evaluated for binding with IgM and IgG antibodies in CSF samples from HSE and non-HSE patients in ELISA. The QLHDLRF peptide, derived from gB of HSV was found to be an immunodominant epitope in the IgM and IgG antibody response. The patients with confirmed and suspected HSE showed in ELISA against this peptide 26% and 23% positivities for IgM, 43% and 37% positivities for IgG and 17% and 15% for both IgM and IgG antibodies, respectively. The total positivities of 86% and 75% for both IgM and IgG antibodies were obtained in the patients with confirmed and suspected HSE, respectively. These results demonstrate that a synthetic peptide-based diagnostics of HSE can be an efficient and easily accessible alternative. This is the first report describing the use of synthetic peptides derived from HSVs in diagnostics of HSE using patientsʹ CSF samples.

Combined cytotoxic activity of an infectious, but non-replicative herpes simplex virus type 1 and plasmacytoid dendritic cells against tumour cells

PubMed Central

Thomann, Sabrina; Boscheinen, Jan B; Vogel, Karin; Knipe, David M; DeLuca, Neal; Gross, Stefanie; Schuler-Thurner, Beatrice; Schuster, Philipp; Schmidt, Barbara

2015-01-01

Malignant melanoma is an aggressive tumour of the skin with increasing incidence, frequent metastasis and poor prognosis. At the same time, it is an immunogenic type of cancer with spontaneous regressions. Most recently, the tumoricidal effect of plasmacytoid dendritic cells (pDC) and their capacity to overcome the immunosuppressive tumour microenvironment are being investigated. In this respect, we studied the effect of the infectious, but replication-deficient, herpes simplex virus 1 (HSV-1) d106S vaccine strain, which lacks essential immediate early genes, in pDC co-cultures with 11 melanoma cell lines. We observed a strong cytotoxic activity, inducing apoptotic and necrotic cell death in most melanoma cell lines. The cytotoxic activity of HSV-1 d106S plus pDC was comparable to the levels of cytotoxicity induced by natural killer cells, but required only a fraction of cells with effector : target ratios of 1 : 20 (P < 0·05). The suppressive activity of cell-free supernatants derived from virus-stimulated pDC was significantly neutralized using antibodies against the interferon-α receptor (P < 0·05). In addition to type I interferons, TRAIL and granzyme B contributed to the inhibitory effect of HSV-1 d106S plus pDC to a minor extent. UV-irradiated viral stocks were significantly less active than infectious particles, both in the absence and presence of pDC (P < 0·05), indicating that residual activity of HSV-1 d106S is a major component and sensitizes the tumour cells to interferon-producing pDC. Three leukaemic cell lines were also susceptible to this treatment, suggesting a general anti-tumour effect. In conclusion, the potential of HSV-1 d106S for therapeutic vaccination should be further evaluated in patients suffering from different malignancies. PMID:26194553

Evaluation of scopadulciol-related molecules for their stimulatory effect on the cytotoxicity of acyclovir and ganciclovir against Herpes simplex virus type 1 thymidine kinase gene-transfected HeLa cells.

PubMed

Hayashi, Kyoko; Rahman, S M Abdur; Ohno, Hiroaki; Tanaka, Tetsuaki; Toyooka, Naoki; Nemoto, Hideo; Hayashi, Toshimitsu

2004-08-01

Herpes simplex virus type 1 thymidine kinase (HSV TK) is involved in both antiherpetic therapy and cancer gene therapy with acyclovir (ACV) and ganciclovir (GCV). Enhanced sensitivity to these drugs is advantageous in their clinical use. In the present study, scopadulciol (SDC) and its related compounds were evaluated for their stimulatory effect on the cytotoxicity of ACV and GCV by determination of selective toxicities against HSV TK-expressing HeLa cells. Although SDC remarkably potenciated the cytotoxicity of ACV and GCV, the other tested compounds showed only weak selectivity, except for compound 34.

Studies on the constituents of seeds of Pachyrrhizus erosus and their anti herpes simplex virus (HSV) activities.

PubMed

Phrutivorapongkul, Ampai; Lipipun, Vimolmas; Ruangrungsi, Nijsiri; Watanabe, Toshiko; Ishikawa, Tsutomu

2002-04-01

Studies on the chemical constituents of the seeds of Pachyrrhizus erosus (Leguminosae) resulted in the isolation of nine known components: five rotenoids [dolineone (3), pachyrrhizone (5), 12a-hydroxydolineone (7), 12a-hydroxypachyrrhizone (9), and 12a-hydroxyrotenone (2)], two isoflavonoids [neotenone (4) and dehydroneotenone (8)], one phenylfuranocoumarin [pachyrrhizine (6)], and a monosaccharide (dulcitol). The full 1H- and 13C-NMR assignments for the isolated products except a sugar, including revision of previous assignments in the literature, are reported. Moderate anti herpes simplex virus (HSV) activity was observed in 12a-hydroxydolineone (7) and 12a-hydroxypachyrrhizone (9) among the isolated products.

Herpes simplex virus type 2 recurrent meningitis (Mollaret's meningitis): a consideration for the recurrent pathogenesis.

PubMed

Sato, Rumi; Ayabe, Mitsuyoshi; Shoji, Hiroshi; Ichiyama, Takashi; Saito, Yumiko; Hondo, Ryo; Eizuru, Yoshito

2005-11-01

We report a 44-year-old Japanese woman with herpes simplex virus (HSV) type 2 recurrent meningitis (Mollaret's meningitis). The diagnosis was confirmed by nested polymerase chain reaction in her cerebrospinal fluid, but the patient's conventional HSV antibodies by complement fixation, neutralizing test or enzyme immunoassay showed low titres with low lymphoproliferative response. Several similar cases are discussed. Although the reason for the recurrent pathogenesis is uncertain, our report suggests that the low immune response including immune evasion may be involved in the pathogenesis of HSV type 2 recurrent meningitis. For this patient, long-term suppressive and patient-initiated therapies were conducted to prevent the recurrence of meningitis.

A case of recurrent benign lymphocytic (Mollaret's) meningitis and review of the literature.

PubMed

Poulikakos, P J; Sergi, E E; Margaritis, A S; Kioumourtzis, A G; Kanellopoulos, G D; Mallios, P K; Dimitrakis, D J; Poulikakos, D J; Aspiotis, A A; Deliousis, A D; Flevaris, C P; Zacharof, A K

2010-12-01

Mollaret's meningitis is a rare form of benign recurrent aseptic meningitis first described in 1944. We report a case of Mollaret's meningitis due to Herpes Simplex Virus type 2 (HSV2), diagnosed with Polymerase Chain Reaction (PCR) implementation in the Cerebrospinal fluid (CSF) of the patient and treated successfully with acyclovir. To our knowledge, this is the first case of Mollaret's meningitis reported in Greece. We reviewed the literature since PCR has become widely available. Herpes Simplex Virus type 2 has been the most commonly identified causative agent of Mollaret's meningitis. Copyright © 2010 King Saud Bin Abdulaziz University for Health Sciences. Published by Elsevier Ltd. All rights reserved.

Human Antiviral Protein IFIX Suppresses Viral Gene Expression during Herpes Simplex Virus 1 (HSV-1) Infection and Is Counteracted by Virus-induced Proteasomal Degradation.

PubMed

Crow, Marni S; Cristea, Ileana M

2017-04-01

The interferon-inducible protein X (IFIX), a member of the PYHIN family, was recently recognized as an antiviral factor against infection with herpes simplex virus 1 (HSV-1). IFIX binds viral DNA upon infection and promotes expression of antiviral cytokines. How IFIX exerts its host defense functions and whether it is inhibited by the virus remain unknown. Here, we integrated live cell microscopy, proteomics, IFIX domain characterization, and molecular virology to investigate IFIX regulation and antiviral functions during HSV-1 infection. We find that IFIX has a dynamic localization during infection that changes from diffuse nuclear and nucleoli distribution in uninfected cells to discrete nuclear puncta early in infection. This is rapidly followed by a reduction in IFIX protein levels. Indeed, using immunoaffinity purification and mass spectrometry, we define IFIX interactions during HSV-1 infection, finding an association with a proteasome subunit and proteins involved in ubiquitin-proteasome processes. Using synchronized HSV-1 infection, microscopy, and proteasome-inhibition experiments, we demonstrate that IFIX co-localizes with nuclear proteasome puncta shortly after 3 h of infection and that its pyrin domain is rapidly degraded in a proteasome-dependent manner. We further demonstrate that, in contrast to several other host defense factors, IFIX degradation is not dependent on the E3 ubiquitin ligase activity of the viral protein ICP0. However, we show IFIX degradation requires immediate-early viral gene expression, suggesting a viral host suppression mechanism. The IFIX interactome also demonstrated its association with transcriptional regulatory proteins, including the 5FMC complex. We validate this interaction using microscopy and reciprocal isolations and determine it is mediated by the IFIX HIN domain. Finally, we show IFIX suppresses immediate-early and early viral gene expression during infection. Altogether, our study demonstrates that IFIX antiviral functions work in part via viral transcriptional suppression and that HSV-1 has acquired mechanisms to block its functions via proteasome-dependent degradation. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Macrophages and cytokines in the early defence against herpes simplex virus

PubMed Central

Ellermann-Eriksen, Svend

2005-01-01

Herpes simplex virus (HSV) type 1 and 2 are old viruses, with a history of evolution shared with humans. Thus, it is generally well-adapted viruses, infecting many of us without doing much harm, and with the capacity to hide in our neurons for life. In rare situations, however, the primary infection becomes generalized or involves the brain. Normally, the primary HSV infection is asymptomatic, and a crucial element in the early restriction of virus replication and thus avoidance of symptoms from the infection is the concerted action of different arms of the innate immune response. An early and light struggle inhibiting some HSV replication will spare the host from the real war against huge amounts of virus later in infection. As far as such a war will jeopardize the life of the host, it will be in both interests, including the virus, to settle the conflict amicably. Some important weapons of the unspecific defence and the early strikes and beginning battle during the first days of a HSV infection are discussed in this review. Generally, macrophages are orchestrating a multitude of anti-herpetic actions during the first hours of the attack. In a first wave of responses, cytokines, primarily type I interferons (IFN) and tumour necrosis factor are produced and exert a direct antiviral effect and activate the macrophages themselves. In the next wave, interleukin (IL)-12 together with the above and other cytokines induce production of IFN-γ in mainly NK cells. Many positive feed-back mechanisms and synergistic interactions intensify these systems and give rise to heavy antiviral weapons such as reactive oxygen species and nitric oxide. This results in the generation of an alliance against the viral enemy. However, these heavy weapons have to be controlled to avoid too much harm to the host. By IL-4 and others, these reactions are hampered, but they are still allowed in foci of HSV replication, thus focusing the activity to only relevant sites. So, no hero does it alone. Rather, an alliance of cytokines, macrophages and other cells seems to play a central role. Implications of this for future treatment modalities are shortly considered. PMID:16076403

A Herpes Simplex Virus Type 1 Mutant Expressing a Baculovirus Inhibitor of Apoptosis Gene in Place of Latency-Associated Transcript Has a Wild-Type Reactivation Phenotype in the Mouse

PubMed Central

Jin, Ling; Perng, Guey-Chuen; Mott, Kevin R.; Osorio, Nelson; Naito, Julia; Brick, David J.; Carpenter, Dale; Jones, Clinton; Wechsler, Steven L.

2005-01-01

The latency-associated transcript (LAT) is essential for the wild-type herpes simplex virus type 1 (HSV-1) high-reactivation phenotype since LAT− mutants have a low-reactivation phenotype. We previously reported that LAT can decrease apoptosis and proposed that this activity is involved in LAT's ability to enhance the HSV-1 reactivation phenotype. The first 20% of the primary 8.3-kb LAT transcript is sufficient for enhancing the reactivation phenotype and for decreasing apoptosis, supporting this proposal. For this study, we constructed an HSV-1 LAT− mutant that expresses the baculovirus antiapoptosis gene product cpIAP under control of the LAT promoter and in place of the LAT region mentioned above. Mice were ocularly infected with this mutant, designated dLAT-cpIAP, and the reactivation phenotype was determined using the trigeminal ganglion explant model. dLAT-cpIAP had a reactivation phenotype similar to that of wild-type virus and significantly higher than that of (i) the LAT− mutant dLAT2903; (ii) dLAT1.5, a control virus containing the same LAT deletion as dLAT-cpIAP, but with no insertion of foreign DNA, thereby controlling for potential readthrough transcription past the cpIAP insert; and (iii) dLAT-EGFP, a control virus identical to dLAT-cpIAP except that it contained the enhanced green fluorescent protein open reading frame (ORF) in place of the cpIAP ORF, thereby controlling for expression of a random foreign gene instead of the cpIAP gene. These results show that an antiapoptosis gene with no sequence similarity to LAT can efficiently substitute for the LAT function involved in enhancing the in vitro-induced HSV-1 reactivation phenotype in the mouse. PMID:16160155

Herpes Simplex Virus Type 2 Glycoprotein G Is Targeted by the Sulfated Oligo- and Polysaccharide Inhibitors of Virus Attachment to Cells▿

PubMed Central

Adamiak, Beata; Ekblad, Maria; Bergström, Tomas; Ferro, Vito; Trybala, Edward

2007-01-01

Variants of herpes simplex virus type 2 (HSV-2) generated by virus passage in GMK-AH1 cells in the presence of the sulfated oligosaccharide PI-88 were analyzed. Many of these variants were substantially resistant to PI-88 in their initial infection of cells and/or their cell-to-cell spread. The major alteration detected in all variants resistant to PI-88 in the initial infection of cells was a frameshift mutation(s) in the glycoprotein G (gG) gene that resulted in the lack of protein expression. Molecular transfer of the altered gG gene into the wild-type background confirmed that the gG-deficient recombinants were resistant to PI-88. In addition to PI-88, all gG-deficient variants of HSV-2 were resistant to the sulfated polysaccharide heparin. The gG-deficient virions were capable of attaching to cells, and this activity was relatively resistant to PI-88. In addition to having a drug-resistant phenotype, the gG-deficient variants were inefficiently released from infected cells. Purified gG bound to heparin and showed the cell-binding activity which was inhibited by PI-88. Many PI-88 variants produced syncytia in cultured cells and contained alterations in gB, including the syncytium-inducing L792P amino acid substitution. Although this phenotype can enhance the lateral spread of HSV in cells, it conferred no virus resistance to PI-88. Some PI-88 variants also contained occasional alterations in gC, gD, gE, gK, and UL24. In conclusion, we found that glycoprotein gG, a mucin-like component of the HSV-2 envelope, was targeted by sulfated oligo- and polysaccharides. This is a novel finding that suggests the involvement of HSV-2 gG in interactions with sulfated polysaccharides, including cell surface glycosaminoglycans. PMID:17928351

Functional genomics reveals an essential and specific role for Stat1 in protection of the central nervous system following herpes simplex virus corneal infection.

