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.

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.

Unique spectrum of activity of 9-[(1,3-dihydroxy-2-propoxy)methyl]-guanine against herpesviruses in vitro and its mode of action against herpes simplex virus type 1.

PubMed Central

Cheng, Y C; Huang, E S; Lin, J C; Mar, E C; Pagano, J S; Dutschman, G E; Grill, S P

1983-01-01

A guanosine analog, 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine (DHPG), was found to inhibit herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2, cytomegalovirus, and Epstein-Barr virus replication by greater than 50% at concentrations that do not inhibit cell growth in culture. The potency of the drug against all of these viruses is greater than that of 9-[(2-hydroxyethoxy)methyl]guanine (acyclovir). DHPG was active against HSV-1 growth during the early phase of virus replication and had no activity when added at a later time after infection. Its antiviral activity was irreversible. Thymidine partially neutralized its action. The anti-HSV-1 activity of DHPG was dependent on the induction and the properties of virus-induced thymidine kinase. Virus variants that induced altered virus thymidine kinase and became resistant to acyclovir were still as sensitive to DHPG as the parental virus. DHPG is active against five different HSV variants with induced altered DNA polymerase and resistance to acyclovir. PMID:6302704

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.

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.

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

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

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.

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…

Serine/Arginine-rich Splicing Factor 2 Modulates Herpes Simplex Virus Type 1 Replication via Regulating Viral Gene Transcriptional Activity and Pre-mRNA Splicing.

PubMed

Wang, Ziqiang; Liu, Qing; Lu, Jinhua; Fan, Ping; Xie, Weidong; Qiu, Wei; Wang, Fan; Hu, Guangnan; Zhang, Yaou

2016-12-16

Once it enters the host cell, herpes simplex virus type 1 (HSV-1) recruits a series of host cell factors to facilitate its life cycle. Here, we demonstrate that serine/arginine-rich splicing factor 2 (SRSF2), which is an important component of the splicing speckle, mediates HSV-1 replication by regulating viral gene expression at the transcriptional and posttranscriptional levels. Our results indicate that SRSF2 functions as a transcriptional activator by directly binding to infected cell polypeptide 0 (ICP0), infected cell polypeptide 27 (ICP27), and thymidine kinase promoters. Moreover, SRSF2 participates in ICP0 pre-mRNA splicing by recognizing binding sites in ICP0 exon 3. These findings provide insight into the functions of SRSF2 in HSV-1 replication and gene expression. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

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

PubMed

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

2014-08-01

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

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.

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

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

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.

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

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

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

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

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

1986-07-15

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

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

Nuclear Localization of the C1 Factor (Host Cell Factor) in Sensory Neurons Correlates with Reactivation of Herpes Simplex Virus from Latency

NASA Astrophysics Data System (ADS)

Kristie, Thomas M.; Vogel, Jodi L.; Sears, Amy E.

1999-02-01

After a primary infection, herpes simplex virus is maintained in a latent state in neurons of sensory ganglia until complex stimuli reactivate viral lytic replication. Although the mechanisms governing reactivation from the latent state remain unknown, the regulated expression of the viral immediate early genes represents a critical point in this process. These genes are controlled by transcription enhancer complexes whose assembly requires and is coordinated by the cellular C1 factor (host cell factor). In contrast to other tissues, the C1 factor is not detected in the nuclei of sensory neurons. Experimental conditions that induce the reactivation of herpes simplex virus in mouse model systems result in rapid nuclear localization of the protein, indicating that the C1 factor is sequestered in these cells until reactivation signals induce a redistribution of the protein. The regulated localization suggests that C1 is a critical switch determinant of the viral lytic-latent cycle.

[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.

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

Oncolytic Herpes Simplex Virus Vectors Fully Retargeted to Tumor- Associated Antigens.

PubMed

Uchida, Hiroaki; Hamada, Hirofumi; Nakano, Kenji; Kwon, Heechung; Tahara, Hideaki; Cohen, Justus B; Glorioso, Joseph C

2018-01-01

Oncolytic virotherapy is a novel therapeutic modality for malignant diseases that exploits selective viral replication in cancer cells. Herpes simplex virus (HSV) is a promising agent for oncolytic virotherapy due to its broad cell tropism and the identification of mutations that favor its replication in tumor over normal cells. However, these attenuating mutations also tend to limit the potency of current oncolytic HSV vectors that have entered clinical studies. As an alternative, vector retargeting to novel entry receptors has the potential to achieve tumor specificity at the stage of virus entry, eliminating the need for replication-attenuating mutations. Here, we summarize the molecular mechanism of HSV entry and recent advances in the development of fully retargeted HSV vectors for oncolytic virotherapy. Retargeted HSV vectors offer an attractive platform for the creation of a new generation of oncolytic HSV with improved efficacy and specificity. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Identification of a small molecule that inhibits herpes simplex virus DNA Polymerase subunit interactions and viral replication.

PubMed

Pilger, Beatrice D; Cui, Can; Coen, Donald M

2004-05-01

The interaction between the catalytic subunit Pol and the processivity subunit UL42 of herpes simplex virus DNA polymerase has been characterized structurally and mutationally and is a potential target for novel antiviral drugs. We developed and validated an assay for small molecules that could disrupt the interaction of UL42 and a Pol-derived peptide and used it to screen approximately 16,000 compounds. Of 37 "hits" identified, four inhibited UL42-stimulated long-chain DNA synthesis by Pol in vitro, of which two exhibited little inhibition of polymerase activity by Pol alone. One of these specifically inhibited the physical interaction of Pol and UL42 and also inhibited viral replication at concentrations below those that caused cytotoxic effects. Thus, a small molecule can inhibit this protein-protein interaction, which provides a starting point for the discovery of new antiviral drugs.

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

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

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.

Novel Composite Efficacy Measure To Demonstrate the Rationale and Efficacy of Combination Antiviral–Anti-Inflammatory Treatment for Recurrent Herpes Simplex Labialis

PubMed Central

Levin, Myron J.; Tyring, Stephen K.; Spruance, Spotswood L.

2014-01-01

Historically, the primary target for research and treatment of recurrent herpes simplex labialis (HSL) has been limited to inhibiting herpes simplex virus (HSV) replication. Antiviral monotherapy, however, has proven only marginally effective in curtailing the duration and severity of recurrent lesions. Recently, the role of inflammation in the progression and resolution of recurrences has been identified as an additional target. This was evaluated in a randomized study comparing combination topical 5% acyclovir-1% hydrocortisone cream (AHC) with 5% acyclovir alone (AC; in the AHC vehicle) and the vehicle. The efficacy of each topical therapy was evaluated for cumulative lesion size—a novel composite efficacy endpoint incorporating episode duration, lesion area, and proportion of nonulcerative lesions. In that study, cumulative lesion area was significantly decreased with AHC compared with AC (25% decrease; P < 0.05) and the vehicle (50% decrease; P < 0.0001). As research continues in this arena, cumulative lesion area should be included as a measure of efficacy in clinical trials of recurrent HSL therapies. PMID:24342632

HSV Recombinant Vectors for Gene Therapy

PubMed Central

Manservigi, Roberto; Argnani, Rafaela; Marconi, Peggy

2010-01-01

The very deep knowledge acquired on the genetics and molecular biology of herpes simplex virus (HSV), has allowed the development of potential replication-competent and replication-defective vectors for several applications in human healthcare. These include delivery and expression of human genes to cells of the nervous systems, selective destruction of cancer cells, prophylaxis against infection with HSV or other infectious diseases, and targeted infection to specific tissues or organs. Replication-defective recombinant vectors are non-toxic gene transfer tools that preserve most of the neurotropic features of wild type HSV-1, particularly the ability to express genes after having established latent infections, and are thus proficient candidates for therapeutic gene transfer settings in neurons. A replication-defective HSV vector for the treatment of pain has recently entered in phase 1 clinical trial. Replication-competent (oncolytic) vectors are becoming a suitable and powerful tool to eradicate brain tumours due to their ability to replicate and spread only within the tumour mass, and have reached phase II/III clinical trials in some cases. The progress in understanding the host immune response induced by the vector is also improving the use of HSV as a vaccine vector against both HSV infection and other pathogens. This review briefly summarizes the obstacle encountered in the delivery of HSV vectors and examines the various strategies developed or proposed to overcome such challenges. PMID:20835362

HSV as a vector in vaccine development and gene therapy.

PubMed

Marconi, Peggy; Argnani, Rafaela; Epstein, Alberto L; Manservigi, Roberto

2009-01-01

The very deep knowledge acquired on the genetics and molecular biology of herpes simplex virus (HSV), major human pathogen whose lifestyle is based on a long-term dual interaction with the infected host characterized by the existence of lytic and latent infections, has allowed the development of potential vectors for several applications in human healthcare. These include delivery and expression of human genes to cells of the nervous system, selective destruction of cancer cells, prophylaxis against infection with HSV or other infectious diseases and targeted infection of specific tissues or organs. Three different classes of vectors can be derived from HSV-1: replication-competent attenuated vectors, replication-incompetent recombinant vectors and defective helper-dependent vectors known as amplicons. This chapter highlights the current knowledge concerning design, construction and recent applications, as well as the potential and current limitations of the three different classes of HSV-1-based vectors.

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

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 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.

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

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.

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.

Helicase-primase inhibitor amenamevir for herpesvirus infection: Towards practical application for treating herpes zoster.

PubMed

Shiraki, K

2017-11-01

Valacyclovir and famciclovir enabled successful systemic therapy for treating herpes simplex virus (HSV) and varicella zoster virus (VZV) infection by their phosphorylation with viral thymidine kinase. Helicase-primase inhibitors (HPIs) inhibit the progression of the replication fork, an initial step in DNA synthesis to separate the double strand into two single strands. The HPIs amenamevir and pritelivir have a novel mechanism of action, once-daily administration with nonrenal excretory characteristics, and clinical efficacy for genital herpes. Amenamevir exhibits anti-VZV and anti-HSV activity while pritelivir only has anti-HSV activity. A clinical trial of amenamevir for herpes zoster has been completed, and amenamevir has been licensed and successfully used in 20,000 patients with herpes zoster so far in Japan. We have characterized the features of the antiviral action of amenamevir and, unlike acyclovir, the drug's antiviral activity is not influenced by the viral replication cycle. Amenamevir is opening a new era of antiherpes therapy. Copyright 2017 Clarivate Analytics.

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.

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.

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

Unusual Clinical Presentation and Role of Decompressive Craniectomy in Herpes Simplex Encephalitis.

PubMed

Singhi, Pratibha; Saini, Arushi Gahlot; Sahu, Jitendra Kumar; Kumar, Nuthan; Vyas, Sameer; Vasishta, Rakesh Kumar; Aggarwal, Ashish

2015-08-01

Decompressive craniectomy in pediatric central nervous infections with refractory intracranial hypertension is less commonly practiced. We describe improved outcome of decompressive craniectomy in a 7-year-old boy with severe herpes simplex encephalitis and medically refractory intracranial hypertension, along with a brief review of the literature. Timely recognition of refractory intracranial hypertension and surgical decompression in children with herpes simplex encephalitis can be life-saving. Additionally, strokelike atypical presentations are being increasingly recognized in children with herpes simplex encephalitis and should not take one away from the underlying herpes simplex encephalitis. © The Author(s) 2014.

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

Topical treatment of herpes simplex virus infection with enzymatically created siRNA swarm.

PubMed

Paavilainen, Henrik; Lehtinen, Jenni; Romanovskaya, Alesia; Nygårdas, Michaela; Bamford, Dennis H; Poranen, Minna M; Hukkanen, Veijo

2017-01-01

Herpes simplex virus (HSV) is a common human pathogen. Despite current antivirals, it causes a significant medical burden. Drug resistant strains exist and they are especially prevalent in immunocompromised patients and in HSV eye infections. New treatment modalities are needed. BALB/c mice were corneally infected with HSV and subsequently treated with a swarm of enzymatically created, Dicer-substrate small interfering RNA (siRNA) molecules that targeted the HSV gene UL29. Two infection models were used, one in which the infection was predominantly peripheral and another in which it spread to the central nervous system. Mouse survival, as well as viral spread, load, latency and peripheral shedding, was studied. The anti-HSV-UL29 siRNA swarm alleviated HSV infection symptoms, inhibited viral shedding and replication and had a favourable effect on mouse survival. Treatment with anti-HSV-UL29 siRNA swarm reduced symptoms and viral spread in HSV infection of mice and also inhibited local viral replication in mouse corneas.

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.

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.

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

Herpes Simplex Virus 1 Reactivates from Autonomic Ciliary Ganglia Independently from Sensory Trigeminal Ganglia To Cause Recurrent Ocular Disease

PubMed Central

Lee, Sungseok; Ives, Angela M.

2015-01-01

ABSTRACT Herpes simplex virus 1 (HSV-1) and HSV-2 establish latency in sensory and autonomic neurons after ocular or genital infection, but their recurrence patterns differ. HSV-1 reactivates from latency to cause recurrent orofacial disease, and while HSV-1 also causes genital lesions, HSV-2 recurs more efficiently in the genital region and rarely causes ocular disease. The mechanisms regulating these anatomical preferences are unclear. To determine whether differences in latent infection and reactivation in autonomic ganglia contribute to differences in HSV-1 and HSV-2 anatomical preferences for recurrent disease, we compared HSV-1 and HSV-2 clinical disease, acute and latent viral loads, and viral gene expression in sensory trigeminal and autonomic superior cervical and ciliary ganglia in a guinea pig ocular infection model. HSV-2 produced more severe acute disease, correlating with higher viral DNA loads in sensory and autonomic ganglia, as well as higher levels of thymidine kinase expression, a marker of productive infection, in autonomic ganglia. HSV-1 reactivated in ciliary ganglia, independently from trigeminal ganglia, to cause more frequent recurrent symptoms, while HSV-2 replicated simultaneously in autonomic and sensory ganglia to cause more persistent disease. While both HSV-1 and HSV-2 expressed the latency-associated transcript (LAT) in the trigeminal and superior cervical ganglia, only HSV-1 expressed LAT in ciliary ganglia, suggesting that HSV-2 is not reactivation competent or does not fully establish latency in ciliary ganglia. Thus, differences in replication and viral gene expression in autonomic ganglia may contribute to differences in HSV-1 and HSV-2 acute and recurrent clinical disease. IMPORTANCE Herpes simplex virus 1 (HSV-1) and HSV-2 establish latent infections, from which the viruses reactivate to cause recurrent disease throughout the life of the host. However, the viruses exhibit different manifestations and frequencies of recurrent disease. HSV-1 and HSV-2 establish latency in both sensory and autonomic ganglia. Autonomic ganglia are more responsive than sensory ganglia to stimuli associated with recurrent disease in humans, such as stress and hormone fluctuations, suggesting that autonomic ganglia may play an important role in recurrent disease. We show that HSV-1 can reactivate from autonomic ganglia, independently from sensory ganglia, to cause recurrent ocular disease. We found no evidence that HSV-2 could reactivate from autonomic ganglia independently from sensory ganglia after ocular infection, but HSV-2 did replicate in both ganglia simultaneously to cause persistent disease. Thus, viral replication and reactivation in autonomic ganglia contribute to different clinical disease manifestations of HSV-1 and HSV-2 after ocular infection. PMID:26041294

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

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

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 ...

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

Antiviral drug resistance and helicase-primase inhibitors of herpes simplex virus.

PubMed

Field, Hugh J; Biswas, Subhajit

2011-02-01

A new class of chemical inhibitors has been discovered that interferes with the process of herpesvirus DNA replication. To date, the majority of useful herpesvirus antivirals are nucleoside analogues that block herpesvirus DNA replication by targeting the DNA polymerase. The new helicase-primase inhibitors (HPI) target a different enzyme complex that is also essential for herpesvirus DNA replication. This review will place the HPI in the context of previous work on the nucleoside analogues. Several promising highly potent HPI will be described with a particular focus on the identification of drug-resistance mutations. Several HPI have good pharmacological profiles and are now at the outset of phase II clinical trials. Provided there are no safety issues to stop their progress, this new class of compound will be a major advance in the herpesvirus antiviral field. Furthermore, HPI are likely to have a major impact on the therapy and prevention of herpes simplex virus and varicella zoster in both immunocompetent and immunocompromised patients alone or in combination with current nucleoside analogues. The possibility of acquired drug-resistance to HPI will then become an issue of great practical importance. Copyright © 2010 Elsevier Ltd. All rights reserved.

Identification of two novel functional p53 responsive elements in the Herpes Simplex Virus-1 genome

PubMed Central

Hsieh, Jui-Cheng; Kuta, Ryan; Armour, Courtney R.; Boehmer, Paul E.

2014-01-01

Analysis of the herpes simplex virus-1 (HSV-1) genome reveals two candidate p53 responsive elements (p53RE), located in proximity to the replication origins oriL and oriS, referred to as p53RE-L and p53RE-S, respectively. The sequences of p53RE-L and p53RE-S conform to the p53 consensus site and are present in HSV-1 strains KOS, 17, and F. p53 binds to both elements in vitro and in virus-infected cells. Both p53RE-L and p53RE-S are capable of conferring p53-dependent transcriptional activation onto a heterologous reporter gene. Importantly, expression of the essential immediate early viral transactivator ICP4 and the essential DNA replication protein ICP8, that are adjacent to p53RE-S and p53RE-L, are repressed in a p53-dependent manner. Taken together, this study identifies two novel functional p53RE in the HSV-1 genome and suggests a complex mechanism of viral gene regulation by p53 which may determine progression of the lytic viral replication cycle or the establishment of latency. PMID:25010269

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

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.

Herpes simplex virus VP16, but not ICP0, is required to reduce histone occupancy and enhance histone acetylation on viral genomes in U2OS osteosarcoma cells.

PubMed

Hancock, Meaghan H; Cliffe, Anna R; Knipe, David M; Smiley, James R

2010-02-01

The herpes simplex virus (HSV) genome rapidly becomes associated with histones after injection into the host cell nucleus. The viral proteins ICP0 and VP16 are required for efficient viral gene expression and have been implicated in reducing the levels of underacetylated histones on the viral genome, raising the possibility that high levels of underacetylated histones inhibit viral gene expression. The U2OS osteosarcoma cell line is permissive for replication of ICP0 and VP16 mutants and appears to lack an innate antiviral repression mechanism present in other cell types. We therefore used chromatin immunoprecipitation to determine whether U2OS cells are competent to load histones onto HSV DNA and, if so, whether ICP0 and/or VP16 are required to reduce histone occupancy and enhance acetylation in this cell type. High levels of underacetylated histone H3 accumulated at several locations on the viral genome in the absence of VP16 activation function; in contrast, an ICP0 mutant displayed markedly reduced histone levels and enhanced acetylation, similar to wild-type HSV. These results demonstrate that U2OS cells are competent to load underacetylated histones onto HSV DNA and uncover an unexpected role for VP16 in modulating chromatin structure at viral early and late loci. One interpretation of these findings is that ICP0 and VP16 affect viral chromatin structure through separate pathways, and the pathway targeted by ICP0 is defective in U2OS cells. We also show that HSV infection results in decreased histone levels on some actively transcribed genes within the cellular genome, demonstrating that viral infection alters cellular chromatin structure.

Herpes Simplex Virus VP16, but Not ICP0, Is Required To Reduce Histone Occupancy and Enhance Histone Acetylation on Viral Genomes in U2OS Osteosarcoma Cells▿ †

PubMed Central

Hancock, Meaghan H.; Cliffe, Anna R.; Knipe, David M.; Smiley, James R.

2010-01-01

The herpes simplex virus (HSV) genome rapidly becomes associated with histones after injection into the host cell nucleus. The viral proteins ICP0 and VP16 are required for efficient viral gene expression and have been implicated in reducing the levels of underacetylated histones on the viral genome, raising the possibility that high levels of underacetylated histones inhibit viral gene expression. The U2OS osteosarcoma cell line is permissive for replication of ICP0 and VP16 mutants and appears to lack an innate antiviral repression mechanism present in other cell types. We therefore used chromatin immunoprecipitation to determine whether U2OS cells are competent to load histones onto HSV DNA and, if so, whether ICP0 and/or VP16 are required to reduce histone occupancy and enhance acetylation in this cell type. High levels of underacetylated histone H3 accumulated at several locations on the viral genome in the absence of VP16 activation function; in contrast, an ICP0 mutant displayed markedly reduced histone levels and enhanced acetylation, similar to wild-type HSV. These results demonstrate that U2OS cells are competent to load underacetylated histones onto HSV DNA and uncover an unexpected role for VP16 in modulating chromatin structure at viral early and late loci. One interpretation of these findings is that ICP0 and VP16 affect viral chromatin structure through separate pathways, and the pathway targeted by ICP0 is defective in U2OS cells. We also show that HSV infection results in decreased histone levels on some actively transcribed genes within the cellular genome, demonstrating that viral infection alters cellular chromatin structure. PMID:19939931

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

DNA immunization against experimental genital herpes simplex virus infection.

PubMed

Bourne, N; Stanberry, L R; Bernstein, D I; Lew, D

1996-04-01

A nucleic acid vaccine, expressing the gene encoding herpes simplex virus (HSV) type 2 glycoprotein D (gD2) under control of the cytomegalovirus immediate-early gene promoter, was used to immunize guinea pigs against genital HSV-2 infection. The vaccine elicited humoral immune responses comparable to those seen after HSV-2 infection. Immunized animals exhibited protection from primary genital HSV-2 disease with little or no development of vesicular skin lesions and significantly reduced HSV-2 replication in the genital tract. After recovery from primary infection, immunized guinea pigs experienced significantly fewer recurrences and had significantly less HSV-2 genomic DNA detected in the sacral dorsal root ganglia compared with control animals. Thus, immunization reduced the burden of latent infection resulting from intravaginal HSV-2 challenge, and a nucleic acid vaccine expressing the HSV-2 gD2 antigen protected guinea pigs against genital herpes, limiting primary infection and reducing the magnitude of latent infection and the frequency of recurrent disease.

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.

[Meningoradiculitis caused by herpes simplex virus type 2].

PubMed

Bollen, A E; Venema, A W; Veldkamp, K E

2007-10-27

A 24-year-old immune-competent woman was admitted to hospital with a three-day history of fever and headache. On examination bilateral facial nerve palsy, lumbosacral radicular pain, reduced sacral sensibility and urinary retention were found. Open perianal lesions were suspect for genital herpes. The symptoms were compatible with a meningoradiculitis including a sacral polyradiculitis. On testing, cerebrospinal fluid was found to be abnormal with a lymphocytic cell reaction. Polymerase chain reaction (PCR) of cerebrospinal fluid and of the perianal lesions was positive for herpes simplex virus type 2 (HSV-2). An MRI scan showed colouration of part of the cauda equina. The patient was treated by intravenous injections of acyclovir 10 mg/kg t.i.d. for 21 days, after which she completely recovered. HSV-2 infection of the nervous system can cause lymphocytic, and sometimes recurrent meningitis as well as sacral polyradiculitis. It may also occur without any symptomatic genital herpes infection. A positive result from a PCR test of the cerebrospinal fluid confirms this diagnosis. Treatment with acyclovir should be started as soon as possible.

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.

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.

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.

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

Screening and identification of host factors interacting with UL14 of herpes simplex virus 1.

PubMed

Wu, Fuqing; Xing, Junji; Wang, Shuai; Li, Meili; Zheng, Chunfu

2011-08-01

The UL14 protein of herpes simplex virus type 1 (HSV-1) is highly conserved in herpesvirus family. However, its exact function during the HSV-1 replication cycle is little known. In the present study, a high throughput yeast two-hybrid system was employed to screen the cellular factors interacting with UL14, and five target candidates were yielded: (1) TSC22 domain family protein 3 (TSC22D3); (2) Mediator of RNA polymerase II transcription subunit 8 isoform 1(MED8); (3) Runt-related transcription factor 3 (RUNX3); (4) Arrestin beta-2 (ARRB2); (5) Cereblon (CRBN). Indirect immunofluorescent assay showed that both TSC22D3 and MED8 co-localized with UL14. Co-immunoprecipitation assay demonstrated that UL14 could be immunoprecipitated by TSC22D3, suggesting that UL14 interacted with TSC22D3 under physiological condition. In summary, this study opened up new avenues toward delineating the function and physiological significance of UL14 during the HSV-1 replication cycle.

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.

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.

Expression of IFN-Inducible Genes with Antiviral Function OAS1 and MX1 in Health and under Conditions of Recurrent Herpes Simplex Infection.