PubMed

Pasieka, Tracy Jo; Cilloniz, Cristian; Carter, Victoria S; Rosato, Pamela; Katze, Michael G; Leib, David A

2011-12-01

Innate immune deficiencies result in a spectrum of severe clinical outcomes following infection. In particular, there is a strong association between loss of the signal transducer and activator of transcription (Stat) pathway, breach of the blood-brain barrier (BBB), and virus-induced neuropathology. The gene signatures that characterize resistance, disease, and mortality in the virus-infected nervous system have not been defined. Herpes simplex virus type 1 (HSV-1) is commonly associated with encephalitis in humans, and humans and mice lacking Stat1 display increased susceptibility to HSV central nervous system (CNS) infections. In this study, two HSV-1 strains were used, KOS (wild type [WT]), and Δvhs, an avirulent recombinant lacking the virion host shutoff (vhs) function. In addition, two mouse strains were used: strain 129 (control) and a Stat1-deficient (Stat1(-/-)) strain. Using combinations of these virus and mouse strains, we established a model of infection resulting in three different outcomes: viral clearance without neurological disease (Δvhs infection of control mice), neurological disease followed by viral clearance (Δvhs infection of Stat1(-/-) mice and WT infection of control mice), or neurological disease followed by death (WT infection of Stat1(-/-) mice). Through the use of functional genomics on the infected brain stems, we determined gene signatures that were representative of the three infection outcomes. We demonstrated a pathological signature in the brain stem of Stat1-deficient mice characterized by upregulation of transcripts encoding chemokine receptors, inflammatory markers, neutrophil chemoattractants, leukocyte adhesion proteins, and matrix metalloproteases. Additionally, there was a greater than 100-fold increase in the inflammatory markers interleukin 1β (IL-1β) and IL-6. Consistent with this gene signature, we demonstrated profound CNS inflammation with a concomitant lethal breach of the BBB. Taken together, our results indicated an essential role for normal Stat1-dependent signaling in mediating a nonpathological immune response to viral CNS infection.

[Herpes simplex virus and malignancies of female genital organs].

PubMed

Cokić-Damjanović, J; Horvat, E; Balog, A

2001-01-01

Primary herpes simplex virus (HSV) infections of female genital tract usually end with remission, while the virus remains in the organism--almost in the sacral ganglion in a latent form, protected from humoral and cellular immunity. Stress induces the virus and the result is recurrent genital infection. Frequent exacerbations damage some parts of vital cellular structures without cytolysis, but stimulate malignant transformations. Vulvar (portio vaginalis uteri) and endometrial tumor tissue samples were analyzed for HSV by direct and indirect fluorescent antibody technique (FAT). Pre and postoperative sera samples were analyzed for presence of anti-HSV antibodies--IgM and IgG by Elisa-Enzygnost method. Acellular filtrates obtained by ultrasonic destruction of malignant tissues were used as inoculum for rabbit corneal scarification. Out of 63 tissue samples, 42 were positive for HSV antigen i.e. 67.3%. According to location 50% of vulvar, 76% PVU and 65% of endometrial tissues were positive. This antigen induces production of virus specific antibodies. Two types of antigens are known: the so-called T-antigen persisting in the cell nucleus and cell-surface antigen--product of the viral genome and can be evidenced by immunofluorescence method. Anti HSV antibodies were present in 63 preoperative serum samples and belonged to IgG group, but not one to IgM, implying a long and chronic course of infection excluding acute primary. Out of 38 postoperative serums the titer of antibodies decreased in 36 evidently, but in two samples remained unchanged. Two samples of endometrial and one from PVU origin contained HSV antigen type one. In the remaining 16 samples HSV 2 antigen was present. Rabbit corneal scarification was the proof of complete infectious virus in malignant tissues. Acellular filtrate of malignant tissues served as inoculum. Corneas of examined rabbits showed a mild inflammation after 24 hours which disappeared in the next 24 hours. We could not isolate the infectious virus by rabbit corneal scarification. Instead of herpetic changes, mild inflammation was evident. This abortive, incomplete symptomatology was probably caused by nonstructural early protein, which is a product of viral genome incorporated in malignant cells. On the basis of our results, we can conclude that HSV can have, beside other factors, a very important, maybe an initial role in development of malignant changes of female genital tract, not only on vulva and PVU, but on endometrium as well. HSV I can cause genital infections and have some role in malignant changes as well as HSV 2. However, complete infective virion couldn't be isolated from malignant tissues.

Validity of the coding for herpes simplex encephalitis in the Danish National Patient Registry.

PubMed

Jørgensen, Laura Krogh; Dalgaard, Lars Skov; Østergaard, Lars Jørgen; Andersen, Nanna Skaarup; Nørgaard, Mette; Mogensen, Trine Hyrup

2016-01-01

Large health care databases are a valuable source of infectious disease epidemiology if diagnoses are valid. The aim of this study was to investigate the accuracy of the recorded diagnosis coding of herpes simplex encephalitis (HSE) in the Danish National Patient Registry (DNPR). The DNPR was used to identify all hospitalized patients, aged ≥15 years, with a first-time diagnosis of HSE according to the International Classification of Diseases, tenth revision (ICD-10), from 2004 to 2014. To validate the coding of HSE, we collected data from the Danish Microbiology Database, from departments of clinical microbiology, and from patient medical records. Cases were classified as confirmed, probable, or no evidence of HSE. We estimated the positive predictive value (PPV) of the HSE diagnosis coding stratified by diagnosis type, study period, and department type. Furthermore, we estimated the proportion of HSE cases coded with nonspecific ICD-10 codes of viral encephalitis and also the sensitivity of the HSE diagnosis coding. We were able to validate 398 (94.3%) of the 422 HSE diagnoses identified via the DNPR. Hereof, 202 (50.8%) were classified as confirmed cases and 29 (7.3%) as probable cases providing an overall PPV of 58.0% (95% confidence interval [CI]: 53.0-62.9). For "Encephalitis due to herpes simplex virus" (ICD-10 code B00.4), the PPV was 56.6% (95% CI: 51.1-62.0). Similarly, the PPV for "Meningoencephalitis due to herpes simplex virus" (ICD-10 code B00.4A) was 56.8% (95% CI: 39.5-72.9). "Herpes viral encephalitis" (ICD-10 code G05.1E) had a PPV of 75.9% (95% CI: 56.5-89.7), thereby representing the highest PPV. The estimated sensitivity was 95.5%. The PPVs of the ICD-10 diagnosis coding for adult HSE in the DNPR were relatively low. Hence, the DNPR should be used with caution when studying patients with encephalitis caused by herpes simplex virus.

Clonal analysis of T-cell responses to herpes simplex virus: isolation, characterization and antiviral properties of an antigen-specific helper T-cell clone.

PubMed

Leung, K N; Nash, A A; Sia, D Y; Wildy, P

1984-12-01

A herpes simplex virus (HSV)-specific long-term T-cell clone has been established from the draining lymph node cells of BALB/c mice; the cells required repeated in vitro restimulation with UV-irradiated virus. The established T-cell clone expresses the Thy-1 and Lyt-1+2,3- surface antigens. For optimal proliferation of the cloned cells, both the presence of specific antigen and an exogenous source of T-cell growth factor are required. The proliferative response of the cloned T cells was found to be virus-specific but it did not distinguish between HSV-1 and HSV-2. Adoptive cell transfer of the cloned T cells helped primed B cells to produce anti-herpes antibodies: the response was antigen-specific and cell dose-dependent. The clone failed to produce a significant DTH reaction in vivo, but did produce high levels of macrophage-activating factor. Furthermore, the T-cell clone could protect from HSV infection, as measured by a reduction in local virus growth, and by enhanced survival following the challenge of mice with a lethal dose of virus. The mechanism(s) whereby this clone protects in vivo is discussed.

Recurrent Cutaneous Herpes Simplex in Hairless Mice

PubMed Central

Underwood, Gerald E.; Weed, Sheldon D.

1974-01-01

Passively immunized hairless mice were inoculated cutaneously with herpes simplex virus. Thirty-nine days later, when the primary cutaneous lesions had completely healed, the mice were treated subcutaneously with prednisone. Within 12 to 30 days after starting prednisone treatment, herpesvirus was recovered by skin swabs from 12 of 71 (17%) of the treated mice. This new model has potential application for understanding and treating recurrent cutaneous herpes infections. PMID:4372171

Medical Surveillance Monthly Report (MSMR). Volume 17, Number 08, August 2010

DTIC Science & Technology

2010-08-01

notifi able medical event reports that included diagnostic codes (ICD-9-CM) indicative of chlamydia, gonorrhea, syphilis, herpes simplex virus (HSV...infections of interest for this report Results: Condition Diagnostic codes Chlamydia 099.41, 099.5 Gonorrhea 098 Herpes simplex (HSV) 054 Human...housing arrangements may also play roles and off er opportunities for targeted prevention.6 Human papillomavirus (HPV), the cause of genital warts

Does natalizumab treatment increase the risk of herpes simplex encephalitis in multiple sclerosis? Case and discussion.

PubMed

Sharma, Kanchan; Ballham, Samantha A; Inglis, Kirsty E A; Renowden, Shelley; Cottrell, David A

2013-10-01

This report presents the 4th documented case worldwide of herpes simplex encephalitis in multiple sclerosis (MS) patients treated with natalizumab and the first case in the UK. Natalizumab is licensed for relapsing remitting multiple sclerosis in patients with high disease activity despite treatment with interferon-beta and patients with rapidly evolving severe, multiple sclerosis. Natalizumab is a monoclonal antibody targeted against alpha-4 integrin. Its proposed mechanism is attenuation of the migration of immune cells into the central nervous system. Reactivation of the JC virus causing progressive multifocal leucoencephalopathy (PML) and its association with natalizumab is well documented. This case adds support to the suggestion that natalizumab also increases the reactivation risk of CNS herpes simplex infection. A 34 year old woman was admitted with a generalized tonic-clonic seizure, fever and confusion following her 40th infusion of natalizumab. MRI demonstrated increased signal in the medial temporal lobes and EEG showed focal sharp waves over the temporal lobe. CSF PCR later confirmed herpes simplex virus. The patient made an eventual excellent recovery following 21 days of intravenous acyclovir therapy followed by 14 days of oral treatment. Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.

Diagnosis of Herpes Simplex Encephalitis by ELISA Using Antipeptide Antibodies Against Type-Common Epitopes of Glycoprotein B of Herpes Simplex Viruses.

PubMed

Bhullar, Shradha S; Chandak, Nitin H; Baheti, Neeraj N; Purohit, Hemant J; Taori, Girdhar M; Daginawala, Hatim F; Kashyap, Rajpal S

2016-01-01

Herpes simplex encephalitis (HSE) represents one of the most severe infectious diseases of the central nervous system (CNS). As effective antiviral drugs are available, an early, rapid, and reliable diagnosis has become important. The objective of this article was to develop a sensitive ELISA protocol for herpes simplex viruses (HSV) antigen detection and quantitation by assessing the usefulness of antipeptide antibodies against potential peptides of HSV glycoprotein B (gB). A total of 180 cerebrospinal fluid (CSF) samples of HSE and non-HSE patients were analyzed using a panel of antipeptide antibodies against synthetic peptides of HSV glycoprotein gB. The cases of confirmed and suspected HSE showed 80% and 51% positivity for antipeptide against synthetic peptide QLHDLRF and 77% and 53% positivity for antipeptide against synthetic peptide MKALYPLTT, respectively for the detection of HSV antigen in CSF. The concentration of HSV antigen was found to be higher in confirmed HSE as compared to suspected HSE group and the viral load correlated well with antigen concentration obtained using the two antipeptides in CSF of confirmed HSE group. This is the first article describing the use of antibodies obtained against synthetic peptides derived from HSV in diagnostics of HSE using patients' CSF samples.

NLRC3, a member of the NLR family of proteins, is a negative regulator of innate immune signaling induced by the DNA sensor STING.

PubMed

Zhang, Lu; Mo, Jinyao; Swanson, Karen V; Wen, Haitao; Petrucelli, Alex; Gregory, Sean M; Zhang, Zhigang; Schneider, Monika; Jiang, Yan; Fitzgerald, Katherine A; Ouyang, Songying; Liu, Zhi-Jie; Damania, Blossom; Shu, Hong-Bing; Duncan, Joseph A; Ting, Jenny P-Y

2014-03-20

Stimulator of interferon genes (STING, also named MITA, MYPS, or ERIS) is an intracellular DNA sensor that induces type I interferon through its interaction with TANK-binding kinase 1 (TBK1). Here we found that the nucleotide-binding, leucine-rich-repeat-containing protein, NLRC3, reduced STING-dependent innate immune activation in response to cytosolic DNA, cyclic di-GMP (c-di-GMP), and DNA viruses. NLRC3 associated with both STING and TBK1 and impeded STING-TBK1 interaction and downstream type I interferon production. By using purified recombinant proteins, we found NLRC3 to interact directly with STING. Furthermore, NLRC3 prevented proper trafficking of STING to perinuclear and punctated region, known to be important for its activation. In animals, herpes simplex virus 1 (HSV-1)-infected Nlrc3(-/-) mice exhibited enhanced innate immunity and reduced morbidity and viral load. This demonstrates the intersection of two key pathways of innate immune regulation, NLR and STING, to fine tune host response to intracellular DNA, DNA virus, and c-di-GMP. Copyright © 2014 Elsevier Inc. All rights reserved.

Further observations on inclusion-bearing cells in urinary sediment in infectious diseases

PubMed Central

Boyd, J. F.; Nedelkoska, Nada

1967-01-01

A study of the cytology of the urinary sediment in 43 patients with known viral diseases has revealed a variety of inclusion-bearing cells in 28. The morphology of the cells suggest that the changes recorded may be due to the viral infections, at least in some instances, bearing in mind the findings of workers quoted in our 1964 report that cellular changes very similar to those induced by virus infections can be initiated by non-viral stimuli. Multinucleate giant cells are occasionally found in chickenpox, measles, herpes simplex infection, and in mumps. Images PMID:5614069

Journal of Virology

Science.gov Websites

Herpes Simplex Virus 1 Improved Control of Simian/Human Immunodeficiency Virus in Macaques following Hemisphere Analysis of cis and trans Requirements for DNA Replication at the Right-End Hairpin of the Human -associated retrovirus in human and nonhuman cells transfected with an infectious molecular clone. Temporal

Isolation and Characterization of a Novel Alphaherpesvirus in Fruit Bats

PubMed Central

Sasaki, Michihito; Setiyono, Agus; Handharyani, Ekowati; Kobayashi, Shintaro; Rahmadani, Ibenu; Taha, Siswatiana; Adiani, Sri; Subangkit, Mawar; Nakamura, Ichiro; Sawa, Hirofumi

2014-01-01

ABSTRACT Bats are known to harbor emerging RNA viruses. Recent studies have used high-throughput sequencing technology to identify various virus species, including DNA viruses that are harbored by bats; however, little is known about the nature of these potentially novel viruses. Here, we report the characterization of a novel herpesvirus isolated from an Indonesian pteropodid bat. The virus, tentatively named fruit bat alphaherpesvirus 1 (FBAHV1), has a double-stranded DNA genome of 149,459 bp. The phylogenetic analyses suggested that FBAHV1 is phylogenetically grouped with simplexviruses within the subfamily Alphaherpesvirinae. Inoculation of FBAHV1 into laboratory mice caused a lethal infection. Virus infection was observed in lung, liver, and brain tissue. Serological and PCR screening revealed that fruit bats infected with FBAHV1 or its related virus are widely distributed in Indonesia. The identification of FBAHV1 makes a considerable contribution to our understanding of simplexviruses associated with bats. IMPORTANCE Bats are known to harbor emerging viruses, such as lyssaviruses, henipaviruses, severe acute respiratory syndrome-like coronaviruses, and filoviruses. Although alphaherpesviruses are disseminated in humans and other animals, there is little information about their distribution in bats. Here, we isolated a previously unknown alphaherpesvirus from an Indonesian fruit bat. Genome sequence analysis suggested that the virus is a member of the genus Simplexvirus within the subfamily Alphaherpesvirinae, which also includes common human viruses, such as herpes simplex virus 1 and herpes simplex virus 2. FBAHV1 is the first bat-derived alphaherpesvirus whose complete genome has been sequenced. PMID:24942567

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.