PubMed

Karaulov, A V; Shulzhenko, A E; Karsonova, A V

2017-07-01

We studied the expression of IFN-inducible genes OAS1 and Mx1 in lysates of peripheral blood mononuclear cells from patients suffering from recurrent Herpes simplex infections in comparison with healthy people. To induce the expression of the studied genes, blood mononuclears were incubated with recombinant IFN-α2b in concentrations of 1, 10, and 100 U/ml for 3 h and then the content of the studied transcripts was evaluated. Relative expression of OAS1 and Mx1 in patients with recurrent forms of Herpes simplex both during the acute stage and clinical remission did not differ significantly from that in healthy people after stimulation with IFN-α2b in a concentration of 1 U/ml and in higher concentrations (10 and 100 U/ml). It was concluded that intracellular signal transduction in IFN-α-activated cells in vitro was not disturbed in patients with recurrent forms of Herpes simplex infection. Thus, the reported phenomenon of IFN-signalling distortion by Herpes simplex virus proteins observed in experiments on model cell lines infected with Herpes simplex virus was not confirmed in our experiments on peripheral blood mononuclear cells from patients with Herpes simplex infection.

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 of host cell proteins which interact with herpes simplex virus type 1 tegument protein pUL37.

PubMed

Kelly, Barbara J; Diefenbach, Eve; Fraefel, Cornel; Diefenbach, Russell J

2012-01-20

The herpes simplex virus type 1 (HSV-1) structural tegument protein pUL37, which is conserved across the Herpesviridae family, is known to be essential for secondary envelopment during the egress of viral particles. To shed light on additional roles of pUL37 during viral replication a yeast two-hybrid screen of a human brain cDNA library was undertaken. This screen identified ten host cell proteins as potential pUL37 interactors. One of the interactors, serine threonine kinase TAOK3, was subsequently confirmed to interact with pUL37 using an in vitro pulldown assay. Such host cell/pUL37 interactions provide further insights into the multifunctional role of this herpesviral tegument protein. Copyright © 2011 Elsevier Inc. All rights reserved.

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.

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.

Intrinsic Innate Immunity Fails To Control Herpes Simplex Virus and Vesicular Stomatitis Virus Replication in Sensory Neurons and Fibroblasts

PubMed Central

Rosato, Pamela C.

2014-01-01

ABSTRACT Herpes simplex virus 1 (HSV-1) establishes lifelong latent infections in the sensory neurons of the trigeminal ganglia (TG), wherein it retains the capacity to reactivate. The interferon (IFN)-driven antiviral response is critical for the control of HSV-1 acute replication. We therefore sought to further investigate this response in TG neurons cultured from adult mice deficient in a variety of IFN signaling components. Parallel experiments were also performed in fibroblasts isolated concurrently. We showed that HSV-1 replication was comparable in wild-type (WT) and IFN signaling-deficient neurons and fibroblasts. Unexpectedly, a similar pattern was observed for the IFN-sensitive vesicular stomatitis virus (VSV). Despite these findings, TG neurons responded to IFN-β pretreatment with STAT1 nuclear localization and restricted replication of both VSV and an HSV-1 strain deficient in γ34.5, while wild-type HSV-1 replication was unaffected. This was in contrast to fibroblasts in which all viruses were restricted by the addition of IFN-β. Taken together, these data show that adult TG neurons can mount an effective antiviral response only if provided with an exogenous source of IFN-β, and HSV-1 combats this response through γ34.5. These results further our understanding of the antiviral response of neurons and highlight the importance of paracrine IFN-β signaling in establishing an antiviral state. IMPORTANCE Herpes simplex virus 1 (HSV-1) is a ubiquitous virus that establishes a lifelong latent infection in neurons. Reactivation from latency can cause cold sores, blindness, and death from encephalitis. Humans with deficiencies in innate immunity have significant problems controlling HSV infections. In this study, we therefore sought to elucidate the role of neuronal innate immunity in the control of viral infection. Using neurons isolated from mice, we found that the intrinsic capacity of neurons to restrict virus replication was unaffected by the presence or absence of innate immunity. In contrast, neurons were able to mount a robust antiviral response when provided with beta interferon, a molecule that strongly stimulates innate immunity, and that HSV-1 can combat this response through the γ34.5 viral gene. Our results have important implications for understanding how the nervous system defends itself against virus infections. PMID:24942587

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.

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.

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

The replicative DNA polymerase of herpes simplex virus 1 exhibits apurinic/apyrimidinic and 5′-deoxyribose phosphate lyase activities

PubMed Central

Bogani, Federica; Boehmer, Paul E.

2008-01-01

Base excision repair (BER) is essential for maintaining genome stability both to counter the accumulation of unusual bases and to protect from base loss in the DNA. Herpes simplex virus 1 (HSV-1) is a large dsDNA virus that encodes its own DNA replication machinery, including enzymes involved in nucleotide metabolism. We report on a replicative family B and a herpesvirus-encoded DNA Pol that possesses DNA lyase activity. We have discovered that the catalytic subunit of the HSV-1 DNA polymerase (Pol) (UL30) exhibits apurinic/apyrimidinic (AP) and 5′-deoxyribose phosphate (dRP) lyase activities. These activities are integral to BER and lead to DNA cleavage on the 3′ side of abasic sites and 5′-dRP residues that remain after cleavage by 5′-AP endonuclease. The UL30-catalyzed reaction occurs independently of divalent cation and proceeds via a Schiff base intermediate, indicating that it occurs via a lyase mechanism. Partial proteolysis of the Schiff base shows that the DNA lyase activity resides in the Pol domain of UL30. These observations together with the presence of a virus-encoded uracil DNA glycosylase indicates that HSV-1 has the capacity to perform critical steps in BER. These findings have implications on the role of BER in viral genome maintenance during lytic replication and reactivation from latency. PMID:18695225

Identification of two novel functional p53 responsive elements in the herpes simplex virus-1 genome.

PubMed

Hsieh, Jui-Cheng; Kuta, Ryan; Armour, Courtney R; Boehmer, Paul E

2014-07-01

Analysis of the herpes simplex virus-1 (HSV-1) genome reveals two candidate p53 responsive elements (p53RE), located in proximity to the replication origins oriL and oriS, referred to as p53RE-L and p53RE-S, respectively. The sequences of p53RE-L and p53RE-S conform to the p53 consensus site and are present in HSV-1 strains KOS, 17, and F. p53 binds to both elements in vitro and in virus-infected cells. Both p53RE-L and p53RE-S are capable of conferring p53-dependent transcriptional activation onto a heterologous reporter gene. Importantly, expression of the essential immediate early viral transactivator ICP4 and the essential DNA replication protein ICP8, that are adjacent to p53RE-S and p53RE-L, are repressed in a p53-dependent manner. Taken together, this study identifies two novel functional p53RE in the HSV-1 genome and suggests a complex mechanism of viral gene regulation by p53 which may determine progression of the lytic viral replication cycle or the establishment of latency. Copyright © 2014 Elsevier Inc. All rights reserved.

Protein arginine methyltransferase 1 regulates herpes simplex virus replication through ICP27 RGG-box methylation

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

Yu, Jungeun; Shin, Bongjin; Park, Eui-Soon

2010-01-01

Protein arginine methylation is involved in viral infection and replication through the modulation of diverse cellular processes including RNA metabolism, cytokine signaling, and subcellular localization. It has been suggested previously that the protein arginine methylation of the RGG-box of ICP27 is required for herpes simplex virus type-1 (HSV-1) viral replication and gene expression in vivo. However, a cellular mediator for this process has not yet been identified. In our current study, we show that the protein arginine methyltransferase 1 (PRMT1) is a cellular mediator of the arginine methylation of ICP27 RGG-box. We generated arginine substitution mutants in this domain andmore » examined which arginine residues are required for methylation by PRMT1. R138, R148 and R150 were found to be the major sites of this methylation but additional arginine residues serving as minor methylation sites are still required to sustain the fully methylated form of ICP27 RGG. We also demonstrate that the nuclear foci-like structure formation, SRPK interactions, and RNA-binding activity of ICP27 are modulated by the arginine methylation of the ICP27 RGG-box. Furthermore, HSV-1 replication is inhibited by hypomethylation of this domain resulting from the use of general PRMT inhibitors or arginine mutations. Our data thus suggest that the PRMT1 plays a key role as a cellular regulator of HSV-1 replication through ICP27 RGG-box methylation.« less

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.

Engineering HSV-1 vectors for gene therapy.

PubMed

Goins, William F; Huang, Shaohua; Cohen, Justus B; Glorioso, Joseph C

2014-01-01

Virus vectors have been employed as gene transfer vehicles for various preclinical and clinical gene therapy applications, and with the approval of Glybera (alipogene tiparvovec) as the first gene therapy product as a standard medical treatment (Yla-Herttuala, Mol Ther 20: 1831-1832, 2013), gene therapy has reached the status of being a part of standard patient care. Replication-competent herpes simplex virus (HSV) vectors that replicate specifically in actively dividing tumor cells have been used in Phase I-III human trials in patients with glioblastoma multiforme, a fatal form of brain cancer, and in malignant melanoma. In fact, T-VEC (talimogene laherparepvec, formerly known as OncoVex GM-CSF) displayed efficacy in a recent Phase III trial when compared to standard GM-CSF treatment alone (Andtbacka et al. J Clin Oncol 31: sLBA9008, 2013) and may soon become the second FDA-approved gene therapy product used in standard patient care. In addition to the replication-competent oncolytic HSV vectors like T-VEC, replication-defective HSV vectors have been employed in Phase I-II human trials and have been explored as delivery vehicles for disorders such as pain, neuropathy, and other neurodegenerative conditions. Research during the last decade on the development of HSV vectors has resulted in the engineering of recombinant vectors that are totally replication defective, nontoxic, and capable of long-term transgene expression in neurons. This chapter describes methods for the construction of recombinant genomic HSV vectors based on the HSV-1 replication-defective vector backbones, steps in their purification, and their small-scale production for use in cell culture experiments as well as preclinical animal studies.

Cell culture replication of herpes simplex virus and, or human cytomegalovirus is inhibited by 3,7-dialkoxylated, 1-hydroxyacridone derivatives.

PubMed

Lowden, C T; Bastow, K F

2003-08-01

The synthetic acridone compound, 5-chloro-1,3-dihydroxyacridone inhibits herpes simplex virus (HSV) replication by inducing the formation of defective viral (B-type) capsids [Antiviral Res. 53 (2002) 113]. In this report, synthetic elaboration of the 1-hydroxyacridone scaffold coupled with antiviral testing led to the identification of 3,7-dimethoxy-1-hydroxy-acridone (2) as an inhibitor of low multiplicity human cytomegalovirus (HCMV) infection (ED(50) value of 1.4 microM (0.5 microg/ml); greater than 35-fold selectivity). Compound 2 was inactive against HSV replication and the efficacy as an anti-HCMV agent at higher viral loads was only apparent if host cells were replicated in the presence of the compound prior to infection. Interestingly, the 3,5-dimethoxy regioisomer inhibited cell replication (mean CC(50) 33 microM) and was inactive as a selective anti-herpes agent. A limited parallel synthesis and testing of ten 3,7-dialkoxylated compounds closely related to compound 2 led to the discovery of the 3-ethoxy-, 3-propoxy-, 3-isopropoxy- and 3-allyloxy-derivatives as dual inhibitors of both HSV and HCMV (selectivity of the 3-allyloxy analog was greater than 10- and 36-fold, respectively). The 3-benzyloxy-derivative was active (ED(50) value of 6.9 microM) against HCMV only. Moreover, the corresponding C-7 variable alkoxylated parallel series were either weakly active or inactive antiviral agents suggesting an apparent requirement for a C-7 methoxy substituent in the active structure. Exploratory mode of action studies showed that dual inhibitors were most active against a low multiplicity HSV infection and potent inhibition of viral release likely contributed to this. Furthermore, suppression of late viral protein synthesis by dual inhibitors did not correlate with anti-HSV activity. On the basis of the present findings, the 1-hydroxyacridone scaffold is further expanded as a useful template for the discovery of investigational anti-herpes agents. As a group, the active 3,7-dialkoxylated compounds likely have diverse mechanisms of action, consequently they are of potential medicinal interest.

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.

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.

A trivalent subunit antigen glycoprotein vaccine as immunotherapy for genital herpes in the guinea pig genital infection model.

PubMed

Awasthi, Sita; Hook, Lauren M; Shaw, Carolyn E; Friedman, Harvey M

2017-12-02

An estimated 417 million people worldwide ages 15 to 49 are infected with herpes simplex virus type 2 (HSV-2), the most common cause of genital ulcer disease. Some individuals experience frequent recurrences of genital lesions, while others only have subclinical infection, yet all risk transmitting infection to their intimate partners. A vaccine was developed that prevents shingles, which is a recurrent infection caused by varicella-zoster virus (VZV), a closely related member of the Herpesviridae family. The success of the VZV vaccine has stimulated renewed interest in a therapeutic vaccine for genital herpes. We have been evaluating a trivalent subunit antigen vaccine for prevention of genital herpes. Here, we assess the trivalent vaccine as immunotherapy in guinea pigs that were previously infected intravaginally with HSV-2. The trivalent vaccine contains HSV-2 glycoproteins C, D, and E (gC2, gD2, gE2) subunit antigens administered with CpG and alum as adjuvants. We previously demonstrated that antibodies to gD2 neutralize the virus while antibodies to gC2 and gE2 block their immune evasion activities, including evading complement attack and inhibiting activities mediated by the IgG Fc domain, respectively. Here, we demonstrate that the trivalent vaccine significantly boosts ELISA titers and neutralizing antibody titers. The trivalent vaccine reduces the frequency of recurrent genital lesions and vaginal shedding of HSV-2 DNA by approximately 50% and almost totally eliminates vaginal shedding of replication-competent virus, suggesting that the trivalent vaccine is a worthy candidate for immunotherapy of genital herpes.

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

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

NASA Technical Reports Server (NTRS)

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

1992-01-01

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

Mathematical analysis demonstrates that interferons-β and -γ Interact in a multiplicative manner to disrupt herpes simplex virus replication

USGS Publications Warehouse

Halford, William P.; Halford, Keith J.; Pierce, Amy T.

2005-01-01

Several studies suggest that the innate interferons (IFNs), IFN-α and IFN-β, can act in concert with IFN-γto synergistically inhibit the replication of cytomegalovirus and herpes simplex virus type 1 (HSV-1). The significance of this observation is not yet agreed upon in large part because the nature and magnitude of the interaction between IFN-α/β and IFN-γ is not well defined. In the current study, we resolve this issue by demonstrating three points. First, the hyperbolic tangent function, tanh (x  ), can be used to describe the individual effects of IFN-β or IFN-γ on HSV-1 replication over a 320,000-fold range of IFN concentration. Second, pharmacological methods prove that IFN-β and IFN-γ interact in a greater-than-additive manner to inhibit HSV-1 replication. Finally, the potency with which combinations of IFN-β and IFN-γ inhibit HSV-1 replication is accurately predicted by multiplying the individual inhibitory effects of each cytokine. Thus, IFN-β and IFN-γ interact in a multiplicative manner. We infer that a primary antiviral function of IFN-γ lies in its capacity to multiply the potency with which IFN-α/β restricts HSV-1 replication in vivo. This hypothesis has important ramifications for understanding how T lymphocyte-secreted cytokines such as IFN-γ can force herpesviruses into a latent state without destroying the neurons or leukocytes that continue to harbor these viral infections for the lifetime of the host.

Herpes Simplex Virus Type 1 infection: overview on relevant clinico-pathological features.

PubMed

Arduino, Paolo G; Porter, Stephen R

2008-02-01

Herpes Simplex Virus Type 1 (HSV-1) is a nuclear replicating enveloped virus, usually acquired through direct contact with infected lesions or body fluids (typically saliva). The prevalence of HSV-1 infection increases progressively from childhood, the seroprevalence being inversely related to socioeconomic background. Primary HSV-1 infections in children are either asymptomatic or following an incubation period of about 1 week gives rise to mucocutaneous vesicular eruptions. Herpetic gingivostomatitis typically affects the tongue, lips, gingival, buccal mucosa and the hard and soft palate. Most primary oro-facial HSV infection is caused by HSV-1, infection by HSV-2 is increasingly common. Recurrent infections, which occur at variable intervals, typically give rise to vesiculo-ulcerative lesions at mucocutaneous junctions particularly the lips (herpes labialis). Recurrent HSV-1 infection within the mouth is uncommon in otherwise healthy patients, although in immunocompromised patients, recurrent infection can be more extensive and/or aggressive. The diagnosis of common herpetic infection can usually be based upon the clinical history and presenting features. Confirmatory laboratory diagnosis is, however, required when patients are, or may be, immunocompromised.

In vitro virucidal activity of a styrylpyrone derivative against herpes simplex virus strain KOS-1

NASA Astrophysics Data System (ADS)

Moses, Micheal; Nor, Norefrina Shafinaz Md.; Ibrahim, Nazlina

2014-09-01

In this study, styrylpyrone derivative (SPD) extracted from Goniothalamus umbrosus root was tested against herpes simplex virus (HSV) strain KOS-1. Firstly, the cytotoxicity of SPD on Vero cells was tested and the value of cytotoxic concentration, CC50, was 44 μM (8.88 μg/mL), and the 50% Effective Concentration, EC50, was 3.35 μM (0.67 μg/mL). Selectivity index of SPD against HSV Kos-1 was more than 13 indicating potential as antiviral agent. Three treatments were used in the antiviral test; 1) post-treatment, 2) pre-treatment, and 3) virucidal. The results revealed that the post-treatment was more effective in inhibiting viral replication compared to pre-treatment. The findings indicated that the SPD from G. umbrosus has good potential for prospective nature-based antiviral drug.

Ultraviolet irradiation of herpes simplex virus (type 1): delayed transcription and comparative sensitivites of virus functions.

PubMed

Eglin, R P; Gugerli, P; Wildy, P

1980-07-01

The delay in the replication of herpes simplex virus surviving u.v. irradiation occurs after the uncoating of virus, as judged by sensitivity to DNase. It occurs before translation, judged by the kinetics of appearance of various virus-specific proteins, and before transcription, judged by the detection of virus-specific RNA by in situ hybridization. Since the delays in both transcription and translation are reversed by photoreactivation, the simplest hypothesis is that pyrimidine dimers directly obstruct transcription;unless these are broken by photoreactivating enzymes, there will be transcriptional delay until reactivating processes have repaired the lesion. The u.v. sensitivities of the abilities to induce various enzymes (thymidine kinase, DNase and DNA polymerase) were only about four times less than that of infectivity. The The ability to induce the three enzymes was three times less sensitive than that of the structural antigen (Band II).

Herpes simplex virus 1 induces egress channels through marginalized host chromatin

DOE PAGES

Myllys, Markko; Ruokolainen, Visa; Aho, Vesa; ...

2016-06-28

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

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 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 (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 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.

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

PubMed

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

2015-10-01

The life cycle of herpes simplex virus (HSV) has the potential to be further manipulated to yield novel, more effective therapeutic treatments. Recent research has demonstrated that HSV-1 can increase telomerase activity and that expression of the catalytic component of telomerase, telomerase reverse transcriptase (TERT), alters sensitivity to HSV-dependent apoptosis. Telomerase is a cellular enzyme that synthesizes nucleotide repeats at the ends of chromosomes (telomeres), which prevents shortening of the 3' ends of DNA with each cell division. Once telomeres reach a critical length, cells undergo senescence and apoptosis. Here, we used a cell-permeable, reversible inhibitor of the telomerase enzyme, MST-312, to investigate telomerase activity during HSV infection. Human mammary epithelial cells immortalized through TERT expression and human carcinoma HEp-2 cells were infected with the KOS1.1 strain of HSV-1 in the presence of MST-312. MST-312 treatment reduced the number of cells displaying a cytopathic effect and the accumulation of immediate early and late viral proteins. Moreover, the presence of 20 μM to 100 μM MST-312 during infection led to a 2.5- to 5.5-log10 decrease in viral titers. MST-312 also inhibited the replication of HSV-2 and a recent clinical isolate of HSV-1. Additionally, we determined that MST-312 has the largest impact on viral events that take place prior to 5 h postinfection (hpi). Furthermore, MST-312 treatment inhibited virus replication, as measured by adsorption assays and quantification of genome replication. Together, these findings demonstrate that MST-312 interferes with the HSV life cycle. Further investigation into the mechanism for MST-312 is warranted and may provide novel targets for HSV therapies. Herpes simplex virus (HSV) infections can lead to cold sores, blindness, and brain damage. Identification of host factors that are important for the virus life cycle may provide novel targets for HSV antivirals. One such factor, telomerase, is the cellular enzyme that synthesizes DNA repeats at the ends of chromosomes during replication to prevent DNA shortening. In this study, we investigate role of telomerase in HSV infection. The data demonstrate that the telomerase inhibitor MST-312 suppressed HSV replication at multiple steps of viral infection. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

[Herpetic folliculitis barbae. A rare cause of folliculitis].

PubMed

Anliker, M D; Itin, P

2003-03-01

Viral folliculitis is a rare disease usually caused by herpes simplex, herpes zoster and molluscum contagiosum in immune-compromised patients. An otherwise healthy 30 year old patient without history of herpes simplex contracted a folliculitis in the beard region after a flu-like illness. He had no oral or labial lesions but instead showed a crusty erythematous folliculitis confined to the beard region with small grouped vesicles on the neck and reactive cervical lymph nodes. Bacterial and mycological analysis from swabs were negative. The culture was positive for herpes simplex virus and the immune fluorescence showed HSV type 1. Systemic therapy with valaciclovir 2x 500 mg/d and lotio alba locally led to rapid improvement. When confronted with folliculitis, non-bacterial causes such as viral (herpes simplex, herpes zoster, molluscum contagiosum), mycological (pityrosporon, candida), demodex and eosinophilic follicultitis should be taken under consideration.

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

Statistical analysis of Amenamevir (ASP2151) between pharmacokinetics and clinical efficacies with non-linear effect model for the treatment of genital herpes.

PubMed

Takada, Akitsugu; Katashima, Masataka; Kaibara, Atsunori; Sawamoto, Taiji; Zhang, Wenhui; Keirns, James

2014-09-01

Amenamevir is the international non-proprietary name for ASP2151 synthesized by Astellas Pharma, Inc. It is a structurally novel class of helicase-primase inhibitor and demonstrated more potency in vitro anti-viral activity with low cytotoxicity against varicella-zoster virus (VZV), herpes simplex virus type 1 (HSV-1), and herpes simplex virus type 2 (HSV-2) than acyclovir (ACV). Phase II randomized trial assessed the safety and efficacy of ASP2151 for episodic therapy of recurrent genital herpes was conducted. Participants self-initiated with ASP2151 (100, 200, or 400 mg daily for 3 days), ASP2151 (1,200 mg as a single dose), placebo for 3 days, or Valacyclovir (500 mg twice daily for 3 days). We present a first population pharmacokinetic (PPK) modeling analysis of Amenamevir for genital herpes patients. The final model retained the effect of Weight and Albumin on CL. Statistical analysis between pharmacokinetics and clinical efficacies was done by using the time above 200 ng/mL (T200 ). T200 derived from the final PPK model to consider the correlation with Time to lesion healing and viral shedding. This finding suggested that it could be necessary to maintain the Amenamevir concentration above the threshold level to prevent the virus replication. © 2014, The American College of Clinical Pharmacology.

Effects of RNA interference therapy against herpes simplex virus type 1 encephalitis.

PubMed

da Silva, Alexandre S; Raposo, Jéssica V; Pereira, Tiago C; Pinto, Marcelo A; de Paula, Vanessa S

2016-01-01

Herpetic encephalitis (HSE) is caused mainly by herpes simplex virus type 1 (HSV-1) with an annual incidence of 1-4 cases/million inhabitants. Currently, HSE treatment faces difficulties such as the use of antivirals with elevated toxicity, metabolic side effects and HSV-1 resistance. An alternative to antivirals is the use of small interfering RNA (siRNA) as a viral replication inhibitor. In this work, siRNA targeting the UL-39 region was evaluated for HSE treatment in vivo. BALB/c mice were inoculated with HSV-1 and treated with siRNA. The treatment was evaluated through kinetics of HSV-1 replication inhibition, number of siRNA doses administered and treatment with siRNA plus acyclovir. All groups were evaluated for signs of HSE, mortality and HSV-1 replication inhibition. The treated group of the kinetic experiment demonstrated a reduction of HSE signs and an HSV-1 replication inhibition of 43.6-99.9% in the brain and 53-98% in trigeminal ganglia (TG). Animals treated with one or two doses of siRNA had a prolonged survival time, reduced clinical signs of HSE and HSV-1 replication inhibition of 67.7% in brains and 85.7% in TG of animals treated with two doses of siRNA. Also, animals treated with siRNA plus acyclovir demonstrated reduced signs of HSE and mortality, as well as HSV-1 replication inhibition in the brain (83.2%) and TG (74.5%). These findings demonstrated that siRNA was capable of reducing HSE clinical signs, prolonging survival time and inhibiting HSV-1 replication in mice. Thus, siRNA can be a potential alternative to the standard HSE treatment especially to reduce clinical signs and extend survival time in vivo.