Herpes simplex encephalitis : from virus to therapy.

PubMed

Rozenberg, Flore; Deback, Claire; Agut, Henri

2011-06-01

Herpes simplex virus (HSV) is the cause of herpes simplex encephalitis (HSE), a devastating human disease which occurs in 2-4 cases per million/year. HSE results either from a primary infection or virus reactivation, in accordance with the common pattern of HSV infection which is a chronic lifelong process. However its pathophysiology remains largely unknown and its poor prognosis is in contrast with the usually good tolerance of most clinical herpetic manifestations. HSE is due to HSV type 1 (HSV-1) in most cases but HSV type 2 (HSV-2) may be also implicated, especially in infants in the context of neonatal herpes. Polymerase chain reaction detection of HSV DNA in cerebrospinal fluid is the diagnosis of choice for HSE. Acyclovir, a nucleoside analogue which inhibits viral DNA polymerase activity, is the reference treatment of HSE while foscarnet constitutes an alternative therapy and the efficacy of cidofovir is currently uncertain in that context. The emergence of HSV resistance to acyclovir, a phenomenon which is mainly observed among immunocompromised patients, is a current concern although no case of HSE due to an acyclovir-resistant HSV strain has been reported to date. Nevertheless the identification and development of novel therapeutic strategies against HSV appears to be a non dispensable objective for future research in virology.

[Identification of occult disseminated tumor cells by recombinant herpes simplex virus expressing GFP (HSV(GFP))].

PubMed

Han, Xiang-ping; Shi, Gui-lan; Wang, Cheng-feng; Li, Jie; Zhang, Jian-wei; Zhang, Yu; Zhang, Shu-ren; Liu, Bin-lei

2012-12-01

To develop a novel rapid protocol for the detection of occult disseminated tumor cells by a recombinant herpes simplex virus expressing GFP (HSV(GFP)). Tumor cells of seven cell lines were exposed to HSV(GFP) and then examined for GFP expression by fluorescence microscopy. Various numbers of tumor cells (10, 100, 1000, 10 000) were mixed into 2 ml human whole blood, separated with lymphocytes separation medium, exposed to HSV(GFP), incubated at 37°C for 6 - 24 h and then counted for the number of green cells under the fluorescence microscope. Some clinical samples including peripheral blood, pleural effusion, ascites, spinal fluid from tumor-bearing patients were screened using this protocol in parallel with routine cytological examination. HSV(GFP) was able to infect all 7 tumor cell lines indicating that the HSV(GFP) can be used to detect different types of tumor cells. The detection sensitivity was 10 cancer cells in 2 ml whole blood. In the clinical samples, there were 4/15 positive by routine cytological examination but 11/15 positive by HSV(GFP), indicating a higher sensitivity of this new protocol. Recombinant herpes simplex virus-mediated green fluorescence is a simple and sensitive technique for the identification of occult disseminated cancer cells including circulating tumor cells (CTCs).

Identification and characterization of 20 immunocompetent patients with simultaneous varicella zoster and herpes simplex virus infection.

PubMed

Giehl, K A; Müller-Sander, E; Rottenkolber, M; Degitz, K; Volkenandt, M; Berking, C

2008-06-01

It has been shown that varicella zoster virus (VZV) and herpes simplex virus (HSV) can co-localize to the same sensory ganglion. However, only a few case reports on VZV/HSV co-infections exist. Objective To identify and characterize patients with concurrent VZV and HSV infection at the same body site. In 1718 patients, the presence of VZV and HSV in suspicious skin lesions was investigated by polymerase chain reaction analysis. Clinical characteristics of co-infected patients were compared with matched control patients infected with either VZV or HSV. The data are discussed in the context of an extensive review of the literature. Twenty (1.2%) of 1718 patients were infected with both VZV and HSV at the same body site. The mean age was 54 years (range, 2-83). The clinical diagnosis was zoster in 65%, herpes simplex in 20%, varicella in 10% and erythema multiforme in 5% of cases. The trigeminus region was affected in 60% and the trunk in 25%. Involvement of the head was most commonly associated with a severe course of disease and with older age. Simultaneous VZV/HSV infection is rare but can occur in immunocompetent patients, which is often overlooked. The majority of cases is localized to the trigeminus region and affects elderly people.

Herpes Simplex Virus Encephalitis: Atypical Presentation as a Right Middle Cerebral Artery Stroke.

PubMed

Shoaib, Maria; Kraus, Jacqueline J; Khan, Muhammad T

2018-01-15

Herpes simplex virus encephalitis (HSVE) is a medical emergency associated with high mortality and morbidity. Definitive diagnosis is established by history, clinical examination, neuroimaging studies, supportive electroencephalogram (EEG) findings, and cerebrospinal fluid (CSF) analysis. We report a case of HSVE presenting as a stroke mimic in a 76-year-old female with a history of atrial fibrillation on warfarin. She was admitted to our medical intensive care unit with intermittent fever, lethargy, and new onset left-sided hemiparesis. A computed tomography (CT) of the head showed a right middle cerebral artery (MCA) acute ischemic stroke with midline shift and a dense right MCA sign. Brain magnetic resonance imaging (MRI) showed evidence of acute stroke with consideration of herpes encephalitis. CSF analysis was positive for herpes simplex virus (HSV) type one. She recovered with high-dose intravenous acyclovir therapy. Our patient was a diagnostic dilemma, initially being diagnosed with an acute ischemic stroke and yet found to have HSVE, which mimicked an acute ischemic stroke. Delay in treatment may result in devastating clinical outcomes that may include severe cognitive, focal neurological deficits, persistent seizures, and even death. This case highlights the importance of a multidisciplinary approach and the need for increased awareness of an atypical presentation of HSVE among emergency physicians, neurologist, intensivists, and radiologists.

The genome of herpesvirus papio 2 is closely related to the genomes of human herpes simplex viruses.

PubMed

Bigger, John E; Martin, David W

2003-06-01

Infection of baboons (Papio species) with herpesvirus papio 2 (HVP-2) produces a disease that is clinically similar to herpes simplex virus (HSV-1 and HSV-2) infection of humans. The development of a primate model of simplexvirus infection based on HVP-2 would provide a powerful resource to study virus biology and test vaccine strategies. In order to characterize the molecular biology of HVP-2 and justify further development of this model system we have constructed a physical map of the HVP-2 genome. The results of these studies have identified the presence of 26 reading frames that closely resemble HSV homologues. Furthermore, the HVP-2 genome shares a collinear arrangement with the genome of HSV. These studies further validate the development of the HVP-2 model as a surrogate system to study the biology of HSV infections.

Chromatin organization regulates viral egress dynamics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aho, Vesa; Myllys, Markko; Ruokolainen, Visa

Various types of DNA viruses are known to elicit the formation of a large nuclear viral replication compartment and marginalization of the cell chromatin. We used three-dimensional soft x-ray tomography, confocal and electron microscopy, combined with numerical modelling of capsid diffusion to analyse the molecular organization of chromatin in herpes simplex virus 1 infection and its effect on the transport of progeny viral capsids to the nuclear envelope. Our data showed that the formation of the viral replication compartment at late infection resulted in the enrichment of heterochromatin in the nuclear periphery accompanied by the compaction of chromatin. Random walkmore » modelling of herpes simplex virus 1–sized particles in a three-dimensional soft x-ray tomography reconstruction of an infected cell nucleus demonstrated that the peripheral, compacted chromatin restricts viral capsid diffusion, but due to interchromatin channels capsids are able to reach the nuclear envelope, the site of their nuclear egress.« less

Optimal management of genital herpes: current perspectives

PubMed Central

Sauerbrei, Andreas

2016-01-01

As one of the most common sexually transmitted diseases, genital herpes is a global medical problem with significant physical and psychological morbidity. Genital herpes is caused by herpes simplex virus type 1 or type 2 and can manifest as primary and/or recurrent infection. This manuscript provides an overview about the fundamental knowledge on the virus, its epidemiology, and infection. Furthermore, the current possibilities of antiviral therapeutic interventions and laboratory diagnosis of genital herpes as well as the present situation and perspectives for the treatment by novel antivirals and prevention of disease by vaccination are presented. Since the medical management of patients with genital herpes simplex virus infection is often unsatisfactory, this review aims at all physicians and health professionals who are involved in the care of patients with genital herpes. The information provided would help to improve the counseling of affected patients and to optimize the diagnosis, treatment, and prevention of this particular disease. PMID:27358569

Asymptomatic Herpes Simplex Virus Infection in Iranian Mothers and Their Newborns.

PubMed

Tavakoli, Ahmad; Monavari, Seyed Hamidreza; Bokharaei-Salim, Farah; Mollaei, Hamidreza; Abedi-Kiasari, Bahman; Fallah, Fatemeh Hoda; Mortazavi, Helya Sadat

2017-02-01

This study aims to determine the prevalence of herpes simplex virus (HSV) infection among pregnant women as well as congenital infection of their newborns in Tehran. One hundred samples of blood sera from pregnant women were analyzed for the presence of HSV specific antibodies. Umbilical cord blood samples from the newborns were analyzed for the presence of HSV DNA using real-time PCR. HSV IgG and IgM antibodies were found in 97% and 2% of pregnant women, respectively. Of all the 100 cord blood samples, 6 were positive for HSV DNA in which 2 cases were from mothers who had detectable IgM. It was notable that all corresponding mothers of six HSV positive infants had detectable IgG antibodies in their sera. It was demonstrated that the presence of HSV DNA in cord blood of newborns could be a risk marker for maternal-fetal transmission of the virus in asymptomatic pregnant women.

Autophagy interaction with herpes simplex virus type-1 infection

PubMed Central

O'Connell, Douglas; Liang, Chengyu

2016-01-01

abstract More than 50% of the U.S. population is infected with herpes simplex virus type-I (HSV-1) and global infectious estimates are nearly 90%. HSV-1 is normally seen as a harmless virus but debilitating diseases can arise, including encephalitis and ocular diseases. HSV-1 is unique in that it can undermine host defenses and establish lifelong infection in neurons. Viral reactivation from latency may allow HSV-1 to lay siege to the brain (Herpes encephalitis). Recent advances maintain that HSV-1 proteins act to suppress and/or control the lysosome-dependent degradation pathway of macroautophagy (hereafter autophagy) and consequently, in neurons, may be coupled with the advancement of HSV-1-associated pathogenesis. Furthermore, increasing evidence suggests that HSV-1 infection may constitute a gradual risk factor for neurodegenerative disorders. The relationship between HSV-1 infection and autophagy manipulation combined with neuropathogenesis may be intimately intertwined demanding further investigation. PMID:26934628

A random PCR screening system for the identification of type 1 human herpes simplex virus.

PubMed

Yu, Xuelian; Shi, Bisheng; Gong, Yan; Zhang, Xiaonan; Shen, Silan; Qian, Fangxing; Gu, Shimin; Hu, Yunwen; Yuan, Zhenghong

2009-10-01

Several viral diseases exhibit measles-like symptoms. Differentiation of suspected cases of measles with molecular epidemiological techniques in the laboratory is useful for measles surveillance. In this study, a random PCR screening system was undertaken for the identification of isolates from patients with measles-like symptoms who exhibited cytopathic effects, but who had negative results for measles virus-specific reverse transcription (RT)-PCR and indirect immunofluorescence assays. Sequence analysis of random amplified PCR products showed that they were highly homologous to type 1 human herpes simplex virus (HSV-1). The results were further confirmed by an HSV-1-specific TaqMan real-time PCR assay. The random PCR screening system described in this study provides an efficient procedure for the identification of unknown viral pathogens. Measles-like symptoms can also be caused by HSV-1, suggesting the need to include HSV-1 in differential diagnoses of measles-like diseases.

Optimal management of genital herpes: current perspectives.

PubMed

Sauerbrei, Andreas

2016-01-01

As one of the most common sexually transmitted diseases, genital herpes is a global medical problem with significant physical and psychological morbidity. Genital herpes is caused by herpes simplex virus type 1 or type 2 and can manifest as primary and/or recurrent infection. This manuscript provides an overview about the fundamental knowledge on the virus, its epidemiology, and infection. Furthermore, the current possibilities of antiviral therapeutic interventions and laboratory diagnosis of genital herpes as well as the present situation and perspectives for the treatment by novel antivirals and prevention of disease by vaccination are presented. Since the medical management of patients with genital herpes simplex virus infection is often unsatisfactory, this review aims at all physicians and health professionals who are involved in the care of patients with genital herpes. The information provided would help to improve the counseling of affected patients and to optimize the diagnosis, treatment, and prevention of this particular disease.

Chromatin organization regulates viral egress dynamics

DOE PAGES

Aho, Vesa; Myllys, Markko; Ruokolainen, Visa; ...

2017-06-16

Various types of DNA viruses are known to elicit the formation of a large nuclear viral replication compartment and marginalization of the cell chromatin. We used three-dimensional soft x-ray tomography, confocal and electron microscopy, combined with numerical modelling of capsid diffusion to analyse the molecular organization of chromatin in herpes simplex virus 1 infection and its effect on the transport of progeny viral capsids to the nuclear envelope. Our data showed that the formation of the viral replication compartment at late infection resulted in the enrichment of heterochromatin in the nuclear periphery accompanied by the compaction of chromatin. Random walkmore » modelling of herpes simplex virus 1–sized particles in a three-dimensional soft x-ray tomography reconstruction of an infected cell nucleus demonstrated that the peripheral, compacted chromatin restricts viral capsid diffusion, but due to interchromatin channels capsids are able to reach the nuclear envelope, the site of their nuclear egress.« less

Herpes Simplex Encephalitis Complicated by Cerebral Hemorrhage during Acyclovir Therapy.

PubMed

Harada, Yukinori; Hara, Yuuta

2017-01-01

Herpes simplex encephalitis (HSE) can be complicated by adverse events in the acute phase. We herein present the case of a 71-year-old woman with HSE complicated by cerebral hemorrhage. She presented with acute deterioration of consciousness and fever and was diagnosed with HSE based on the detection of herpes simplex virus-1 in the cerebrospinal fluid by a polymerase chain reaction. The cerebral hemorrhage developed during acyclovir therapy; however, its diagnosis was delayed for 2 days. After the conservative treatment of the cerebral hemorrhage, the patient made a near-complete recovery. Cerebral hemorrhage should be considered as an acute-phase complication of HSE.

Identification of conserved amino acids in the herpes simplex virus type 1 UL8 protein required for DNA synthesis and UL52 primase interaction in the virus replisome.

PubMed

Muylaert, Isabella; Zhao, Zhiyuan; Andersson, Torbjörn; Elias, Per

2012-09-28

We have used oriS-dependent transient replication assays to search for species-specific interactions within the herpes simplex virus replisome. Hybrid replisomes derived from herpes simplex virus type 1 (HSV-1) and equine herpesvirus type 1 (EHV-1) failed to support DNA replication in cells. Moreover, the replisomes showed a preference for their cognate origin of replication. The results demonstrate that the herpesvirus replisome behaves as a molecular machine relying on functionally important interactions. We then searched for functional interactions in the replisome context by subjecting HSV-1 UL8 protein to extensive mutagenesis. 52 mutants were made by replacing single or clustered charged amino acids with alanines. Four mutants showed severe replication defects. Mutant A23 exhibited a lethal phenotype, and mutants A49, A52 and A53 had temperature-sensitive phenotypes. Mutants A49 and A53 did not interact with UL52 primase as determined by co-immunoprecipitation experiments. Using GFP-tagged UL8, we demonstrate that all mutants were unable to support formation of ICP8-containing nuclear replication foci. Extended mutagenesis suggested that a highly conserved motif corresponding to mutant A49 serves an important role for establishing a physical contact between UL8 and UL52. The replication-defective mutations affected conserved amino acids, and similar phenotypes were observed when the corresponding mutations were introduced into EHV-1 UL8.

Response of dairy calves to vaccinia viruses that express foreign genes.

PubMed Central

Gillespie, J H; Geissinger, C; Scott, F W; Higgins, W P; Holmes, D F; Perkus, M; Mercer, S; Paoletti, E

1986-01-01

Repeated intradermal inoculations of calves with wild-type vaccinia virus and recombinant vaccinia viruses expressing human hepatitis B virus surface antigen and herpes simplex virus, type 1, glycoprotein D produced characteristic pox lesions at each site of injection. In some instances, calves were inoculated as many as five times at intervals from 4 to 7 weeks. The lesions invariably were more severe after the second inoculation. Subsequent inoculations produced a less severe area of redness, swelling, necrosis, and scab formation. No other signs of illness, such as an elevation in temperature, were noted in the calves. Vaccinia virus was isolated in low titers from scabs taken at various times after inoculation. No lesions were formed at the sites injected with tissue culture fluid and cellular debris at the same time that virus inoculations were made. Calf contact controls remained normal through the 8-week exposure in isolation units with calves inoculated twice with vaccinia virus. No neutralizing antibody to vaccinia virus was detected in the contact controls. In contrast, the virus-inoculated calves developed neutralizing antibody to vaccinia virus and to herpes simplex virus glycoprotein D in serum. In all cattle, a second inoculation significantly enhanced the neutralizing antibody response within 1 week, suggesting that an anamnestic response had occurred. No antibody to hepatitis B virus surface antigen was elicited in calves after repeated inoculations with vaccinia recombinants that express hepatitis B virus surface antigen and are known to elicit in rabbits antibodies reactive with hepatitis B virus surface antigen. Images PMID:3700615

A Real-Time PCR Assay to Identify and Discriminate Among Wild-Type and Vaccine Strains of Varicella-Zoster Virus and Herpes Simplex Virus in Clinical Specimens, and Comparison With the Clinical Diagnoses

PubMed Central

Harbecke, Ruth; Oxman, Michael N.; Arnold, Beth A.; Ip, Charlotte; Johnson, Gary R.; Levin, Myron J.; Gelb, Lawrence D.; Schmader, Kenneth E.; Straus, Stephen E.; Wang, Hui; Wright, Peter F.; Pachucki, Constance T.; Gershon, Anne A.; Arbeit, Robert D.; Davis, Larry E.; Simberkoff, Michael S.; Weinberg, Adriana; Williams, Heather M.; Cheney, Carol; Petrukhin, Luba; Abraham, Katalin G.; Shaw, Alan; Manoff, Susan; Antonello, Joseph M.; Green, Tina; Wang, Yue; Tan, Charles; Keller, Paul M.

2014-01-01

A real-time PCR assay was developed to identify varicella-zoster virus (VZV) and herpes simplex virus (HSV) DNA in clinical specimens from subjects with suspected herpes zoster (HZ; shingles). Three sets of primers and probes were used in separate PCR reactions to detect and discriminate among wild-type VZV (VZV-WT), Oka vaccine strain VZV (VZV-Oka), and HSV DNA, and the reaction for each virus DNA was multiplexed with primers and probe specific for the human β-globin gene to assess specimen adequacy. Discrimination of all VZV-WT strains, including Japanese isolates and the Oka parent strain, from VZV-Oka was based upon a single nucleotide polymorphism at position 106262 in ORF 62, resulting in preferential amplification by the homologous primer pair. The assay was highly sensitive and specific for the target virus DNA, and no cross-reactions were detected with any other infectious agent. With the PCR assay as the gold standard, the sensitivity of virus culture was 53% for VZV and 77% for HSV. There was 92% agreement between the clinical diagnosis of HZ by the Clinical Evaluation Committee and the PCR assay results. PMID:19475609

42 CFR 493.919 - Virology.

Code of Federal Regulations, 2011 CFR

2011-10-01

... specimens. (2) An approved program may vary over time. For example, the types of viruses that might be included in an approved program over time are the more commonly identified viruses such as Herpes simplex... derived from infected tissues or free in fluid specimens; and (2) Those that are able to isolate and...

42 CFR 493.919 - Virology.

Code of Federal Regulations, 2010 CFR

2010-10-01

... specimens. (2) An approved program may vary over time. For example, the types of viruses that might be included in an approved program over time are the more commonly identified viruses such as Herpes simplex... derived from infected tissues or free in fluid specimens; and (2) Those that are able to isolate and...

Sodium Lauryl Sulfate Increases the Efficacy of a Topical Formulation of Foscarnet against Herpes Simplex Virus Type 1 Cutaneous Lesions in Mice

PubMed Central

Piret, Jocelyne; Désormeaux, André; Cormier, Hélène; Lamontagne, Julie; Gourde, Pierrette; Juhász, Julianna; Bergeron, Michel G.

2000-01-01

The influence of sodium lauryl sulfate (SLS) on the efficacies of topical gel formulations of foscarnet against herpes simplex virus type 1 (HSV-1) cutaneous infection has been evaluated in mice. A single application of the gel formulation containing 3% foscarnet given 24 h postinfection exerted only a modest effect on the development of herpetic skin lesions. Of prime interest, the addition of 5% SLS to this gel formulation markedly reduced the mean lesion score. The improved efficacy of the foscarnet formulation containing SLS could be attributed to an increased penetration of the antiviral agent into the epidermis. In vitro, SLS decreased in a concentration-dependent manner the infectivities of herpesviruses for Vero cells. SLS also inhibited the HSV-1 strain F-induced cytopathic effect. Combinations of foscarnet and SLS resulted in subsynergistic to subantagonistic effects, depending on the concentration used. Foscarnet in phosphate-buffered saline decreased in a dose-dependent manner the viability of cultured human skin fibroblasts. This toxic effect was markedly decreased when foscarnet was incorporated into the polymer matrix. The presence of SLS in the gel formulations did not alter the viabilities of these cells. The use of gel formulations containing foscarnet and SLS could represent an attractive approach to the treatment of herpetic mucocutaneous lesions, especially those caused by acyclovir-resistant strains. PMID:10952566

Effects of Toll-like receptor 3 on herpes simplex virus type-1-infected mouse neural stem cells.

PubMed

Sun, Xiuning; Shi, Lihong; Zhang, Haoyun; Li, Ruifang; Liang, Ruiwen; Liu, Zhijun

2015-03-01

In this study, we aimed to investigate the effect of herpes simplex virus type-1 (HSV-1) infection on the phosphorylation of interferon regulatory factor 3 (IRF3) and the expression of interferon-β (IFN-β), as well as to clarify the functions of toll-like receptor 3 (TLR3) in mouse neural stem cells (NSCs) infected with HSV-1. In HSV-1-infected cultured NSCs, immunofluorescence, reverse transcription - polymerase chain reaction, Western blot, and ELISA were performed to reveal the expression patterns of TLR3, IRF3, and IFN-β. Then, lentivirus-mediated RNA interference (RNAi) was used to block the expression of TLR3, and its effect on host resistance to HSV-1 infection was investigated. Under uninfected conditions, NSCs expressed TLR3 and phosphorylated IRF3, but after infection, the expression level of TLR3 was upregulated and the phosphorylation level of IRF3 in the nucleus was significantly enhanced, while IFN-β was also expressed. After TLR3 expression was blocked by lentivirus-mediated RNAi, IRF3 phosphorylation and IFN-β expression were downregulated. Therefore, HSV-1 upregulated the expression of TLR3 in NSCs and promoted nuclear translocation after IRF3 was phosphorylated to induce IFN-β expression. TLR3 exhibited an anti-HSV-1 infection capacity via innate immune functions.

[Herpes simplex virus-mediated RNA interference targeting vesicular glutamate transporter 3 attenuates tactile allodynia in mice].

PubMed

Liu, Jie-Qiong; Li, Chen-Hong; Luo, Qiong; Yin, Ping-Ping; Lei, Tao; Luo, Fang

2016-11-20

To construct a replication-deficient herpes simplex virus (HSV-1) for delivering a short hairpin RNA (shRNA) targeting vesicular glutamate transporter 3 (VGLUT3) and observe its effect in alleviating allodynia in mice. The recombinant HSV-1 vector carrying the shRNA targeting Vglut3 (HSV-1-shvglut3) was constructed and inoculated in the sciatic nerve in a mouse model of mechanical allodynia to test its analgesia effect. Mechanical allodynia and heat hypersensitivity of the mice were tested by von Frey filaments and Hargreaves' test, respectively. VGLUT3 expression in the dorsal root ganglion (DRG) was evaluated by immunohistochemistry and Western blotting. Following inoculation in the sciatic nerve, the HSV vector HSV-1-shvglut3 was retrogradely transported to the DRG. Mechanical withdraw thresholds of the mouse models receiving HSV-1-shvglut3 inoculation were reversed to nearly the baseline level, and VGLUT3 expression in the DRG was down-regulated 2 weeks after vector inoculation. The analgesic effect lasted for over 2 weeks in these mice without obvious systematic side effects or changes in heat hypersensitivity threshold. Vglut3 in the DRG is a promising therapeutic target for alleviating mechanical allodynia, and HSV-1 vector-mediated RNA interference is safe and efficient for inducing long-lasting analgesia after peripheral inoculation of the vector.

Anti-herpesvirus activity of the acyclic nucleoside 9-(1,3-dihydroxy-2-propoxymethyl)guanine.

PubMed Central

Smee, D F; Martin, J C; Verheyden, J P; Matthews, T R

1983-01-01

The antiherpetic effects of a novel purine acyclic nucleoside, 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG), were compared with those of acyclovir in cell cultures and in mice. The modes of action of DHPG and acyclovir were similar in that herpes thymidine kinase phosphorylated each compound, and both agents selectively inhibited viral over host cell DNA synthesis. In 50% plaque reduction assays in Vero cells, the drugs inhibited herpes simplex virus types 1 and 2 thymidine kinase-positive strains at 0.2 to 2.4 microM. DHPG was markedly more active than acyclovir against human cytomegalovirus (50% inhibitory doses were 7 and 95 microM, respectively). Each nucleoside inhibited uninfected cell macromolecule synthesis and cell proliferation at concentrations far above those required to inhibit herpes simplex virus replication. Although the two compounds had many similarities in their behavior in vitro, the important difference was the superior performance of DHPG against herpesvirus-induced encephalitis and vaginitis in vivo. Thus, mortality in mice infected with herpesvirus type 2 was reduced 50% by daily doses of 7 to 10 mg of DHPG/kg, whereas an equally effective daily dose of acyclovir was approximately 500 mg/kg. DHPG at a daily dose of 50 mg/kg was also superior to acyclovir at 100 mg/kg per day in its inhibition of herpetic vaginal lesions in mice. PMID:6307132

Kinetics of Cell Fusion Induced by a Syncytia-Producing Mutant of Herpes Simplex Virus Type I

PubMed Central

Person, Stanley; Knowles, Robert W.; Read, G. Sullivan; Warner, Susan C.; Bond, Vincent C.

1976-01-01

We have isolated a number of plaque-morphology mutants from a strain of herpes simplex virus type I which, unlike the wild type, cause extensive cell fusion during a productive viral infection. After the onset of fusion, there is an exponential decrease in the number of single cells as a function of time after infection. At a multiplicity of infection (MOI) of 3.8 plaque-forming units per cell, fusion begins 5.3 h after infection with the number of single cells decreasing to 10% of the original number 10.2 h after infection. As the MOI is gradually increased from 0.4 to 8, the onset of fusion occurs earlier during infection. However, when the MOI is increased from 8 to 86, the onset of fusion does not occur any earlier. The rate of fusion is independent of the MOI for an MOI greater than 1. The rate of fusion varies linearly with initial cell density up to 3.5 × 104 cells/cm2 and is independent of initial cell density at higher cell concentrations. To assay cell fusion we have developed a simple quantitative assay using a Coulter counter to measure the number of single cells as a function of time after infection. Data obtained using a Coulter counter are similar to those obtained with a microscope assay. PMID:173881

Mistletoe lectins enhance immune responses to intranasally co-administered herpes simplex virus glycoprotein D2

PubMed Central

Lavelle, E C; Grant, G; Pusztai, A; Pfüller, U; Leavy, O; McNeela, E; Mills, K H G; O'Hagan, D T

2002-01-01

The mucosal adjuvant properties of the three type 2 ribosome-inactivating proteins (RIPs) from the European mistletoe, Viscum album L., were investigated. Mistletoe lectins were compared with cholera toxin (CT) as adjuvants when delivered nasotracheally together with herpes simplex virus glycoprotein D2 (gD2). All three mistletoe lectins (MLI, MLII, MLIII) were potent mucosal adjuvants. Co-administration of MLI, MLII or MLIII with gD2 led to significantly higher levels of gD2-specific mucosal immunoglobulin A (IgA) and systemic immunoglobulin G (IgG) antibody than when the antigen was delivered alone. The levels of antibodies induced were similar to those generated in mice immunized with gD2 and the potent mucosal adjuvant CT. Administration of ML1 with gD2 enhanced the antigen-specific splenic T-cell proliferative response. Interleukin-5 (IL-5), but not interferon-γ (IFN-γ), was detected in supernatants from splenocytes stimulated in vitro with gD2. This indicates that MLI enhanced type 2 T-helper cell (Th2) responses to the bystander antigen, gD2. Analysis of the gD2- and lectin-specific IgG subclass titres in mice immunized with gD2 and MLI, MLII or MLIII revealed a high ratio of IgG1 : IgG2a, which is compatible with the selective induction of Th2-type immune responses. PMID:12383207

Serological relatedness of herpes simplex viruses. Type-specificity of antibody response.

PubMed Central

Skinner, G R; Thouless, M E; Trueman, S; Edwards, J; Gibbs, A J

1976-01-01

The serological relatedness of forty-seven strains of type 1 and type 2 herpes simplex virus was investigated by reciprocal and non-reciprocal neutralization kinetics. Early rabbit antisera divided the virus strains into two distinct groups where confident indentification of virus type was possible. Hyperimmune mouse and rabbit antisera did not divide the two virus types into two distinct non-over-lapping groups. The extent of overlap varied with the particular attribute of the virus being studied. The virus types were best discriminated by their neutralizability by type 1 antisera and least well by their neutralizability by type 2 antisera. The results of reciprocal kinetic neutralization test with hyperimmune mouse antisera were analysed by multi-dimensional cluster analysis. Hyperimmune mouse or rabbit antisera could not be discriminated with respect to their immunogenic type by their absolute neutralization rate constants against either type 1 or type 2 virus, but could be distinguished on a group basis by their relative neutralizability against both virus types (antiserum specificity attribute); however, using this latter criterion, the type of immunogen could only be predicted in seven of the forty antisera under test. 'Early' mouse antisera could also be distinguished as groups by their absolute k-values against type 1 herpes virus. Thus, immunogenic identification, on other than a group basis, was unreliable. The specificity of a given serum was inversely related to its titre. There was a positive correlation between the specificity of a given virus strain and of its corresponding antiserum. PMID:194831

Prevalence of human herpes virus types 1-7 in the semen of men attending an infertility clinic and correlation with semen parameters.