Electron Microscopic Analysis of the Products of DNA Synthesis by DNA Polymerases from Calf Thymus and Herpes Simplex Virus Type I

DTIC Science & Technology

1988-10-03

DNA replication showed an average of 2.5 primers per M13 DNA circle. The measurement of the double stranded length from individual replicative intermediates by electron microscopy was within the accuracy of 10% standard deviation. The product length distribution obtained from the HSV-1 DNA polymerase catalyzed replication of M13 DNA primed with a specific pentadecamer and in the presence of E. Coli SSB protein showed a near Poisson distribution. Replication of the same primer-template system or DNA primase primed M13 DNA template by calf thymus DNA polymerase a showed a

The serum and glucocorticoid-regulated protein kinases (SGK) stimulate bovine herpesvirus 1 and herpes simplex virus 1 productive infection.

PubMed

Kook, Insun; Jones, Clinton

2016-08-15

Serum and glucocorticoid-regulated protein kinases (SGK) are serine/threonine protein kinases that contain a catalytic domain resembling other protein kinases: AKT/protein kinase B, protein kinase A, and protein kinase C-Zeta for example. Unlike these constitutively expressed protein kinases, SGK1 RNA and protein levels are increased by growth factors and corticosteroids. Stress can directly stimulate SGK1 levels as well as stimulate bovine herpesvirus 1 (BoHV-1) and herpes simplex virus 1 (HSV-1) productive infection and reactivation from latency suggesting SGK1 can stimulate productive infection. For the first time, we provide evidence that a specific SGK inhibitor (GSK650394) significantly reduced BoHV-1 and HSV-1 replication in cultured cells. Proteins encoded by the three BoHV-1 immediate early genes (bICP0, bICP4, and bICP22) and two late proteins (VP16 and gE) were consistently reduced by GSK650394 during early stages of productive infection. In summary, these studies suggest SGK may stimulate viral replication following stressful stimuli. Copyright © 2016 Elsevier B.V. All rights reserved.

Herpes Simplex Virus DNA Packaging without Measurable DNA Synthesis

PubMed Central

Church, Geoffrey A.; Dasgupta, Anindya; Wilson, Duncan W.

1998-01-01

Herpes simplex virus (HSV) type 1 DNA synthesis and packaging occur within the nuclei of infected cells; however, the extent to which the two processes are coupled remains unclear. Correct packaging is thought to be dependent upon DNA debranching or other repair processes, and such events commonly involve new DNA synthesis. Furthermore, the HSV UL15 gene product, essential for packaging, nevertheless localizes to sites of active DNA replication and may link the two events. It has previously been difficult to determine whether packaging requires concomitant DNA synthesis due to the complexity of these processes and of the viral life cycle; however, we have recently described a model system which simplifies the study of HSV assembly. Cells infected with HSV strain tsProt.A accumulate unpackaged capsids at the nonpermissive temperature of 39°C. Following release of the temperature block, these capsids proceed to package viral DNA in a single, synchronous wave. Here we report that, when DNA replication was inhibited prior to release of the temperature block, DNA packaging and later events in viral assembly nevertheless occurred at near-normal levels. We conclude that, under our conditions, HSV DNA packaging does not require detectable levels of DNA synthesis. PMID:9525593

Rapid host immune response and viral dynamics in herpes simplex virus-2 infection

PubMed Central

Schiffer, Joshua T; Corey, Lawrence

2014-01-01

Herpes Simplex Virus-2 (HSV-2) is episodically shed throughout the human genital tract. While high viral load correlates with development of genital ulcers, shedding also commonly occurs even when ulcers are not present, allowing for silent transmission during coitus and contributing to high seroprevalence of HSV-2 worldwide. Frequent viral reactivation occurs despite diverse and complementary host and viral mechanisms within ganglionic tissue that predispose towards latency, suggesting that viral replication may be constantly occurring in a small minority of neurons within the ganglia. Within genital mucosa, the in vivo expansion and clearance rates of HSV-2 are extremely rapid. Resident dendritic cells and memory HSV-specific T cells persist at prior sites of genital tract reactivation, and in conjunction with prompt innate recognition of infected cells, lead to rapid containment of infected cells. Shedding episodes vary greatly in duration and severity within a single person over time: this heterogeneity appears best explained by variation in the densities of host immunity across the genital tract. The fact that immune responses usually control viral replication in genital skin prior to development of lesions provides optimism that enhancing such responses could lead to effective vaccines and immunotherapies. PMID:23467247

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

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.

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

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.

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.

An attenuated herpes simplex virus type 1 (HSV1) encoding the HIV-1 Tat protein protects mice from a deadly mucosal HSV1 challenge.

PubMed

Sicurella, Mariaconcetta; Nicoli, Francesco; Gallerani, Eleonora; Volpi, Ilaria; Berto, Elena; Finessi, Valentina; Destro, Federica; Manservigi, Roberto; Cafaro, Aurelio; Ensoli, Barbara; Caputo, Antonella; Gavioli, Riccardo; Marconi, Peggy C

2014-01-01

Herpes simplex virus types 1 and 2 (HSV1 and HSV2) are common infectious agents in both industrialized and developing countries. They cause recurrent asymptomatic and/or symptomatic infections, and life-threatening diseases and death in newborns and immunocompromised patients. Current treatment for HSV relies on antiviral medications, which can halt the symptomatic diseases but cannot prevent the shedding that occurs in asymptomatic patients or, consequently, the spread of the viruses. Therefore, prevention rather than treatment of HSV infections has long been an area of intense research, but thus far effective anti-HSV vaccines still remain elusive. One of the key hurdles to overcome in anti-HSV vaccine development is the identification and effective use of strategies that promote the emergence of Th1-type immune responses against a wide range of epitopes involved in the control of viral replication. Since the HIV1 Tat protein has several immunomodulatory activities and increases CTL recognition of dominant and subdominant epitopes of heterologous antigens, we generated and assayed a recombinant attenuated replication-competent HSV1 vector containing the tat gene (HSV1-Tat). In this proof-of-concept study we show that immunization with this vector conferred protection in 100% of mice challenged intravaginally with a lethal dose of wild-type HSV1. We demonstrate that the presence of Tat within the recombinant virus increased and broadened Th1-like and CTL responses against HSV-derived T-cell epitopes and elicited in most immunized mice detectable IgG responses. In sharp contrast, a similarly attenuated HSV1 recombinant vector without Tat (HSV1-LacZ), induced low and different T cell responses, no measurable antibody responses and did not protect mice against the wild-type HSV1 challenge. These findings strongly suggest that recombinant HSV1 vectors expressing Tat merit further investigation for their potential to prevent and/or contain HSV1 infection and dissemination.

An Attenuated Herpes Simplex Virus Type 1 (HSV1) Encoding the HIV-1 Tat Protein Protects Mice from a Deadly Mucosal HSV1 Challenge

PubMed Central

Sicurella, Mariaconcetta; Nicoli, Francesco; Gallerani, Eleonora; Volpi, Ilaria; Berto, Elena; Finessi, Valentina; Destro, Federica; Manservigi, Roberto; Cafaro, Aurelio; Ensoli, Barbara; Caputo, Antonella; Gavioli, Riccardo; Marconi, Peggy C.

2014-01-01

Herpes simplex virus types 1 and 2 (HSV1 and HSV2) are common infectious agents in both industrialized and developing countries. They cause recurrent asymptomatic and/or symptomatic infections, and life-threatening diseases and death in newborns and immunocompromised patients. Current treatment for HSV relies on antiviral medications, which can halt the symptomatic diseases but cannot prevent the shedding that occurs in asymptomatic patients or, consequently, the spread of the viruses. Therefore, prevention rather than treatment of HSV infections has long been an area of intense research, but thus far effective anti-HSV vaccines still remain elusive. One of the key hurdles to overcome in anti-HSV vaccine development is the identification and effective use of strategies that promote the emergence of Th1-type immune responses against a wide range of epitopes involved in the control of viral replication. Since the HIV1 Tat protein has several immunomodulatory activities and increases CTL recognition of dominant and subdominant epitopes of heterologous antigens, we generated and assayed a recombinant attenuated replication-competent HSV1 vector containing the tat gene (HSV1-Tat). In this proof-of-concept study we show that immunization with this vector conferred protection in 100% of mice challenged intravaginally with a lethal dose of wild-type HSV1. We demonstrate that the presence of Tat within the recombinant virus increased and broadened Th1-like and CTL responses against HSV-derived T-cell epitopes and elicited in most immunized mice detectable IgG responses. In sharp contrast, a similarly attenuated HSV1 recombinant vector without Tat (HSV1-LacZ), induced low and different T cell responses, no measurable antibody responses and did not protect mice against the wild-type HSV1 challenge. These findings strongly suggest that recombinant HSV1 vectors expressing Tat merit further investigation for their potential to prevent and/or contain HSV1 infection and dissemination. PMID:25033084

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.

Calcium spirulan derived from Spirulina platensis inhibits herpes simplex virus 1 attachment to human keratinocytes and protects against herpes labialis.

PubMed

Mader, Julia; Gallo, Antonio; Schommartz, Tim; Handke, Wiebke; Nagel, Claus-Henning; Günther, Patrick; Brune, Wolfram; Reich, Kristian

2016-01-01

Chronic infections with herpes simplex virus (HSV) type 1 are highly prevalent in populations worldwide and cause recurrent oral lesions in up to 40% of infected subjects. We investigated the antiviral activity of a defined Spirulina platensis microalga extract and of purified calcium spirulan (Ca-SP), a sulfated polysaccharide contained therein. The inhibitory effects of HSV-1 were assessed by using a plaque reduction assay and quantitative PCR in a susceptible mammalian epithelial cell line and confirmed in human keratinocytes. Time-of-addition and attachment experiments and fluorescence detection of the HSV-1 tegument protein VP16 were used to analyze the mechanism of HSV-1 inhibition. Effects of Ca-SP on Kaposi sarcoma-associated herpesvirus/human herpes virus 8 replication and uptake of the ORF45 tegument protein were tested in human retinal pigment epithelial cells. In an observational trial the prophylactic effects of topically applied Ca-SP were compared with those of systemic and topical nucleoside analogues in 198 volunteers with recurrent herpes labialis receiving permanent lip makeup. Ca-SP inhibited HSV-1 infection in vitro with a potency at least comparable to that of acyclovir by blocking viral attachment and penetration into host cells. Ca-SP also inhibited entry of Kaposi sarcoma-associated herpesvirus/human herpes virus 8. In the clinical model of herpes exacerbation, the prophylactic effect of a Ca-SP and microalgae extract containing cream was superior to that of acyclovir cream. These data indicate a potential clinical use of Ca-SP containing Spirulina species extract for the prophylactic treatment of herpes labialis and suggest possible activity of Ca-SP against infections caused by other herpesviruses. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

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

PubMed Central

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

2015-01-01

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

Database of Autotransplants for Breast Cancer.

DTIC Science & Technology

1998-11-01

atypical bacteria in Q.79, 81.) 301 Herpes Simplex (HSV1, HSV2) 100 Atypical bacteria, not otherwise specified 302 Herpes Zoster ( Chicken pox , Varicella...100 Atypical bacteria, not otherwise specified 302 Herpes Zoster ( Chicken pox , Varicella) 101 Coxiella 303 Cytomegalovirus (CMV) 102 Legionella 304...atypical bacteria in Q.329, 330.) 301 Herpes Simplex (HSV1, HSV2) 100 Atypical bacteria, not otherwise specified 302 Herpes Zoster ( Chicken pox , Vadcella

CD11c controls herpes simplex virus 1 responses to limit virus replication during primary infection.

PubMed

Allen, Sariah J; Mott, Kevin R; Chentoufi, Aziz A; BenMohamed, Lbachir; Wechsler, Steven L; Ballantyne, Christie M; Ghiasi, Homayon

2011-10-01

CD11c is expressed on the surface of dendritic cells (DCs) and is one of the main markers for identification of DCs. DCs are the effectors of central innate immune responses, but they also affect acquired immune responses to infection. However, how DCs influence the efficacy of adaptive immunity is poorly understood. Here, we show that CD11c(+) DCs negatively orchestrate both adaptive and innate immunity against herpes simplex virus type 1 (HSV-1) ocular infection. The effectiveness and quantity of virus-specific CD8(+) T cell responses are increased in CD11c-deficient animals. In addition, the levels of CD83, CD11b, alpha interferon (IFN-α), and IFN-β, but not IFN-γ, were significantly increased in CD11c-deficient animals. Higher levels of IFN-α, IFN-β, and CD8(+) T cells in the CD11c-deficient mice may have contributed to lower virus replication in the eye and trigeminal ganglia (TG) during the early period of infection than in wild-type mice. However, the absence of CD11c did not influence survival, severity of eye disease, or latency. Our studies provide for the first time evidence that CD11c expression may abrogate the ability to reduce primary virus replication in the eye and TG via higher activities of type 1 interferon and CD8(+) T cell responses.