PubMed

Neofytou, Eirini; Sourvinos, George; Asmarianaki, Maria; Spandidos, Demetrios A; Makrigiannakis, Antonios

2009-06-01

To determine the prevalence of herpes viruses in the semen of an asymptomatic male cohort with and without infertility problems and its association with altered semen parameters. A prospective randomized study. Medical school and IVF clinic. One hundred seventy-two male patients undergoing routine semen analysis: 80 with normal semen parameters (control group) and 92 with abnormal semen parameters. Semen samples were collected by masturbation. The DNA from the Herpesviridae family (herpes simplex virus 1 [HSV-1], herpes simplex virus 2 [HSV-2], Varicella zoster virus [VZV], Epstein-Barr virus [EBV], cytomegalovirus [CMV], human herpes virus type 6 [HHV-6], human herpes virus type 7 [HHV-7]) and routine semen parameters. Viral DNA was detected in 143/172 (83.1%) of the total samples for at least one herpes virus: HSV-1, 2.5%; VZV, 1.2%; EBV, 45%; CMV, 62.5%; HHV-6, 70%; HHV-7, 0% in the normal semen samples and HSV-1, 2.1%; VZV, 3.2%; EBV, 39.1%; CMV, 56.5%; HHV-6, 66.3%; HHV-7, 0% in the abnormal semen samples. No association was found between the presence of viral DNA and semen parameters. Interestingly, a statistical significance between leukocytospermia and the presence of EBV DNA was observed. The DNA of herpes viruses is frequently detected in the semen of asymptomatic fertile and infertile male patients. Further studies are required to investigate the role of herpes viruses in male factor infertility.

Prior Corneal Scarification and Injection of Immune Serum are Not Required Before Ocular HSV-1 Infection for UV-B-Induced Virus Reactivation and Recurrent Herpetic Corneal Disease in Latently Infected Mice

PubMed Central

BenMohamed, Lbachir; Osorio, Nelson; Khan, Arif A.; Srivastava, Ruchi; Huang, Lei; Krochmal, John J.; Garcia, Jairo M.; Simpson, Jennifer L.; Wechsler, Steven L.

2017-01-01

Purpose Blinding ocular herpetic disease in humans is due to spontaneous reactivation of herpes simplex virus type 1 (HSV-1) from latency, rather than to primary acute infection. Mice latently infected with HSV-1 undergo little or no in vivo spontaneous reactivation with accompanying virus shedding in tears. HSV-1 reactivation can be induced in latently infected mice by several in vivo procedures, with UV-B-induced reactivation being one commonly used method. In the UV-B model, corneas are scarified (lightly scratched) just prior to ocular infection to increase efficiency of the primary infection and immune serum containing HSV-1 neutralizing antibodies is injected intraperitoneally (i.p.) to increase survival and decrease acute corneal damage. Since scarification can significantly alter host gene transcription in the cornea and in the trigeminal ganglia (TG; the site of HSV-1 latency) and since injection of immune serum likely modulates innate and adaptive herpes immunity, we investigated eliminating both treatments. Material and Methods Mice were infected with HSV-1 with or without corneal scarification and immune serum. HSV-1 reactivation and recurrent disease were induced by UV-B irradiation. Results When corneal scarification and immune serum were both eliminated, UV-B irradiation still induced both HSV-1 reactivation, as measured by shedding of reactivated virus in tears and herpetic eye disease, albeit at reduced levels compared to the original procedure. Conclusion Despite the reduced reactivation and disease, avoidance of both corneal scarification and immune serum should improve the clinical relevance of the UV-B mouse model. PMID:26398722

Human Asymptomatic Epitopes Identified from the Herpes Simplex Virus Tegument Protein VP13/14 (UL47) Preferentially Recall Polyfunctional Effector Memory CD44high CD62Llow CD8+ TEM Cells and Protect Humanized HLA-A*02:01 Transgenic Mice against Ocular Herpesvirus Infection.

PubMed

Srivastava, Ruchi; Khan, Arif A; Garg, Sumit; Syed, Sabrina A; Furness, Julie N; Vahed, Hawa; Pham, Tiffany; Yu, Howard T; Nesburn, Anthony B; BenMohamed, Lbachir

2017-01-15

Herpes simplex virus 1 (HSV-1) infection is widespread among humans. The HSV-1 virion protein 13/14 (VP13/14), also known as UL47, is a tegument antigen targeted by CD8 + T cells from HSV-seropositive individuals. However, whether VP13/14-specific CD8 + T cells play a role in the natural protection seen in asymptomatic (ASYMP) individuals (individuals who have never had a clinical herpetic disease) has not been elucidated. Using predictive computer-assisted algorithms, we identified 10 potential HLA-A*02:01-restricted CD8 + T-cell epitopes from the 693-amino-acid sequence of the VP13/14 protein. Three out of 10 epitopes exhibited a high to moderate affinity of binding to soluble HLA-A*02:01 molecules. The phenotype and function of CD8 + T cells specific for each epitope were compared in HLA-A*02:01-positive ASYMP individuals and symptomatic (SYMP) individuals (individuals who have frequent clinical herpetic diseases) using determination of a combination of tetramer frequency and the levels of granzyme B, granzyme K, perforin, gamma interferon, tumor necrosis factor alpha, and interleukin-2 production and CD107 a/b cytotoxic degranulation. High frequencies of multifunctional CD8 + T cells directed against three epitopes, VP13/14 from amino acids 286 to 294 (VP13/14 286-294 ), VP13/14 from amino acids 504 to 512 (VP13/14 504-512 ), and VP13/14 from amino acids 544 to 552 (VP13/14 544-552 ), were detected in ASYMP individuals, while only low frequencies were detected in SYMP individuals. The three epitopes also predominantly recalled more CD45RA low CD44 high CCR7 low CD62L low CD8 + effector memory T cells (T EM cells) in ASYMP individuals than SYMP individuals. Moreover, immunization of HLA-A*02:01 transgenic mice with the three CD8 + T EM -cell epitopes from ASYMP individuals induced robust and polyfunctional HSV-specific CD8 + T EM cells associated with strong protective immunity against ocular herpesvirus infection and disease. Our findings outline the phenotypic and functional features of protective HSV-specific CD8 + T cells that should guide the development of a safe and effective T-cell-based herpes simplex vaccine. Although most herpes simplex virus 1 (HSV-1)-infected individuals shed the virus in their body fluids following reactivation from latently infected sensory ganglia, the majority never develop a recurrent herpetic disease and remain asymptomatic (ASYMP). In contrast, small proportions of individuals are symptomatic (SYMP) and develop frequent bouts of recurrent disease. The present study demonstrates that naturally protected ASYMP individuals have a higher frequency of effector memory CD8 + T cells (CD8 + T EM cells) specific to three epitopes derived from the HSV-1 tegument protein VP13/14 (VP13/14 286-294 ,VP13/14 504-512 , and VP13/14 544-552 ) than SYMP patients. Moreover, immunization of humanized HLA-A*02:01 transgenic mice with the three CD8 + T EM -cell epitopes from ASYMP individuals induced robust and polyfunctional HSV-specific CD8 + T cells associated with strong protective immunity against ocular herpesvirus infection and disease. The findings support the emerging concept of the development of a safe and effective asymptomatic herpes simplex vaccine that is selectively based on CD8 + T-cell epitopes from ASYMP individuals. Copyright © 2017 American Society for Microbiology.

In vitro Cytotoxicity and Anti-herpes Simplex Virus Type 1 Activity of Hydroethanolic Extract, Fractions, and Isolated Compounds from Stem Bark of Schinus terebinthifolius Raddi.

PubMed

Nocchi, Samara Requena; de Moura-Costa, Gislaine Franco; Novello, Claudio Roberto; Rodrigues, Juliana; Longhini, Renata; de Mello, João Carlos Palazzo; Filho, Benedito Prado Dias; Nakamura, Celso Vataru; Ueda-Nakamura, Tânia

2016-01-01

Herpes simplex virus type 1 (HSV-1) is associated with orofacial infections and is transmitted by direct contact with infected secretions. Several efforts have been expended in the search for drugs to the treatment for herpes. Schinus terebinthifolius is used in several illnesses and among them, for the topical treatment of skin wounds, especially wounds of mucous membranes, whether infected or not. To evaluate the cytotoxicity and anti-HSV-1 activity of the crude hydroethanolic extract (CHE) from the stem bark of S. terebinthifolius, as well as its fractions and isolated compounds. The CHE was subjected to bioguided fractionation. The anti-HSV-1 activity and the cytotoxicity of the CHE, its fractions, and isolated compounds were evaluated in vitro by SRB method. A preliminar investigation of the action of CHE in the virus-host interaction was conducted by the same assay. CHE presented flavan-3-ols and showed anti-HSV-1 activity, better than its fractions and isolated compounds. The class of substances found in CHE can bind to proteins to form unstable complexes and enveloped viruses, as HSV-1 may be vulnerable to this action. Our results suggest that the CHE interfered with virion envelope structures, masking viral receptors that are necessary for adsorption or entry into host cells. The plant investigated exhibited potential for future development treatment against HSV-1, but further tests are necessary, especially to elucidate the mechanism of action of CHE, as well as preclinical and clinical studies to confirm its safety and efficacy. Crude hydroethanolic extract (CHE) presents promising activity against herpes simplex virus type 1 (HSV 1), with selectivity index (SI) = 22.50CHE has flavan-3-ols in its composition, such as catechin and gallocatechinThe fractions and isolated compounds obtained from CHE by bioguided fractionation are less active than the CHE against HSV-1CHE interferes with viral entry process in the host cell and acts directly on the viral particle. Abbreviations used: HSV: Herpes simplex virus, CHE: Crude hydroethanolic extract, WF: Water fraction, AF: Ethyl-acetate fraction, MPLC: Medium-performance liquid chromatography, TLC: Thin-layer chromatography, NMR: Nuclear magnetic resonance, ESI-MS: Electrospray ionization mass spectrometry, SRB: Sulforhodamine B, CPE: Cytopathic effect, CC50: 50% cytotoxic concentration, EC50: 50% effective concentration, PBS: Phosphate-buffered saline.

Medical Surveillance Monthly Report (MSMR). Volume 19, Number 8. August 2012

DTIC Science & Technology

2012-08-01

much more common causes than bacteria, fungi, or parasites. Non-polio enteroviruses (members of the subgenera coxsackieviruses, echoviruses, and... enteroviruses ) are the most common causes of viral meningitis; however, vari- cella-zoster virus (VZV), herpes simplex virus (HSV), mumps virus...assessment, the etiologies of many viral meningitis cases are unknown.2 Enteroviruses are spread through both fecal-oral and respiratory transmission. % e

USSR Report, Life Sciences, Biomedical and Behavioral Sciences

DTIC Science & Technology

1987-01-20

Varnek, P. D. Brezhestovskiy; DOKLADY AKADEMII NAUK SSSR, No 6, Aug 86) 13 Effects of Selenomethionine on Proton Magnetic Relaxation in Hepatic ...Virus Expressing Surface Antigen of B Hepatitis Virus and Thymidinekinase of Herpes Simplex Virus (A. D. Altshteyn, 0. G. Andzhaparidze, et al...Influence of Dimetpramide and Metoclopramide on Catecholamine Turnover Rates in Rat Brain Subcortical-Brainstem Structures (V. I. Legeza, M. F. Kamynina

Postviral autoimmune encephalitis: manifestations in children and adults.

PubMed

Prüss, Harald

2017-06-01

Autoimmune encephalitis is an increasingly recognized neuropsychiatric condition seen in patients of all ages. Herpes virus infections of the brain can antedate the development of pathogenic autoantibodies against N-methyl-D-aspartate receptors and further neuronal surface proteins, leading to neuronal dysfunction and relapsing symptoms. This review will recapitulate the recent scientific progress, clinical manifestations in children and adults, therapeutic options, and etiological concepts on how autoimmunity develops. Postviral autoimmune encephalitis has been established as disease mechanism after herpes simplex virus encephalitis. Relapsing symptoms in the absence of virus occur in up to 20% of cases. The clinical presentation is relatively stereotyped in children, consisting of choreoathetosis and reduced levels of consciousness. Adults commonly present with psychiatric abnormalities and cognitive changes. Virus-induced antibody generation seems to be a widespread mechanism not confined to Herpesviridae and N-methyl-D-aspartate receptor antibodies SUMMARY: The presence of prolonged, atypical, or relapsing symptoms after virus encephalitis must be actively determined, requiring early follow-up visits of patients, and should always prompt the search for underlying autoantibodies. Relapsing symptoms can markedly improve with immunotherapy, thus treatment, including corticosteroids, plasma separation, immunoglobulins, and rituximab is usually recommended, even if no specific antibody was detected.

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

Three-dimensional analysis of combination effect of ellagitannins and acyclovir on herpes simplex virus types 1 and 2.

PubMed

Vilhelmova, N; Jacquet, R; Quideau, S; Stoyanova, A; Galabov, A S

2011-02-01

The effects of combinations of three nonahydroxyterphenoyl-bearing C-glucosidic ellagitannins (castalagin, vescalagin and grandinin) with acyclovir (ACV) on the replication of type-1 and type-2 herpes simplex viruses in MDBK cells were tested by the focus-forming units reduction test. Ellagitannins included in these combinations possess a high individual antiviral activity: selectivity index of castalagin and vescalagin versus HSV-1 was similar to that of ACV, and relatively lower against HSV-2. The three-dimensional analytical approach of Prichard and Shipman was used to evaluate the impact of drug-drug interactions. The combination effects of ellagitannins with acyclovir were markedly synergistic. Copyright © 2010 Elsevier B.V. All rights reserved.

Cloning of the active thymidine kinase gene of herpes simplex virus type 1 in Escherichia coli K-12.

PubMed

Colbere-Garapin, F; Chousterman, S; Horodniceanu, F; Kourilsky, P; Garapin, A C

1979-08-01

A herpes simplex virus DNA fragment that is produced by digestion with BamHI endonuclease and carries the thymidine kinase (TK; ATP:thymidine 5'-phosphotransferase, EC 2.7.1.21) gene has been cloned in Escherichia coli. A recombinat plasmid, pFG5, has been analyzed extensively and a detailed restriction map is presented. pFG5 DNA efficiently transforms TK- mouse L cells. The TK coding sequence in the cloned fragment has been localized and a smaller recombinant plasmid, pAG0, also carrying an active TK gene, has been constructed to serve as a more convenient vector for transfer, into TK- cells, of genes previously cloned in E. coli.

Unusual presentation of herpes simplex virus infection in a boxer: 'Boxing glove herpes'.

PubMed

García-García, Begoña; Galache-Osuna, Cristina; Coto-Segura, Pablo; Suárez-Casado, Héctor; Mallo-García, Susana; Jiménez, Jorge Santos-Juanes

2013-02-01

Herein, we describe a patient with lesions of cutaneous herpes simplex virus 1 (HSV-1) infection over the knuckles of both hands in the context of an outbreak among boxers. Interestingly, the infection had an unusually long duration (4 weeks), and was not acquired directly through skin-to-skin contact, as it usually does among athletes (herpes gladiatorum). In our case, transmission was acquired through the use of shared boxing gloves contaminated by HSV-1. To the best of our knowledge, herpes gladiatorum, or wrestler's herpes, has not been described previously in boxers and infection over the knuckles is not commonly reported. © 2011 The Authors. Australasian Journal of Dermatology © 2011 The Australasian College of Dermatologists.

Hemorrhagic and ischemic stroke secondary to herpes simplex virus type 2 meningitis and vasculopathy.

PubMed

Snider, Samuel B; Jacobs, Claire S; Scripko, Patricia S; Klein, Joshua P; Lyons, Jennifer L

2014-08-01

Herpes simplex virus type 2 (HSV-2) meningitis dogmatically is benign and self-limited in the immune competent patient. However, we describe how left untreated HSV-2 meningitis can be complicated by vasculitis and both ischemic and hemorrhagic stroke. We report a 57-year-old woman with lymphocytic meningitis complicated by ischemic stroke and intracerebral hemorrhage in the setting of vasculopathy and HSV-2 DNA detected in CSF successfully treated with acyclovir and corticosteroids. Subsequent angiographic magnetic resonance imaging revealed improvement in the vasculopathy after treatment. This case demonstrates that HSV-2 meningitis may take a less benign course and further provides the first evidence of angiographic improvement in addition to clinical improvement after definitive treatment.

Use of Transcriptional Profiling to Delineate the Initial Response of Mice to Intravaginal Herpes Simplex Virus Type 2 Infection

PubMed Central

Harvey, Stephen A. K.; Phillips, Jaclyn M.; Vicetti Miguel, Rodolfo D.; Melan, Melissa A.; Quispe Calla, Nirk E.; Hendricks, Robert L.

2013-01-01

Abstract Intravaginal (ivag) infection of mice with herpes simplex virus type 2 (HSV-2) causes genital tissue damage, quickly followed by development of fatal encephalopathy. To delineate initial host responses generated by HSV-2 infection, here oligonucleotide microarrays compared gene expression in vaginal tissue from uninfected mice and mice 1, 2, 3, 4, 5, 6, or 7 days after ivag infection with 104 pfu HSV-2. While comparison of mRNA expression in uninfected and HSV-infected vaginal tissue detected few changes during the first 2 days post infection (dpi), there were 156 genes whose expression was first significantly altered 3 dpi that remained significantly modified at all later time points examined. These 156 genes were significantly enriched in canonical pathways associated with interferon (IFN) signaling, activation of IFN elements by intracellular pattern recognition receptors, and antiviral immunity induced by cytosolic RIG-like receptors. Evaluation of this gene set with the National Center for Biotechnology Information Gene and INTERFEROME databases corroborated pathway analysis, as function of most (53%) were linked to IFN-mediated host immunity. In the final set of experiments, ivag administration of the Toll-like receptor 3 agonist polyinosinic: polycytidylic acid (poly I:C) 24 h before ivag HSV-2 infection reduced the incidence of genital pathology and encephalopathy, while these poly I:C-treated mice were subsequently protected from ocular HSV-2 challenge lethal to uninfected controls. The latter results imply that the exuberant antiviral immunity produced in our experimental model is simply formed too late to prevent viral replication and dissemination, and that poly I:C-induced formation of an antiviral state protecting against primary ivag infection also permits development of HSV-specific protective immunity. PMID:23638732

Involvement of TLR2 and TLR9 in the anti-inflammatory effects of chlorogenic acid in HSV-1-infected microglia.

PubMed

Guo, Yuan-Jin; Luo, Tao; Wu, Fei; Mei, Yuan-Wu; Peng, Jun; Liu, Huan; Li, Hua-Rong; Zhang, Shu-Ling; Dong, Ji-Hua; Fang, Yuan; Zhao, Lei

2015-04-15

There is no effective medication to date for herpes simplex virus encephalitis (HSE). In this study, we investigated the anti-inflammatory effect of chlorogenic acid (CGA) on herpes simplex virus (HSV)-1-induced responses in BV2 microglia. The cellular model was established with BV2 cells stimulated by HSV-1 and then treated with CGA at different concentrations. Cell viability was assayed by the MTT assay. The mRNA expression of Toll-like receptor (TLR)-2, TLR9 and myeloid differentiation factor88 (Myd88) was assayed by real-time quantitative PCR, and the protein expression was assayed by flow cytometry or Western blotting. Tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 were measured by ELISA as well as real-time quantitative PCR. Nuclear NF-κB p65 protein was assayed by Western blotting. The cell survival rate was significantly improved after CGA treatment, and CGA prevented increases in TLR2, TLR9 and Myd88 following HSV-1 challenge in BV2 cells both at the mRNA and protein levels. Moreover, CGA could attenuate HSV-induced TNF-α and IL-6 release into the supernatant. The mRNA levels of TNF-α and IL-6 were also significantly inhibited by CGA. The expression of NF-κB p65 increased significantly in the nucleus in HSV-1-stimulated microglia but could be reduced by CGA. CGA inhibits the inflammatory reaction in HSE via the suppression of TLR2/TLR9-Myd88 signaling pathways. CGA may serve as an anti-inflammatory agent and provide a new strategy for treating HSE. Copyright © 2015 Elsevier Inc. All rights reserved.

Vaccine-induced antibodies to herpes simplex virus glycoprotein D epitopes involved in virus entry and cell-to-cell spread correlate with protection against genital disease in guinea pigs

PubMed Central

Brooks, Benjamin D.; Friedman, Harvey M.

2018-01-01

Herpes simplex virus type 2 (HSV-2) glycoprotein D (gD2) subunit antigen is included in many preclinical candidate vaccines. The rationale for including gD2 is to produce antibodies that block crucial gD2 epitopes involved in virus entry and cell-to-cell spread. HSV-2 gD2 was the only antigen in the Herpevac Trial for Women that protected against HSV-1 genital infection but not HSV-2. In that trial, a correlation was detected between gD2 ELISA titers and protection against HSV-1, supporting the importance of antibodies. A possible explanation for the lack of protection against HSV-2 was that HSV-2 neutralization titers were low, four-fold lower than to HSV-1. Here, we evaluated neutralization titers and epitope-specific antibody responses to crucial gD2 epitopes involved in virus entry and cell-to-cell spread as correlates of immune protection against genital lesions in immunized guinea pigs. We detected a strong correlation between neutralizing antibodies and protection against genital disease. We used a high throughput biosensor competition assay to measure epitope-specific responses to seven crucial gD2 linear and conformational epitopes involved in virus entry and spread. Some animals produced antibodies to most crucial epitopes while others produced antibodies to few. The number of epitopes recognized by guinea pig immune serum correlated with protection against genital lesions. We confirmed the importance of antibodies to each crucial epitope using monoclonal antibody passive transfer that improved survival and reduced genital disease in mice after HSV-2 genital challenge. We re-evaluated our prior study of epitope-specific antibody responses in women in the Herpevac Trial. Humans produced antibodies that blocked significantly fewer crucial gD2 epitopes than guinea pigs, and antibody responses in humans to some linear epitopes were virtually absent. Neutralizing antibody titers and epitope-specific antibody responses are important immune parameters to evaluate in future Phase I/II prophylactic human vaccine trials that contain gD2 antigen. PMID:29791513

Vaccine-induced antibodies to herpes simplex virus glycoprotein D epitopes involved in virus entry and cell-to-cell spread correlate with protection against genital disease in guinea pigs.

PubMed

Hook, Lauren M; Cairns, Tina M; Awasthi, Sita; Brooks, Benjamin D; Ditto, Noah T; Eisenberg, Roselyn J; Cohen, Gary H; Friedman, Harvey M

2018-05-01

Herpes simplex virus type 2 (HSV-2) glycoprotein D (gD2) subunit antigen is included in many preclinical candidate vaccines. The rationale for including gD2 is to produce antibodies that block crucial gD2 epitopes involved in virus entry and cell-to-cell spread. HSV-2 gD2 was the only antigen in the Herpevac Trial for Women that protected against HSV-1 genital infection but not HSV-2. In that trial, a correlation was detected between gD2 ELISA titers and protection against HSV-1, supporting the importance of antibodies. A possible explanation for the lack of protection against HSV-2 was that HSV-2 neutralization titers were low, four-fold lower than to HSV-1. Here, we evaluated neutralization titers and epitope-specific antibody responses to crucial gD2 epitopes involved in virus entry and cell-to-cell spread as correlates of immune protection against genital lesions in immunized guinea pigs. We detected a strong correlation between neutralizing antibodies and protection against genital disease. We used a high throughput biosensor competition assay to measure epitope-specific responses to seven crucial gD2 linear and conformational epitopes involved in virus entry and spread. Some animals produced antibodies to most crucial epitopes while others produced antibodies to few. The number of epitopes recognized by guinea pig immune serum correlated with protection against genital lesions. We confirmed the importance of antibodies to each crucial epitope using monoclonal antibody passive transfer that improved survival and reduced genital disease in mice after HSV-2 genital challenge. We re-evaluated our prior study of epitope-specific antibody responses in women in the Herpevac Trial. Humans produced antibodies that blocked significantly fewer crucial gD2 epitopes than guinea pigs, and antibody responses in humans to some linear epitopes were virtually absent. Neutralizing antibody titers and epitope-specific antibody responses are important immune parameters to evaluate in future Phase I/II prophylactic human vaccine trials that contain gD2 antigen.

In vivo Knock-down of the HSV-1 Latency-Associated Transcript Reduces Reactivation from Latency.

PubMed

Watson, Zachary L; Washington, Shannan D; Phelan, Dane M; Lewin, Alfred S; Tuli, Sonal S; Schultz, Gregory S; Neumann, Donna M; Bloom, David C

2018-06-06

During Herpes Simplex Virus (HSV) latency, most viral genes are silenced with the exception of one region of the genome encoding the latency-associated transcript (LAT). This long non-coding RNA was originally described as having a role in enhancing HSV-1 reactivation. However, subsequent evidence showing that the LAT blocked apoptosis and promoted efficient establishment of latency suggested that its effects on reactivation were secondary to establishment. Here, we utilize an Adeno-associated Virus (AAV) vector to deliver a LAT-targeting hammerhead ribozyme to HSV-1-infected neurons of rabbits after the establishment of HSV-1 latency. The rabbits were then induced to reactivate latent HSV-1. Using this model, we show that decreasing LAT levels in neurons following the establishment of latency reduced the ability of the virus to reactivate. This demonstrates that the HSV-1 LAT RNA has a role in reactivation that is independent of its function in establishment of latency. In addition these results suggest the potential of AAV vectors expressing LAT-targeting ribozymes as a potential therapy for recurrent HSV disease such as herpes stromal keratitis, a leading cause of infectious blindness. Importance Herpes Simplex Virus (HSV) establishes a life long infection and remains dormant (latent) in our nerve cells. Occasionally HSV reactivates to cause disease, with HSV-1 typically causing cold sores whereas HSV-2 is the most common cause of genital herpes. The details of how HSV reactivates are largely unknown. Most of HSV's genes are silent during latency with the exception of RNAs made from the latency-associated transcript (LAT) region. While viruses that make less LAT do not reactivate efficiently, these viruses also do not establish latency as efficiently. Here we deliver a ribozyme that can degrade the LAT to the nerve cells of latently infected rabbits using a gene therapy vector. We show that this treatment blocks reactivation in the majority of the rabbits. This work shows that the LAT RNA is important for reactivation and the suggests the potential of this treatment as a therapy for treating HSV infections. Copyright © 2018 American Society for Microbiology.

A double-blind, placebo-controlled oral challenge study with lyophilized larvae and antigen of the fish parasite, Anisakis simplex.

PubMed

Sastre, J; Lluch-Bernal, M; Quirce, S; Arrieta, I; Lahoz, C; Del Amo, A; Fernández-Caldas, E; Marañón, F

2000-06-01

The third-stage larvae of Anisakis simplex may be a hidden source of allergens in fish. The objective was to determine whether the ingestion of lyophilized A. simplex larvae, or antigen, induces clinical symptoms in a group of A. simplex-sensitized patients. Double-blind, placebo-controlled oral challenges were conducted in 11 individuals who had experienced allergic reactions after eating fish. Another patient had chronic urticaria unrelated to the ingestion of fish. All patients had positive skin tests and specific IgE determinations for A. simplex and negative skin tests to a battery of fish species. Conjunctival tests with A. simplex extracts were conducted in all patients and in five controls. The 12 patients received capsules containing either lactose or one, five, or 25 lyophilized larvae of A. simplex at 2-h intervals in a double-blind fashion. The highest single dose was 100 larvae. ECP and tryptase levels in serum were measured before and after the last oral challenge. Lyophilized antigen was also given to five patients. None of the 12 patients experienced a positive reaction after the ingestion of the placebo, the lyophilized larvae, or the antigen. Tryptase and ECP levels before and after challenges did not change significantly. Conjunctival provocation tests were positive in 11 out of the 12 patients and in none of the controls. The ingestion of 100 lyophilized A. simplex larvae, or its equivalent in antigen, does not induce clinical symptoms in individuals with a clinical history and laboratory findings of hypersensitivity to A. simplex. The data suggest that only the ingestion of live larvae may be capable of inducing allergic manifestations.

The antiviral potency of Fagus sylvatica 4OMe-glucuronoxylan sulfates.

PubMed

Pujol, C A; Damonte, E B; Turjan, J; Yanbo, K Z; Capek, P

2016-06-01

Herpes simplex virus belongs to Herpesviridae family and causes infection of humans from ancient times. 4OMe-glucuronoxylans as the renewable biopolymers can be promising glycomaterials for various applications in pharmacy. Control enzymatic degradation of the native 4OMe-glucuronoxylan (GX1) followed by targeted sulfation procedure afforded a range of 4OMe-glucuronoxylan sulfates differed in the degree of sulfation (10-16%) and molecular mass (21,000-5000g/mol; GXS1>GXS2>GXS3>GXS4). Antiviral activity tests on GXS1-4 against herpes simplex virus (HSV) types 1 and 2 revealed the positive effect of all compounds against strains of herpes virus. Of them, the compounds GXS1 and GXS4 were shown to be the most active for both HSV serotypes. The antiviral activity of GXS1 and GXS4 was similar to those of heparin or dextran sulfate, used as reference compounds. It was found that GXS1 and GXS4 were active as well against Polio and dengue viruses, however, on a smaller scale. The mode of antiviral action of 4OMe-glucuronoxylan sulfates is due to inhibition of the virus binding to the cell receptors. Copyright © 2016 Elsevier B.V. All rights reserved.

Herpes simplex virus type 1-derived recombinant and amplicon vectors.

PubMed

Fraefel, Cornel; Marconi, Peggy; Epstein, Alberto L

2011-01-01

Herpes simplex virus type 1 (HSV-1) is a human pathogen whose lifestyle is based on a long-term dual interaction with the infected host, being able to establish both lytic and latent infections. The virus genome is a 153 kbp double-stranded DNA molecule encoding more than 80 genes. The interest of HSV-1 as gene transfer vector stems from its ability to infect many different cell types, both quiescent and proliferating cells, the very high packaging capacity of the virus capsid, the outstanding neurotropic adaptations that this virus has evolved, and the fact that it never integrates into the cellular chromosomes, thus avoiding the risk of insertional mutagenesis. Two types of vectors can be derived from HSV-1, recombinant vectors and amplicon vectors, and different methodologies have been developed to prepare large stocks of each type of vector. This chapter summarizes (1) the two approaches most commonly used to prepare recombinant vectors through homologous recombination, either in eukaryotic cells or in bacteria, and (2) the two methodologies currently used to generate helper-free amplicon vectors, either using a bacterial artificial chromosome (BAC)-based approach or a Cre/loxP site-specific recombination strategy.