Human cytomegalovirus and Herpes Simplex type I virus can engage RNA polymerase I for transcription of immediate early genes

PubMed Central

Kostopoulou, Ourania N.; Wilhelmi, Vanessa; Raiss, Sina; Ananthaseshan, Sharan; Lindström, Mikael S.; Bartek, Jiri; Söderberg-Naucler, Cecilia

2017-01-01

Human cytomegalovirus (HCMV) utilizes RNA polymerase II to transcribe viral genes and produce viral mRNAs. It can specifically target the nucleolus to facilitate viral transcription and translation. As RNA polymerase I (Pol I)-mediated transcription is active in the nucleolus, we investigated the role of Pol I, along with relative contributions of the human Pol II and Pol III, to early phases of viral transcription in HCMV infected cells, compared with Herpes Simplex Virus-1 (HSV-1) and Murine cytomegalovirus (MCMV). Inhibition of Pol I with siRNA or the Pol I inhibitors CX-5461 or Actinomycin D (5nM) resulted in significantly decreased IE and pp65 mRNA and protein levels in human fibroblasts at early times post infection. This initially delayed replication was compensated for later during the replication process, at which stage it didn’t significantly affect virus production. Pol I inhibition also reduced HSV-1 ICP0 and gB transcripts, suggesting that some herpesviruses engage Pol I for their early transcription. In contrast, inhibition of Pol I failed to affect MCMV transcription. Collectively, our results contribute to better understanding of the functional interplay between RNA Pol I-mediated nucleolar events and the Herpes viruses, particularly HCMV whose pathogenic impact ranges from congenital malformations and potentially deadly infections among immunosuppressed patients, up to HCMV’s emerging oncomodulatory role in human tumors. PMID:29228551

[Ulcerating Herpes simplex infections in intensive care patients].

PubMed

Fischer, M; Wohlrab, J; Radke, J; Marsch, W C; Soukup, J

2002-11-01

Herpes simplex infections are potentially a life-threatening situation for immunocompromised as well as critically ill patients. The correct diagnosis is made more difficult in comatose patients by the fact that the characteristic symptom of extreme pain cannot be registered. The clinical dermatological findings (polycyclic configuration, easily bleeding ulcers) are thus especially important in patients under intensive care conditions. As examples, the cases of 3 critically ill patients (subarachnoid bleeding or head injury) developing therapy-resistant, flat sacral or perioral skin ulcers with peripheral blisters are presented. Herpes simplex virus was confirmed immunohistologically and in the smear test. All patients subsequently died. These cases emphasize that patients in the intensive care unit are in danger of developing a chronic persistent Herpes simplex infection due to latent immunosuppression. Chronic persistent Herpes infections may be underrated in intensive therapy, and must always be ruled out in case of therapy-resistant erosions or ulcerations.

A trivalent subunit antigen glycoprotein vaccine as immunotherapy for genital herpes in the guinea pig genital infection model

PubMed Central

Awasthi, Sita; Hook, Lauren M.; Shaw, Carolyn E.; Friedman, Harvey M.

2017-01-01

ABSTRACT An estimated 417 million people worldwide ages 15 to 49 are infected with herpes simplex virus type 2 (HSV-2), the most common cause of genital ulcer disease. Some individuals experience frequent recurrences of genital lesions, while others only have subclinical infection, yet all risk transmitting infection to their intimate partners. A vaccine was developed that prevents shingles, which is a recurrent infection caused by varicella-zoster virus (VZV), a closely related member of the Herpesviridae family. The success of the VZV vaccine has stimulated renewed interest in a therapeutic vaccine for genital herpes. We have been evaluating a trivalent subunit antigen vaccine for prevention of genital herpes. Here, we assess the trivalent vaccine as immunotherapy in guinea pigs that were previously infected intravaginally with HSV-2. The trivalent vaccine contains HSV-2 glycoproteins C, D, and E (gC2, gD2, gE2) subunit antigens administered with CpG and alum as adjuvants. We previously demonstrated that antibodies to gD2 neutralize the virus while antibodies to gC2 and gE2 block their immune evasion activities, including evading complement attack and inhibiting activities mediated by the IgG Fc domain, respectively. Here, we demonstrate that the trivalent vaccine significantly boosts ELISA titers and neutralizing antibody titers. The trivalent vaccine reduces the frequency of recurrent genital lesions and vaginal shedding of HSV-2 DNA by approximately 50% and almost totally eliminates vaginal shedding of replication-competent virus, suggesting that the trivalent vaccine is a worthy candidate for immunotherapy of genital herpes. PMID:28481687

A Potent Oncolytic Herpes Simplex Virus for Therapy of Advanced Prostate Cancer

DTIC Science & Technology

2005-07-01

DNA replication in the targeted cells. As oncolytic HSV can only initiate - viral replication in tumor cells, this restricts the syncytial formation from virus infection to malignant cells only. Therefore fusogenic oncolytic HSV should be no more toxic than its parental construct. Nonetheless, we proposed in the year 2 of this funded project to conduct extensive studies in animal models to confirm its safety in vivo. The results obtained so far from these experiments have demonstrated that the fusogenic oncolytic HSV is indeed not significantly more toxic than the

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.

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.

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.

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

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.

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

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...

[Primary genital herpes with sacral meningoradiculitis].

PubMed

Carron, P-N; Anguenot, J-L; Dubuisson, J-B

2004-02-01

Herpetic genital infection is a common sexually transmitted disease, caused in most cases by type 2 Herpes simplex virus (HSV2). This virus is characterized by its neurotropic properties and its ability to establish latency in sacral sensory ganglions. Some cases of genital primo-infection are complicated by viral replication dissemination to neigbhoring nerve structures like meninges and radicular terminations. In such cases muco-cutaneous manifestations are associated with peripheral neurological impairment in the form of meningo-radiculitis. Physicians should be familiar with these neurological symptoms knowing that they always regress completely. The present report illustrates these complications and reviews the potential neurological implications described in the literature.

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.

Breach of the nuclear lamina during assembly of herpes simplex viruses.

PubMed

Morrison, Lynda A; DeLassus, Gregory S

2011-01-01

Beneath the inner nuclear membrane lies the dense meshwork of the nuclear lamina, which provides structural support for the nuclear envelope and serves as an important organizing center for a number of nuclear and cytoplasmic constituents and processes. Herpesviruses have a significant and wide-ranging impact on human health, and their capacity to replicate and cause disease includes events that occur in the host cell nucleus. Herpesviruses begin assembly of progeny virus in the nuclei of infected cells and their capsids must escape the confines of the nucleus by budding through the inner nuclear membrane (INM) to proceed with later stages of virion assembly and egress. Access of viral capsids to the INM thus necessitates disruption of the dense nuclear lamina layer. We review herpesvirus effects on the nuclear lamina and in particular the roles of the herpes simplex virus-encoded nuclear envelope complex and viral kinases on lamin phosphorylation, dissociation, and nucleocapsid envelopment at the INM.

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.

CCCTC-Binding Factor Acts as a Heterochromatin Barrier on Herpes Simplex Viral Latent Chromatin and Contributes to Poised Latent Infection

PubMed Central

2018-01-01

ABSTRACT Herpes simplex virus 1 (HSV-1) establishes latent infection in neurons via a variety of epigenetic mechanisms that silence its genome. The cellular CCCTC-binding factor (CTCF) functions as a mediator of transcriptional control and chromatin organization and has binding sites in the HSV-1 genome. We constructed an HSV-1 deletion mutant that lacked a pair of CTCF-binding sites (CTRL2) within the latency-associated transcript (LAT) coding sequences and found that loss of these CTCF-binding sites did not alter lytic replication or levels of establishment of latent infection, but their deletion reduced the ability of the virus to reactivate from latent infection. We also observed increased heterochromatin modifications on viral chromatin over the LAT promoter and intron. We therefore propose that CTCF binding at the CTRL2 sites acts as a chromatin insulator to keep viral chromatin in a form that is poised for reactivation, a state which we call poised latency. PMID:29437926

Herpesvirus Entry into Host Cells Mediated by Endosomal Low pH.

PubMed

Nicola, Anthony V

2016-09-01

Herpesviral pathogenesis stems from infection of multiple cell types including the site of latency and cells that support lytic replication. Herpesviruses utilize distinct cellular pathways, including low pH endocytic pathways, to enter different pathophysiologically relevant target cells. This review details the impact of the mildly acidic milieu of endosomes on the entry of herpesviruses, with particular emphasis on herpes simplex virus 1 (HSV-1). Epithelial cells, the portal of primary HSV-1 infection, support entry via low pH endocytosis mechanisms. Mildly acidic pH triggers reversible conformational changes in the HSV-1 class III fusion protein glycoprotein B (gB). In vitro treatment of herpes simplex virions with a similar pH range inactivates infectivity, likely by prematurely activating the viral entry machinery in the absence of a target membrane. How a given herpesvirus mediates both low pH and pH-independent entry events is a key unresolved question. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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

Elements in the transcriptional regulatory region flanking herpes simplex virus type 1 oriS stimulate origin function.

PubMed

Wong, S W; Schaffer, P A

1991-05-01

Like other DNA-containing viruses, the three origins of herpes simplex virus type 1 (HSV-1) DNA replication are flanked by sequences containing transcriptional regulatory elements. In a transient plasmid replication assay, deletion of sequences comprising the transcriptional regulatory elements of ICP4 and ICP22/47, which flank oriS, resulted in a greater than 80-fold decrease in origin function compared with a plasmid, pOS-822, which retains these sequences. In an effort to identify specific cis-acting elements responsible for this effect, we conducted systematic deletion analysis of the flanking region with plasmid pOS-822 and tested the resulting mutant plasmids for origin function. Stimulation by cis-acting elements was shown to be both distance and orientation dependent, as changes in either parameter resulted in a decrease in oriS function. Additional evidence for the stimulatory effect of flanking sequences on origin function was demonstrated by replacement of these sequences with the cytomegalovirus immediate-early promoter, resulting in nearly wild-type levels of oriS function. In competition experiments, cotransfection of cells with the test plasmid, pOS-822, and increasing molar concentrations of a competitor plasmid which contained the ICP4 and ICP22/47 transcriptional regulatory regions but lacked core origin sequences resulted in a significant reduction in the replication efficiency of pOS-822, demonstrating that factors which bind specifically to the oriS-flanking sequences are likely involved as auxiliary proteins in oriS function. Together, these studies demonstrate that trans-acting factors and the sites to which they bind play a critical role in the efficiency of HSV-1 DNA replication from oriS in transient-replication assays.

Potent Oncolytic Herpes Simplex Virus for the Therapy of Advanced Prostate Cancer

DTIC Science & Technology

2007-07-01

are clearly needed to improve this situation. Conditionally replicating (oncolytic) viruses offer unique features as anticancer agents . In this funded...RESEARCH ACCOMPLISHMENTS • Both in vitro and in vivo studies show that the fusogenic oncolytic HSVs are potent antitumor agents against either primary...of fusogenic oncolytic HSVs in the presence of host’s anti -HSV immunity. • Co-administration of fusogenic oncolytic HSV-based virotherapy with

Activation of checkpoint kinase 2 is critical for herpes simplex virus type 1 replication in corneal epithelium.

PubMed

Alekseev, Oleg; Limonnik, Vladimir; Donovan, Kelly; Azizkhan-Clifford, Jane

2015-01-01

Herpes simplex virus (HSV) type I keratitis remains a leading cause of corneal morbidity, despite the availability of effective antiviral drugs. Improved understanding of virus-host interactions at the level of the host DNA damage response (DDR), a known factor in the development of HSV-1 keratitis, may shed light on potential new therapeutic targets. This report examines the role of checkpoint kinase 2 (Chk2), a DDR mediator protein, in corneal epithelial HSV-1 infection. A small-molecule inhibitor of Chk2 (Chk2 inhibitor II) was applied to HSV-1-infected cultured human corneal epithelial cells (hTCEpi and HCE) as well as to explanted and organotypically cultured human and rabbit corneas. Infection levels were assessed by plaque assay and real-time PCR. RNAi-mediated depletion of Chk2 was performed to confirm the effect of the inhibitor. Inhibition of the Chk2 kinase activity greatly suppresses the cytopathic effect, genome replication and infectious progeny production in vitro and ex vivo. This report demonstrates the critical role of Chk2 kinase in the establishment of HSV-1 corneal epithelial infection. These data contribute to our understanding of herpesvirus-host interactions and underscore the significance of DDR activation in HSV-1 keratitis.