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

Polymerase chain reaction analysis of aqueous humour samples in necrotising retinitis.

PubMed

Tran, T H C; Rozenberg, F; Cassoux, N; Rao, N A; LeHoang, P; Bodaghi, B

2003-01-01

To evaluate the diagnostic value of polymerase chain reaction (PCR) performed on aqueous humour for the detection of viral DNA in patients with necrotising herpetic retinitis. The clinical features and laboratory results of 22 patients (29 eyes) presenting with necrotising herpetic retinitis between March 1999 and June 2001 were reviewed retrospectively. Aqueous humour was obtained after anterior chamber paracentesis and PCR was performed in all cases. Viral DNA was detected in the aqueous humour of 19 patients (86.4%). Epstein-Barr virus (EBV) seroconversion was evidenced in one additional patient. In the acute retinal necrosis (ARN) group (n = 19), varicella zoster virus (VZV) DNA was identified in six patients, herpes simplex virus 1 (HSV-1) DNA in two patients, herpes simplex virus 2 (HSV-2) DNA in four patients, and cytomegalovirus (CMV) genome in four patients. In the progressive outer retinal necrosis (PORN) group (n = 3), VZV DNA was detected in all patients. No sample was positive for more than one virus. PCR analysis of aqueous humour in patients with clinical features of necrotising viral retinitis can provide specific aetiological orientation and the method appears to be safe and highly sensitive.

Polymerase chain reaction analysis of aqueous humour samples in necrotising retinitis

PubMed Central

Tran, T H C; Rozenberg, F; Cassoux, N; Rao, N A; LeHoang, P; Bodaghi, B

2003-01-01

Aim: To evaluate the diagnostic value of polymerase chain reaction (PCR) performed on aqueous humour for the detection of viral DNA in patients with necrotising herpetic retinitis. Methods: The clinical features and laboratory results of 22 patients (29 eyes) presenting with necrotising herpetic retinitis between March 1999 and June 2001 were reviewed retrospectively. Aqueous humour was obtained after anterior chamber paracentesis and PCR was performed in all cases. Results: Viral DNA was detected in the aqueous humour of 19 patients (86.4%). Epstein-Barr virus (EBV) seroconversion was evidenced in one additional patient. In the acute retinal necrosis (ARN) group (n = 19), varicella zoster virus (VZV) DNA was identified in six patients, herpes simplex virus 1 (HSV-1) DNA in two patients, herpes simplex virus 2 (HSV-2) DNA in four patients, and cytomegalovirus (CMV) genome in four patients. In the progressive outer retinal necrosis (PORN) group (n = 3), VZV DNA was detected in all patients. No sample was positive for more than one virus. Conclusions: PCR analysis of aqueous humour in patients with clinical features of necrotising viral retinitis can provide specific aetiological orientation and the method appears to be safe and highly sensitive. PMID:12488268

Two-color fluorescence analysis of individual virions determines the distribution of the copy number of proteins in herpes simplex virus particles.

PubMed

Clarke, Richard W; Monnier, Nilah; Li, Haitao; Zhou, Dejian; Browne, Helena; Klenerman, David

2007-08-15

We present a single virion method to determine absolute distributions of copy number in the protein composition of viruses and apply it to herpes simplex virus type 1. Using two-color coincidence fluorescence spectroscopy, we determine the virion-to-virion variability in copy numbers of fluorescently labeled tegument and envelope proteins relative to a capsid protein by analyzing fluorescence intensity ratios for ensembles of individual dual-labeled virions and fitting the resulting histogram of ratios. Using EYFP-tagged capsid protein VP26 as a reference for fluorescence intensity, we are able to calculate the mean and also, for the first time to our knowledge, the variation in numbers of gD, VP16, and VP22 tegument. The measurement of the number of glycoprotein D molecules was in good agreement with independent measurements of average numbers of these glycoproteins in bulk virus preparations, validating the method. The accuracy, straightforward data processing, and high throughput of this technique make it widely applicable to the analysis of the molecular composition of large complexes in general, and it is particularly suited to providing insights into virus structure, assembly, and infectivity.

Cell Cycle-Dependent Expression of Adeno-Associated Virus 2 (AAV2) Rep in Coinfections with Herpes Simplex Virus 1 (HSV-1) Gives Rise to a Mosaic of Cells Replicating either AAV2 or HSV-1

PubMed Central

Franzoso, Francesca D.; Seyffert, Michael; Vogel, Rebecca; Yakimovich, Artur; de Andrade Pereira, Bruna; Meier, Anita F.; Sutter, Sereina O.; Tobler, Kurt; Vogt, Bernd; Greber, Urs F.; Büning, Hildegard; Ackermann, Mathias

2017-01-01

ABSTRACT Adeno-associated virus 2 (AAV2) depends on the simultaneous presence of a helper virus such as herpes simplex virus 1 (HSV-1) for productive replication. At the same time, AAV2 efficiently blocks the replication of HSV-1, which would eventually limit its own replication by diminishing the helper virus reservoir. This discrepancy begs the question of how AAV2 and HSV-1 can coexist in a cell population. Here we show that in coinfected cultures, AAV2 DNA replication takes place almost exclusively in S/G2-phase cells, while HSV-1 DNA replication is restricted to G1 phase. Live microscopy revealed that not only wild-type AAV2 (wtAAV2) replication but also reporter gene expression from both single-stranded and double-stranded (self-complementary) recombinant AAV2 vectors preferentially occurs in S/G2-phase cells, suggesting that the preference for S/G2 phase is independent of the nature of the viral genome. Interestingly, however, a substantial proportion of S/G2-phase cells transduced by the double-stranded but not the single-stranded recombinant AAV2 vectors progressed through mitosis in the absence of the helper virus. We conclude that cell cycle-dependent AAV2 rep expression facilitates cell cycle-dependent AAV2 DNA replication and inhibits HSV-1 DNA replication. This may limit competition for cellular and viral helper factors and, hence, creates a biological niche for either virus to replicate. IMPORTANCE Adeno-associated virus 2 (AAV2) differs from most other viruses, as it requires not only a host cell for replication but also a helper virus such as an adenovirus or a herpesvirus. This situation inevitably leads to competition for cellular resources. AAV2 has been shown to efficiently inhibit the replication of helper viruses. Here we present a new facet of the interaction between AAV2 and one of its helper viruses, herpes simplex virus 1 (HSV-1). We observed that AAV2 rep gene expression is cell cycle dependent and gives rise to distinct time-controlled windows for HSV-1 replication. High Rep protein levels in S/G2 phase support AAV2 replication and inhibit HSV-1 replication. Conversely, low Rep protein levels in G1 phase permit HSV-1 replication but are insufficient for AAV2 replication. This allows both viruses to productively replicate in distinct sets of dividing cells. PMID:28515305

Crystal Structure of the N-Terminal Half of the Traffic Controller UL37 from Herpes Simplex Virus 1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Koenigsberg, Andrea L.; Heldwein, Ekaterina E.; Sandri-Goldin, Rozanne M.

Inner tegument protein UL37 is conserved among all three subfamilies of herpesviruses. Studies of UL37 homologs from two alphaherpesviruses, herpes simplex virus 1 (HSV-1) and pseudorabies virus (PRV), have suggested that UL37 plays an essential albeit poorly defined role in intracellular capsid trafficking. At the same time, HSV and PRV homologs cannot be swapped, which suggests that in addition to a conserved function, UL37 homologs also have divergent virus-specific functions. Accurate dissection of UL37 functions requires detailed maps in the form of atomic-resolution structures. Previously, we reported the crystal structure of the N-terminal half of UL37 (UL37N) from PRV. Here,more » we report the crystal structure of HSV-1 UL37N. Comparison of the two structures reveals that UL37 homologs differ in their overall shapes, distributions of surface charges, and locations of projecting loops. In contrast, the previously identified R2 surface region is structurally conserved. We propose that within the N-terminal half of UL37, functional conservation is centered within the R2 surface region, whereas divergent structural elements pinpoint regions mediating virus-specific functions and may engage different binding partners. Together, the two structures can now serve as templates for a structure-guided exploration of both conserved and virus-specific functions of UL37. IMPORTANCEThe ability to move efficiently within host cell cytoplasm is essential for replication in all viruses. It is especially important in the neuroinvasive alphaherpesviruses, such as human herpes simplex virus 1 (HSV-1), HSV-2, and veterinarian pseudorabies virus (PRV), that infect the peripheral nervous system and have to travel long distances along axons. Capsid movement in these viruses is controlled by capsid-associated tegument proteins, yet their specific roles have not yet been defined. Systematic exploration of the roles of tegument proteins in capsid trafficking requires detailed navigational charts in the form of their three-dimensional structures. Here, we determined the crystal structure of the N-terminal half of a conserved tegument protein, UL37, from HSV-1. This structure, along with our previously reported structure of the UL37 homolog from PRV, provides a much needed 3-dimensional template for the dissection of both conserved and virus-specific functions of UL37 in intracellular capsid trafficking.« less

Communicable Diseases and the Enrolled Student: A Model Policy and Rules.

ERIC Educational Resources Information Center

Iowa State Dept. of Education, Des Moines.

A model school policy provides guidelines for Iowa school systems with regard to students with AIDS (Acquired Immune Deficiency Syndrome), herpes simplex, and cytomegalovirus. The AIDS guidelines include the following: (1) Routine screening students for AIDS associated virus is not recommended. (2) Children infected with the AIDS associated virus,…

Topical application of polyethylenimine as a candidate for novel prophylactic therapeutics against genital herpes caused by herpes simplex virus.

PubMed

Hayashi, Kyoko; Onoue, Hiroki; Sasaki, Kohei; Lee, Jung-Bum; Kumar, Penmetcha K R; Gopinath, Subash C B; Maitani, Yoshie; Kai, Takashi; Hayashi, Toshimitsu

2014-03-01

Herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) cause genital herpes, which can enhance the acquisition of human immunodeficiency virus. The development of anti-HSV agents with novel mechanisms of action is urgently required in the topical therapy of genital herpes. In this study, the in vitro and in vivo anti-HSV effects of Epomin SP-012(®), a highly cationic polyethylenimine, were evaluated. When the in vitro antiviral effects of SP-012 were assessed, this compound showed potent activity against HSV-1 and HSV-2. It inhibited the attachment of HSV-2 to host cells and cell-to-cell spread of infection in a concentration-dependent manner and exerted a virucidal effect. No SP-012-resistant HSV-2 was found when the virus was successively passaged in the presence of SP-012. In a mouse genital herpes model, topically administered SP-012 inhibited the progression of the disease caused by HSV infection. These data illustrate that SP-012 may be a novel class of HSV inhibitor that would be acceptable for long-term topical application.

Ability of herpes simplex virus vectors to boost immune responses to DNA vectors and to protect against challenge by simian immunodeficiency virus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kaur, Amitinder; Sanford, Hannah B.; Garry, Deirdre

2007-01-20

The immunogenicity and protective capacity of replication-defective herpes simplex virus (HSV) vector-based vaccines were examined in rhesus macaques. Three macaques were inoculated with recombinant HSV vectors expressing Gag, Env, and a Tat-Rev-Nef fusion protein of simian immunodeficiency virus (SIV). Three other macaques were primed with recombinant DNA vectors expressing Gag, Env, and a Pol-Tat-Nef-Vif fusion protein prior to boosting with the HSV vectors. Robust anti-Gag and anti-Env cellular responses were detected in all six macaques. Following intravenous challenge with wild-type, cloned SIV239, peak and 12-week plasma viremia levels were significantly lower in vaccinated compared to control macaques. Plasma SIV RNAmore » in vaccinated macaques was inversely correlated with anti-Rev ELISPOT responses on the day of challenge (P value < 0.05), anti-Tat ELISPOT responses at 2 weeks post challenge (P value < 0.05) and peak neutralizing antibody titers pre-challenge (P value 0.06). These findings support continued study of recombinant herpesviruses as a vaccine approach for AIDS.« less

Structure of the transporter associated with antigen processing trapped by herpes simplex virus

PubMed Central

Oldham, Michael L; Grigorieff, Nikolaus; Chen, Jue

2016-01-01

The transporter associated with antigen processing (TAP) is an ATP-binding cassette (ABC) transporter essential to cellular immunity against viral infection. Some persistent viruses have evolved strategies to inhibit TAP so that they may go undetected by the immune system. The herpes simplex virus for example evades immune surveillance by blocking peptide transport with a small viral protein ICP47. In this study, we determined the structure of human TAP bound to ICP47 by electron cryo-microscopy (cryo-EM) to 4.0 Å. The structure shows that ICP47 traps TAP in an inactive conformation distinct from the normal transport cycle. The specificity and potency of ICP47 inhibition result from contacts between the tip of the helical hairpin and the apex of the transmembrane cavity. This work provides a clear molecular description of immune evasion by a persistent virus. It also establishes the molecular structure of TAP to facilitate mechanistic studies of the antigen presentation process. DOI: http://dx.doi.org/10.7554/eLife.21829.001 PMID:27935481

Ancient Recombination Events between Human Herpes Simplex Viruses.

PubMed

Burrel, Sonia; Boutolleau, David; Ryu, Diane; Agut, Henri; Merkel, Kevin; Leendertz, Fabian H; Calvignac-Spencer, Sébastien

2017-07-01

Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) are seen as close relatives but also unambiguously considered as evolutionary independent units. Here, we sequenced the genomes of 18 HSV-2 isolates characterized by divergent UL30 gene sequences to further elucidate the evolutionary history of this virus. Surprisingly, genome-wide recombination analyses showed that all HSV-2 genomes sequenced to date contain HSV-1 fragments. Using phylogenomic analyses, we could also show that two main HSV-2 lineages exist. One lineage is mostly restricted to subSaharan Africa whereas the other has reached a global distribution. Interestingly, only the worldwide lineage is characterized by ancient recombination events with HSV-1. Our findings highlight the complexity of HSV-2 evolution, a virus of putative zoonotic origin which later recombined with its human-adapted relative. They also suggest that coinfections with HSV-1 and 2 may have genomic and potentially functional consequences and should therefore be monitored more closely. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Herpes simplex virus and cytomegalovirus co-infection presenting as exuberant genital ulcer in a woman infected with human immunodeficiency virus.

PubMed

Gouveia, A I; Borges-Costa, J; Soares-Almeida, L; Sacramento-Marques, M; Kutzner, H

2014-12-01

In patients infected with human immunodeficiency virus (HIV), genital herpes can result in severe and atypical clinical presentations, and can become resistant to aciclovir treatment. Rarely, these manifestations may represent concurrent herpes simplex virus (HSV) with other agents. We report a 41-year-old black woman with HIV who presented with extensive and painful ulceration of the genitalia. Histological examination of a biopsy sample was suggestive of herpetic infection, and intravenous aciclovir was started, but produced only partial improvement. PCR was performed on the biopsy sample, and both HSV and cytomegalovirus (CMV) DNA was detected. Oral valganciclovir was started with therapeutic success. CMV infection is common in patients infected with HIV, but its presence in mucocutaneous lesions is rarely reported. This case exemplifies the difficulties of diagnosis of genital ulcers in patients infected with HIV. The presence of exuberant and persistent HSV genital ulcers in patients with HIV should also raise suspicions of the presence of co-infection with other organisms such as CMV. © 2014 British Association of Dermatologists.

The occurrence of herpes simplex viruses 1 and 2 in skin and mucosal lesions in patients with suspicion of genital herpes.

PubMed

Gorka, Emilia; Mlynarczyk-Bonikowska, Beata; Machura, Paulina; Majewska, Anna; Dzieciqtkowski, Tomasz; Mlynarzyk, Grazyna; Malejczyk, Magdalena; Majewski, Slawomir

Infection with herpes simplex viruses 1 and 2 (HSV 1 and 2 or Human herpesvirus HHV) are one of the most common infections in human. Real time PCR is a sensitive and specific method for diagnostics of HHV infections. The aim of the study was to investigate the occurrence of HHV 1 and HHV 2 DNA in patient with clinical symptoms suggesting HHV infection. We used real time PCR to investigate swabs from genital and perianal lesions from 74 patients of the Department of Dermatology and Venereology Medical University Warsaw and of gynecological outpatient clinics in Warsaw 40 women and 34 men. The results were positive for HHV 2 in 25 cases (34%), for HHV 1 in 19 cases (26%) and for both viruses in 20 cases (27%). 10 samples were negative for both viruses. The results confirm that the main cause of symptomatic genital herpes is HHV 2, however the percentage of HHV 1 and specially of mixed HHV 1/HHV 2 infections was unexpectedly high.

Role of L-Particles during Herpes Simplex Virus Infection.

PubMed

Heilingloh, Christiane S; Krawczyk, Adalbert

2017-01-01

Infection of eukaryotic cells with α-herpesviruses results in the formation and secretion of infectious heavy particles (virions; H-particles) and non-infectious light particles (L-particles). Herpes simplex virus type 1 (HSV-1) H-particles consist of a genome-containing capsid surrounded by tegument proteins and a glycoprotein-rich lipid bilayer. Non-infectious L-particles are composed mainly of envelope and tegument proteins and are devoid of capsids and viral DNA. L-particles were first described in the early nineties and from then on investigated for their formation and role during virus infection. The development and secretion of L-particles occur simultaneously to the assembly of complete viral particles. HSV-1 L-particles are assembled by budding of condensed tegument into Golgi-delivered vesicles and are capable of delivering their functional content to non-infected cells. Thereby, HSV-1 L-particles contribute to viral pathogenesis within the infected host by enhancing virion infectivity and providing immune evasion functions. In this review we discuss the emergence of HSV-1 L-particles during virus replication and their biological functions described thus far.

Dual Split Protein-Based Fusion Assay Reveals that Mutations to Herpes Simplex Virus (HSV) Glycoprotein gB Alter the Kinetics of Cell-Cell Fusion Induced by HSV Entry Glycoproteins

PubMed Central

Atanasiu, Doina; Saw, Wan Ting; Gallagher, John R.; Hannah, Brian P.; Matsuda, Zene; Whitbeck, J. Charles; Cohen, Gary H.

2013-01-01

Herpes simplex virus (HSV) entry and cell-cell fusion require glycoproteins gD, gH/gL, and gB. We propose that receptor-activated changes to gD cause it to activate gH/gL, which then triggers gB into an active form. We employed a dual split-protein (DSP) assay to monitor the kinetics of HSV glycoprotein-induced cell-cell fusion. This assay measures content mixing between two cells, i.e., fusion, within the same cell population in real time (minutes to hours). Titration experiments suggest that both gD and gH/gL act in a catalytic fashion to trigger gB. In fact, fusion rates are governed by the amount of gB on the cell surface. We then used the DSP assay to focus on mutants in two functional regions (FRs) of gB, FR1 and FR3. FR1 contains the fusion loops (FL1 and FL2), and FR3 encompasses the crown at the trimer top. All FL mutants initiated fusion very slowly, if at all. However, the fusion rates caused by some FL2 mutants increased over time, so that total fusion by 8 h looked much like that of the WT. Two distinct kinetic patterns, “slow and fast,” emerged for mutants in the crown of gB (FR3), again showing differences in initiation and ongoing fusion. Of note are the fusion kinetics of the gB syn mutant (LL871/872AA). Although this mutant was originally included as an ongoing high-rate-of-fusion control, its initiation of fusion is so rapid that it appears to be on a “hair trigger.” Thus, the DSP assay affords a unique way to examine the dynamics of HSV glycoprotein-induced cell fusion. PMID:23946457

The replication defect of ICP0-null mutant herpes simplex virus 1 can be largely complemented by the combined activities of human cytomegalovirus proteins IE1 and pp71.

PubMed

Everett, Roger D; Bell, Adam J; Lu, Yongxu; Orr, Anne

2013-01-01

Herpes simplex virus 1 (HSV-1) immediate-early protein ICP0 is required for efficient lytic infection and productive reactivation from latency and induces derepression of quiescent viral genomes. Despite being unrelated at the sequence level, ICP0 and human cytomegalovirus proteins IE1 and pp71 share some functional similarities in their abilities to counteract antiviral restriction mediated by components of cellular nuclear structures known as ND10. To investigate the extent to which IE1 and pp71 might substitute for ICP0, cell lines were developed that express either IE1 or pp71, or both together, in an inducible manner. We found that pp71 dissociated the hDaxx-ATRX complex and inhibited accumulation of these proteins at sites juxtaposed to HSV-1 genomes but had no effect on the promyelocytic leukemia protein (PML) or Sp100. IE1 caused loss of the small ubiquitin-like modifier (SUMO)-conjugated forms of PML and Sp100 and inhibited the recruitment of these proteins to HSV-1 genome foci but had little effect on hDaxx or ATRX in these assays. Both IE1 and pp71 stimulated ICP0-null mutant plaque formation, but neither to the extent achieved by ICP0. The combination of IE1 and pp71, however, inhibited recruitment of all ND10 proteins to viral genome foci, stimulated ICP0-null mutant HSV-1 plaque formation to near wild-type levels, and efficiently induced derepression of quiescent HSV-1 genomes. These results suggest that ND10-related intrinsic resistance results from the additive effects of several ND10 components and that the effects of IE1 and pp71 on subsets of these components combine to mirror the overall activities of ICP0.

The Replication Defect of ICP0-Null Mutant Herpes Simplex Virus 1 Can Be Largely Complemented by the Combined Activities of Human Cytomegalovirus Proteins IE1 and pp71

PubMed Central

Bell, Adam J.; Lu, Yongxu; Orr, Anne

2013-01-01

Herpes simplex virus 1 (HSV-1) immediate-early protein ICP0 is required for efficient lytic infection and productive reactivation from latency and induces derepression of quiescent viral genomes. Despite being unrelated at the sequence level, ICP0 and human cytomegalovirus proteins IE1 and pp71 share some functional similarities in their abilities to counteract antiviral restriction mediated by components of cellular nuclear structures known as ND10. To investigate the extent to which IE1 and pp71 might substitute for ICP0, cell lines were developed that express either IE1 or pp71, or both together, in an inducible manner. We found that pp71 dissociated the hDaxx-ATRX complex and inhibited accumulation of these proteins at sites juxtaposed to HSV-1 genomes but had no effect on the promyelocytic leukemia protein (PML) or Sp100. IE1 caused loss of the small ubiquitin-like modifier (SUMO)-conjugated forms of PML and Sp100 and inhibited the recruitment of these proteins to HSV-1 genome foci but had little effect on hDaxx or ATRX in these assays. Both IE1 and pp71 stimulated ICP0-null mutant plaque formation, but neither to the extent achieved by ICP0. The combination of IE1 and pp71, however, inhibited recruitment of all ND10 proteins to viral genome foci, stimulated ICP0-null mutant HSV-1 plaque formation to near wild-type levels, and efficiently induced derepression of quiescent HSV-1 genomes. These results suggest that ND10-related intrinsic resistance results from the additive effects of several ND10 components and that the effects of IE1 and pp71 on subsets of these components combine to mirror the overall activities of ICP0. PMID:23135716

Broadband Respiratory Virus Surveillance

DTIC Science & Technology

2011-10-01

Simplex Virus (HSV) and 19 Enterovirus 7 positive as well as 11 HSV negative specimens as determined by the TAMC Department of Pathology’s current gold...negative, and 19 Enterovirus positive samples were to serve as negative controls as the RVS plate did not have primers to assay for HSV or Enterovirus . As...expected, all of these specimens ( Enterovirus , HSV positive and negative virus samples) tested negative on the RVS plate. This demonstrated 100

IL-2 complex treatment amplifies CD8+ T cell mediated immunity following herpes simplex virus-1 infection.

PubMed

Rajasagi, Naveen K; Rouse, Barry T

2016-12-01

CD8 + T cells play an important role in controlling numerous virus infections and some tumors and therefore several strategies have been adopted to modulate CD8 + T cell responses. One such approach includes treatment with IL-2 bound to a monoclonal antibody against IL-2 (IL-2 complex) which was shown to enhance CD8 + T cell responses and provide protection against some cancers and pathogens. This report analyses the value of IL-2 complex therapy to protect against a cutaneous virus infection as occurs with herpes simplex virus-1 (HSV-1) infection. Treatment with IL-2 complex after infection reduced virus levels and lesion severity in a zosteriform model of HSV infection in mice. Furthermore, IL-2 complex treatment expanded HSV-1-gB epitope-specific CD8 + T cells, IFN-γ and TNF-α producing CD8 + T cells as well as cells that produced more than one cytokine. In addition, IL-2 complex therapy recipients showed enhanced cytolytic activity of CD8 + T cells as shown by increased granzyme B expression and lytic granule release. Taken, together, these studies demonstrate that IL-2 complex therapy can be useful to boost protection against a cutaneous virus infection. Copyright © 2016 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Anti-herpes simplex virus type 1 activity of Houttuynoid A, a flavonoid from Houttuynia cordata Thunb.

PubMed

Li, Ting; Liu, Libao; Wu, Hongling; Chen, Shaodan; Zhu, Qinchang; Gao, Hao; Yu, Xiongtao; Wang, Yi; Su, Wenhan; Yao, Xinsheng; Peng, Tao

2017-08-01

Early events in herpes simplex virus type 1 (HSV-1) infection reactivate latent human immunodeficiency virus, Epstein-Barr virus, and human papillomavirus in the presence of acyclovir (ACV). The common use of nucleoside analog medications, such as ACV and pencyclovir, has resulted in the emergence of drug-resistant HSV-1 strains in clinical therapy. Therefore, new antiherpetics that can inhibit early events in HSV-1 infection should be developed. An example of this treatment is Houttuynia cordata Thunb. water extract, which can inhibit HSV-1 infection through multiple mechanisms. In this study, the anti-HSV-1 activity of Houttuynoid A, a new type of flavonoid isolated from H. cordata, was investigated. Three different assays confirmed that this compound could exhibit strong in vitro anti-HSV-1 activity. One assay verified that this compound could inhibit HSV-1 multiplication and prevent lesion formation in a HSV-1 infection mouse model. Mechanism analysis revealed that this compound could inactivate HSV-1 infectivity by blocking viral membrane fusion. Moreover, Houttuynoid A exhibited antiviral activities against other alpha herpes viruses, such as HSV-2 and varicella zoster virus (VZV). In conclusion, Houttuynoid A may be a useful antiviral agent for HSV-1. Copyright © 2017 Elsevier B.V. All rights reserved.

Clonal analysis of T-cell responses to herpes simplex virus: isolation, characterization and antiviral properties of an antigen-specific helper T-cell clone.

PubMed Central

Leung, K N; Nash, A A; Sia, D Y; Wildy, P

1984-01-01

A herpes simplex virus (HSV)-specific long-term T-cell clone has been established from the draining lymph node cells of BALB/c mice; the cells required repeated in vitro restimulation with UV-irradiated virus. The established T-cell clone expresses the Thy-1 and Lyt-1+2,3- surface antigens. For optimal proliferation of the cloned cells, both the presence of specific antigen and an exogenous source of T-cell growth factor are required. The proliferative response of the cloned T cells was found to be virus-specific but it did not distinguish between HSV-1 and HSV-2. Adoptive cell transfer of the cloned T cells helped primed B cells to produce anti-herpes antibodies: the response was antigen-specific and cell dose-dependent. The clone failed to produce a significant DTH reaction in vivo, but did produce high levels of macrophage-activating factor. Furthermore, the T-cell clone could protect from HSV infection, as measured by a reduction in local virus growth, and by enhanced survival following the challenge of mice with a lethal dose of virus. The mechanism(s) whereby this clone protects in vivo is discussed. PMID:6209206

Anisakis simplex allergy: a murine model of anaphylaxis induced by parasitic proteins displays a mixed Th1/Th2 pattern

PubMed Central

Baeza, M L; Conejero, L; Higaki, Y; Martín, E; Pérez, C; Infante, S; Rubio, M; Zubeldia, J M

2005-01-01

The study of the singular hypersensitivity reactions to Anisakis simplex (A.s) proteins, may help us to undestand many of the unknown immune interactions between helmiths infections and allergy. We have developed a murine model of allergy to A. simplex, that mimics human A. simplex allergy to study the specific aspects of anaphylaxis induced by parasites. Male C3H/HeJ mice were intraperitoneally sensitized to A. simplex. Mice were then intravenous or orally challenged with A. simplex. Antigen-specific immunoglobulins, polyclonal IgE, anaphylactic symptoms, plasma histamine levels and cytokine profiles were determined. Comparative IgE immunoblot analyses were also performed. Specific IgE, IgG1 and IgG2a were detected in sensitized mice since week 3. Polyclonal IgE raised and peaked with different kinetics. Intravenous A. simplex challenge produced anaphylaxis in mice, accompanied by plasma histamine release. Oral A. simplex challenge in similarly sensitized mice did not caused symptoms nor histamine release. Numerous A. simplex allergens were recognized by sensitized mouse sera, some of them similar to human serum. The A. simplex stimulated splenocytes released IL-10, IFN-γ, IL-4, IL-13 and IL-5. We describe a new animal model of anaphylaxis. It exhibits characteristics of type I hypersensitivity reactions to Anisakis simplex similar to those observed in allergic humans. Different responses to i.v. or oral A. simplex challenges emerged, which did not reflect a window tolerization period. The cytokine profile developed (mixed Th1/Th2 pattern) differed from the observed in classical models of anaphylaxis or allergy to food antigens. This model may permit to investigate the peculiar allergic reactions to parasitic proteins. PMID:16297154

The potential of immunostimulatory CpG DNA for inducing immunity against genital herpes: opportunities and challenges.

PubMed

Harandi, Ali M

2004-07-01

Herpes simplex virus type 2 (HSV-2) invades human genital tract mucosa and following local replications can be rapidly transmitted via peripheral nerve axons to the sacral ganglia where it can establish latency. Reactivation of the latent viral reservoir results in recurrent ulcers in the genital region. Innate immunity, the first line of defence during both primary and recurrent genital herpes infections, is crucial during the period of acute infection to limit early virus replication and to facilitate the development of an appropriate specific acquired immunity. Recent developments in immunology reveal that the mammalian innate immune systems use Toll-like receptor (TLR) to specifically sense evolutionary conserved molecules such as bacterial DNA in pathogens. Recently, local-vaginal delivery of CpG containing oligodeoxynucleotide (ODN), a synthetic mimic of bacterial DNA, holds substantial promise as a strong inducer of innate immunity against genital herpes infections in the animal models of the disease. These preclinical observations provide a scientific ground work for introduction of this novel intervention strategy to clinic. This review aims to highlight recent developments and future challenges in use of immunostimulatory CpG ODN for inducing immunity against genital herpes infection and disease.