Adaptive and Innate Transforming Growth Factor β Signaling Impact Herpes Simplex Virus 1 Latency and Reactivation▿

PubMed Central

Allen, Sariah J.; Mott, Kevin R.; Wechsler, Steven L.; Flavell, Richard A.; Town, Terrence; Ghiasi, Homayon

2011-01-01

Innate and adaptive immunity play important protective roles by combating herpes simplex virus 1 (HSV-1) infection. Transforming growth factor β (TGF-β) is a key negative cytokine regulator of both innate and adaptive immune responses. Yet, it is unknown whether TGF-β signaling in either immune compartment impacts HSV-1 replication and latency. We undertook genetic approaches to address these issues by infecting two different dominant negative TGF-β receptor type II transgenic mouse lines. These mice have specific TGF-β signaling blockades in either T cells or innate cells. Mice were ocularly infected with HSV-1 to evaluate the effects of restricted innate or adaptive TGF-β signaling during acute and latent infections. Limiting innate cell but not T cell TGF-β signaling reduced virus replication in the eyes of infected mice. On the other hand, blocking TGF-β signaling in either innate cells or T cells resulted in decreased latency in the trigeminal ganglia of infected mice. Furthermore, inhibiting TGF-β signaling in T cells reduced cell lysis and leukocyte infiltration in corneas and trigeminal ganglia during primary HSV-1 infection of mice. These findings strongly suggest that TGF-β signaling, which generally functions to dampen immune responses, results in increased HSV-1 latency. PMID:21880769

Preclinical Evaluation of Engineered Oncolytic Herpes Simplex Virus for the Treatment of Pediatric Solid Tumors

PubMed Central

Megison, Michael L.; Gillory, Lauren A.; Stewart, Jerry E.; Nabers, Hugh C.; Mroczek-Musulman, Elizabeth; Waters, Alicia M.; Coleman, Jennifer M.; Kelly, Virginia; Markert, James M.; Gillespie, G. Yancey; Friedman, Gregory K.; Beierle, Elizabeth A.

2014-01-01

Recently, investigators showed that mice with syngeneic murine gliomas that were treated with a neuroattenuated oncolytic herpes simplex virus-1 (oHSV), M002, had a significant increase in survival. M002 has deletions in both copies of the γ134.5 gene, enabling replication in tumor cells but precluding infection of normal cells. Previous studies have shown antitumor effects of other oHSV against a number of adult tumors including hepatocellular carcinoma and renal cell carcinoma. The purpose of the current study was to investigate the oncolytic potential of M002 against difficult to treat pediatric liver and kidney tumors. We showed that the oHSV, M002, infected, replicated, and decreased cell survival in hepatoblastoma, malignant rhabdoid kidney tumor, and renal sarcoma cell lines. In addition, we showed that in murine xenografts, treatment with M002 significantly increased survival and decreased tumor growth. Finally, these studies showed that the primary entry protein for oHSV, CD111 (nectin-1) was present in human hepatoblastoma and malignant rhabdoid kidney tumor specimens. We concluded that M002 effectively targeted these rare aggressive tumor types and that M002 may have potential for use in children with unresponsive or relapsed pediatric solid tumors. PMID:24497984

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 ...

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.

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.

[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.

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

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.

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

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

Transcriptional and translational dual-regulated oncolytic herpes simplex virus type 1 for targeting prostate tumors.

PubMed

Lee, Cleo Y F; Bu, Luke X X; DeBenedetti, Arrigo; Williams, B Jill; Rennie, Paul S; Jia, William W G

2010-05-01

The aim of this project was to demonstrate that an oncolytic herpes simplex virus type 1 (HSV-1) can replicate in a tissue- and tumor-specific fashion through both transcriptional (prostate-specific promoter, ARR(2)PB) and translational (5'-untranslated regions (5'UTRs) of rFGF-2) regulation of an essential viral gene, ICP27. We generated two recombinant viruses, ARR(2)PB-ICP27 (A27) and ARR(2)PB-5'UTR-ICP27 (AU27) and tested their efficacy and toxicity both in vitro and in vivo. The ARR(2)PB promoter caused overexpression of ICP27 gene in the presence of activated androgen receptors (ARs) and increased viral replication in prostate cells. However, this transcriptional upregulation was effectively constrained by the 5'UTR-mediated translational regulation. Mice bearing human prostate LNCaP tumors, treated with a single intravenous injection of 5 x 10(7) plaque-forming units (pfu) of AU27 virus exhibited a >85% reduction in tumor size at day 28 after viral injection. Although active viral replication was readily evident in the tumors, no viral DNA was detectable in normal organs as measured by real-time PCR analyses. In conclusion, a transcriptional and translational dual-regulated (TTDR) viral essential gene expression can increase both viral lytic activity and tumor specificity, and this provides a basis for the development of a novel tumor-specific oncolytic virus for systemic treatment of locally advanced and metastatic prostate cancers.

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…

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

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

Retention of urine and sacral paraesthesia in anogenital herpes simplex infection.

PubMed

Edis, R H

1981-01-01

Two definite and 2 probable cases of anogenital herpes simplex and sacral radiculitis are described. Symptoms were typical and consisted of paraesthesia and neuralgic pain in the perineum and legs, urinary retention and constipation occurring within several days to a week after an anogenital herpetic eruption. However, at presentation only 1 case had an obvious history of anogenital herpes simplex. Neurological signs were not striking and consisted of a reduced appreciation of light touch and pin prick over the sacral dermatomes and in 2 cases reduced anal sphincter tone. CSF examination in 3 patients showed a lymphocytosis. Bladder catheterisation was required for up to 2 weeks in 2 patients. The paraesthesia persisted for weeks to months. It should be more widely recognised that anogenital herpes simplex, with sacral radiculitis, is probably the commonest cause of acute retention of urine in young sexually active people.

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.

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.

H2AX phosphorylation and DNA damage kinase activity are dispensable for herpes simplex virus replication.

PubMed

Botting, Carolyn; Lu, Xu; Triezenberg, Steven J

2016-01-27

Herpes simplex virus type 1 (HSV-1) can establish both lytic and latent infections in humans. The phosphorylation of histone H2AX, a common marker of DNA damage, during lytic infection by HSV-1 is well established. However, the role(s) of H2AX phosphorylation in lytic infection remain unclear. Following infection of human foreskin fibroblasts by HSV-1 or HSV-2, we assayed the phosphorylation of H2AX in the presence of inhibitors of transcription, translation, or viral DNA replication, or in the presence of inhibitors of ATM and ATR kinases (KU-55933 and VE-821, respectively). We also assayed viral replication in fibroblasts in the presence of the kinase inhibitors or siRNAs specific for ATM and ATR, as well as in cell lines deficient for either ATR or ATM. The expression of viral immediate-early and early proteins (including the viral DNA polymerase), but not viral DNA replication or late protein expression, were required for H2AX phosphorylation following HSV-1 infection. Inhibition of ATM kinase activity prevented HSV-stimulated H2AX phosphorylation but had only a minor effect on DNA replication and virus yield in HFF cells. These results differ from previous reports of a dramatic reduction in viral yield following chemical inhibition of ATM in oral keratinocytes or following infection of ATM(-/-) cells. Inhibition of the closely related kinase ATR (whether by chemical inhibitor or siRNA disruption) had no effect on H2AX phosphorylation and reduced viral DNA replication only moderately. During infection by HSV-2, H2AX phosphorylation was similarly dispensable but was dependent on both ATM activity and viral DNA replication. H2AX phosphorylation represents a cell type-specific and virus type-specific host response to HSV infection with little impact on viral infection.

Biologic interactions between HSV-2 and HIV-1 and possible implications for HSV vaccine development.

PubMed

Schiffer, Joshua T; Gottlieb, Sami L

2017-09-25

Development of a safe and effective vaccine against herpes simplex virus type 2 (HSV-2) has the potential to limit the global burden of HSV-2 infection and disease, including genital ulcer disease and neonatal herpes, and is a global sexual and reproductive health priority. Another important potential benefit of an HSV-2 vaccine would be to decrease HIV infections, as HSV-2 increases the risk of HIV-1 acquisition several-fold. Acute and chronic HSV-2 infection creates ulcerations and draws dendritic cells and activated CD4+ T cells into genital mucosa. These cells are targets for HIV entry and replication. Prophylactic HSV-2 vaccines (to prevent infection) and therapeutic vaccines (to modify or treat existing infections) are currently under development. By preventing or modifying infection, an effective HSV-2 vaccine could limit HSV-associated genital mucosal inflammation and thus HIV risk. However, a vaccine might have competing effects on HIV risk depending on its mechanism of action and cell populations generated in the genital mucosa. In this article, we review biologic interactions between HSV-2 and HIV-1, consider HSV-2 vaccine development in the context of HIV risk, and discuss implications and research needs for future HSV vaccine development. Copyright © 2017 Elsevier Ltd. All rights reserved.

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.

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.

Loss of the type I interferon pathway increases vulnerability of mice to genital herpes simplex virus 2 infection.

PubMed

Conrady, Christopher D; Halford, William P; Carr, Daniel J J

2011-02-01

The mouse model of genital herpes relies on medoxyprogesterone treatment of female mice to render the vaginal lumen susceptible to inoculation with herpes simplex virus 2 (HSV-2). In the present study, we report that mice deficient in the A1 chain of the type I interferon receptor (CD118(-/-)) are susceptible to HSV-2 in the absence of medroxyprogesterone preconditioning. In the absence of hormone pretreatment, 2,000 PFU of a clinical isolate of HSV-2 was sufficient to establish a productive infection in the vagina of 75% ± 17% and in the spinal cord of 71% ± 14% of CD118(-/-) mice, whereas the same dose of HSV-2 replicated to detectable levels in only 13% ± 13% of vaginal samples and 0% of spinal cord samples from wild-type mice, as determined at day 5 postinfection. The susceptibility to HSV-2 infection in the CD118(-/-) mice was associated with a significant reduction in the infiltration of HSV-specific cytotoxic T lymphocytes into the vaginal tissue, the local production of gamma interferon (IFN-γ), and the expression of T cell-recruiting chemokines CCL5, CXCL9, and CXCL10. Collectively, the results underscore the significant contribution of type I IFNs in resistance to genital HSV-2 infection.

Herpes simplex virus-2 in the genital mucosa: insights into the mucosal host response and vaccine development.

PubMed

Lee, Amanda J; Ashkar, Ali A

2012-02-01

Herpes simplex virus (HSV)-2 is the predominant cause of genital herpes and has been implicated in HIV infection and transmission. Thus far, vaccines developed against HSV-2 have been clinically ineffective in preventing infection. This review aims to summarize the innate and adaptive immune responses against HSV-2 and examines the current status of vaccine development. Both innate and adaptive immune responses are essential for an effective primary immune response and the generation of immunity. The innate response involves Toll-like receptors, natural killer cells, plasmacytoid dendritic cells, and type I, II, and III interferons. The adaptive response requires a balance between CD4+ and CD8+ T-cells for optimal viral clearance. T-regulatory cells may be involved, although their exact function has yet to be determined. Current vaccine development involves the use of HSV-2 peptides or attenuated/replication-defective HSV-2 to generate adaptive anti-HSV-2 immune responses, however the generation of innate responses may also be an important consideration. Although vaccine development has primarily focused on the adaptive response, arguments for innate involvement are emerging. A greater understanding of the innate and adaptive processes underlying the response to HSV-2 infection will provide the foundation for the development of an effective vaccine.

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.

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

Fatal herpes simplex infection in a pygmy African hedgehog (Atelerix albiventris).

PubMed

Allison, N; Chang, T C; Steele, K E; Hilliard, J K

2002-01-01

An adult pygmy African hedgehog developed acute posterior paresis attributed to a prolapsed intervertebral disc diagnosed by C-T scan. Corticosteroid therapy resulted in prompt resolution of the ataxia, but 2 weeks later the animal became anorexic and died. Macroscopically, the liver was stippled with punctate off-white foci which were confirmed microscopically to be foci of necrosis. Numerous hepatocytes contained intranuclear inclusions and syncytial cell formation was also present. A herpes virus was isolated and identified by fluorescent antibody and polymerase chain reaction studies as herpesvirus simplex type 1. To our knowledge, this is the first report of herpes infection in the African hedgehog and the first time herpes simplex has been identified as a cause of disease in insectivores.

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

Extracts of Equisetum giganteum L and Copaifera reticulate Ducke show strong antiviral activity against the sexually transmitted pathogen herpes simplex virus type 2.

PubMed

Churqui, Marianela Patzi; Lind, Liza; Thörn, Karolina; Svensson, Alexandra; Savolainen, Otto; Aranda, Katty Terrazas; Eriksson, Kristina

2018-01-10

Equisetum giganteum L and Copaifera reticulate Ducke have been traditionally used by women of the Tacana tribe in the Bolivian Amazonas for genital hygiene and for treatment of genital infection/inflammation. To assess the ability of extracts from Equisetum giganteum L and Copaifera reticulate Ducke to block genital viral infection by herpes simplex virus type 2. Equisetum giganteum L and Copaifera reticulate Ducke were collected from the Amazon region of La Paz, Bolivia. Extracts were prepared and screened for anti-viral activity against herpes simplex virus type 2 (HSV-2) using both in vitro and in in vivo models of infection. Equisetum giganteum L and Copaifera reticulate Ducke efficiently blocked HSV-2 infection of cell cultures without major cell cytotoxic effects. Extracts of Equisetum giganteum L and Copaifera reticulate Ducke could prevent HSV-2 disease development when administered together with virus in a mouse model of genital HSV-2 infection. In vitro analyses revealed that both plant extracts exerted their anti-HSV-2 effects by interfering with viral cell attachment and entry, but could not block viral replication post entry. These studies show that extracts of Equisetum giganteum L and Copaifera reticulate Ducke have potent antiviral activities against HSV-2 comparable to those two previously identified plants, Croton lechleri Müll. Arg. and Uncaria tomentosa (Willd. ex Schult.) DC. These studies confirm that plants used by the Tacana tribe could be explored further for the development of novel topical antiviral microbicides. Copyright © 2017. Published by Elsevier B.V.

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.

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 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.

Solid-to-fluid DNA transition inside HSV-1 capsid close to the temperature of infection

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

Sae-Ueng, Udom; Li, Dong; Zuo, Xiaobing

2014-10-01

DNA in the human Herpes simplex virus type 1 (HSV-1) capsid is packaged to a tight density. This leads to tens of atmospheres of internal pressure responsible for the delivery of the herpes genome into the cell nucleus. In this study we show that, despite its liquid crystalline state inside the capsid, the DNA is fluid-like, which facilitates its ejection into the cell nucleus during infection. We found that the sliding friction between closely packaged DNA strands, caused by interstrand repulsive interactions, is reduced by the ionic environment of epithelial cells and neurons susceptible to herpes infection. However, variations inmore » the ionic conditions corresponding to neuronal activity can restrict DNA mobility in the capsid, making it more solid-like. This can inhibit intranuclear DNA release and interfere with viral replication. In addition, the temperature of the human host (37 °C) induces a disordering transition of the encapsidated herpes genome, which reduces interstrand interactions and provides genome mobility required for infection.« less

Enhancement of Herpes Simplex Virus (HSV) Infection by Seminal Plasma and Semen Amyloids Implicates a New Target for the Prevention of HSV Infection

PubMed Central

Torres, Lilith; Ortiz, Tatiana; Tang, Qiyi

2015-01-01

Human herpesviruses cause different infectious diseases, resulting in world-wide health problems. Sexual transmission is a major route for the spread of both herpes simplex virus-1 (HSV-1) and -2. Semen plays an important role in carrying the viral particle that invades the vaginal or rectal mucosa and, thereby, initiates viral replication. Previously, we demonstrated that the amyloid fibrils semenogelin (SEM) and semen-derived enhancer of viral infection (SEVI), and seminal plasma (SP) augment cytomegalovirus infection (Tang et al., J. Virol 2013). Whether SEM or SEVI amyloids or SP could also enhance other herpesvirus infections has not been examined. In this study, we found that the two amyloids as well as SP strongly enhance both HSV-1 and -2 infections in cell culture. Along with SP, SEM and SEVI amyloids enhanced viral entry and increased infection rates by more than 10-fold, as assessed by flow cytometry assay and fluorescence microscopy. Viral replication was increased by about 50- to 100-fold. Moreover, viral growth curve assays showed that SEM and SEVI amyloids, as well as SP, sped up the kinetics of HSV replication such that the virus reached its replicative peak more quickly. The interactions of SEM, SEVI, and SP with HSVs are direct. Furthermore, we discovered that the enhancing effects of SP, SEM, and SEVI can be significantly reduced by heparin, a sulfated polysaccharide with an anionic charge. It is probable that heparin abrogates said enhancing effects by interfering with the interaction of the viral particle and the amyloids, which interaction results in the binding of the viral particles and both SEM and SEVI. PMID:25903833

The helicase-primase inhibitor BAY 57-1293 reduces the Alzheimer's disease-related molecules induced by herpes simplex virus type 1.

PubMed

Wozniak, M A; Frost, A L; Itzhaki, R F

2013-09-01

Herpes simplex virus type 1 (HSV1) infection of cultured cells causes the formation of β-amyloid (Aβ) and abnormal tau (P-tau). These molecules comprise the main components of the abnormal protein deposits, amyloid plaques and neurofibrillary tangles, respectively, in Alzheimer's disease (AD) brains, and they have been implicated in disease development. The formation of P-tau, but not of Aβ, depends on viral DNA replication, but nonetheless, three antiviral agents that inhibit HSV1 DNA replication, including acyclovir (ACV), were found to reduce greatly the level of Aβ as well as P-tau, the former probably through prevention of viral spread. Previous studies showed that HSV1 DNA is present and is active in the brain of many elderly people, including AD patients, and that in combination with the type 4 allele of the apolipoprotein E gene, it is likely to play a role in the disease, perhaps via Aβ and P-tau production. With the aim of finding the most suitable antiviral for inhibiting Aβ and P-tau formation as well as HSV1 DNA replication, for future use in a clinical trial for treating AD, we compared the efficacy of ACV with that of another antiviral, BAY 57-1293, which acts by a different mechanism from ACV. We found that BAY 57-1293 is more efficient than ACV not only in inhibiting HSV1 replication, confirming previous studies, but also in decreasing Aβ and P-tau formation. Also, the cell clusters that are formed during infection are reduced in size much more efficiently by BAY 57-1293 than by ACV. These data suggest that BAY 57-1293 would be a more effective agent than ACV for treating AD. Copyright © 2013 Elsevier B.V. All rights reserved.

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

Herpes Simplex

MedlinePlus

... sores around the mouth or face. Genital herpes affects the genitals, buttocks or anal area. Genital herpes is a sexually transmitted disease (STD). It affects the genitals, buttocks or anal area. Other herpes ...

Identification of a divalent metal cation binding site in herpes simplex virus 1 (HSV-1) ICP8 required for HSV replication.

PubMed

Bryant, Kevin F; Yan, Zhipeng; Dreyfus, David H; Knipe, David M

2012-06-01

Herpes simplex virus 1 (HSV-1) ICP8 is a single-stranded DNA-binding protein that is necessary for viral DNA replication and exhibits recombinase activity in vitro. Alignment of the HSV-1 ICP8 amino acid sequence with ICP8 homologs from other herpesviruses revealed conserved aspartic acid (D) and glutamic acid (E) residues. Amino acid residue D1087 was conserved in every ICP8 homolog analyzed, indicating that it is likely critical for ICP8 function. We took a genetic approach to investigate the functions of the conserved ICP8 D and E residues in HSV-1 replication. The E1086A D1087A mutant form of ICP8 failed to support the replication of an ICP8 mutant virus in a complementation assay. E1086A D1087A mutant ICP8 bound DNA, albeit with reduced affinity, demonstrating that the protein is not globally misfolded. This mutant form of ICP8 was also recognized by a conformation-specific antibody, further indicating that its overall structure was intact. A recombinant virus expressing E1086A D1087A mutant ICP8 was defective in viral replication, viral DNA synthesis, and late gene expression in Vero cells. A class of enzymes called DDE recombinases utilize conserved D and E residues to coordinate divalent metal cations in their active sites. We investigated whether the conserved D and E residues in ICP8 were also required for binding metal cations and found that the E1086A D1087A mutant form of ICP8 exhibited altered divalent metal binding in an in vitro iron-induced cleavage assay. These results identify a novel divalent metal cation-binding site in ICP8 that is required for ICP8 functions during viral replication.

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.

NFκB-mediated activation of the cellular FUT3, 5 and 6 gene cluster by herpes simplex virus type 1.

PubMed

Nordén, Rickard; Samuelsson, Ebba; Nyström, Kristina

2017-11-01

Herpes simplex virus type 1 has the ability to induce expression of a human gene cluster located on chromosome 19 upon infection. This gene cluster contains three fucosyltransferases (encoded by FUT3, FUT5 and FUT6) with the ability to add a fucose to an N-acetylglucosamine residue. Little is known regarding the transcriptional activation of these three genes in human cells. Intriguingly, herpes simplex virus type 1 activates all three genes simultaneously during infection, a situation not observed in uninfected tissue, pointing towards a virus specific mechanism for transcriptional activation. The aim of this study was to define the underlying mechanism for the herpes simplex virus type 1 activation of FUT3, FUT5 and FUT6 transcription. The transcriptional activation of the FUT-gene cluster on chromosome 19 in fibroblasts was specific, not involving adjacent genes. Moreover, inhibition of NFκB signaling through panepoxydone treatment significantly decreased the induction of FUT3, FUT5 and FUT6 transcriptional activation, as did siRNA targeting of p65, in herpes simplex virus type 1 infected fibroblasts. NFκB and p65 signaling appears to play an important role in the regulation of FUT3, FUT5 and FUT6 transcriptional activation by herpes simplex virus type 1 although additional, unidentified, viral factors might account for part of the mechanism as direct interferon mediated stimulation of NFκB was not sufficient to induce the fucosyltransferase encoding gene cluster in uninfected cells. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

A novel antivirally active fucan sulfate derived from an edible brown alga, Sargassum horneri.

PubMed

Preeprame, S; Hayashi, K; Lee, J B; Sankawa, U; Hayashi, T

2001-04-01

A novel fucan sulfate (Hor-1) was isolated from the hot water extract of an edible brown alga, Sargassum horneri (Turner) C. Agardh. The fucan sulfate was revealed to have sugar linkage types, sulfate content and uronic acid content different from those of sodium hornan (Na-HOR), another fucan sulfate isolated from this alga. However, it exhibited inhibitory activity against replication of herpes simplex virus type 1 with similar potency to Na-HOR.

A screening dye-uptake assay to evaluate in vitro susceptibility of herpes simplex virus isolates to acyclovir.

PubMed

Danve, Christelle; Morfin, Florence; Thouvenot, Danielle; Aymard, Michèle

2002-09-01

The widespread use of acyclovir (ACV) could increase the prevalence of herpes simplex virus (HSV) ACV-resistant isolates, and a screening assay are thus important for routine surveillance of the ACV susceptibility of HSV. A screening dye-uptake assay was developed, based on the conventional dye-uptake assay [J. Biol. Stand. 14 (1986) 201]. The susceptibility of HSV was measured by testing two virus dilutions (10(-1) and 10(-2)) against two ACV concentrations (5 and 10 microM) on Vero cells and expressed as a reduced percentage of viral replication. The reproducibility was evaluated with HSV1 and HSV2 ACV-sensitive and ACV-resistant reference strains introduced as controls in successive series. The dye-uptake by Vero cells, the growth capacity of the HSV strains and the reduction of the viral replication in the presence of acyclovir varied by less than 14, 20 and 30%, respectively. This assay allowed the detection of a heterogenous population containing as few as 20% of ACV-resistant strain. The screening test was applied to 500 HSV isolates in a prospective study, and over 95% of the HSV isolates tested were characterised using a single test. This test appeared to be half the cost and much easier to carry out than the conventional dye-uptake assay, and consequently is well suited for large scale surveillance.

Preclinical Evaluation of Engineered Oncolytic Herpes Simplex Virus for the Treatment of Neuroblastoma

PubMed Central

Gillory, Lauren A.; Megison, Michael L.; Stewart, Jerry E.; Mroczek-Musulman, Elizabeth; Nabers, Hugh C.; Waters, Alicia M.; Kelly, Virginia; Coleman, Jennifer M.; Markert, James M.; Gillespie, G. Yancey; Friedman, Gregory K.; Beierle, Elizabeth A.

2013-01-01

Despite intensive research efforts and therapeutic advances over the last few decades, the pediatric neural crest tumor, neuroblastoma, continues to be responsible for over 15% of pediatric cancer deaths. Novel therapeutic options are needed for this tumor. Recently, investigators have shown that mice with syngeneic murine gliomas treated with an engineered, neuroattenuated oncolytic herpes simplex virus-1 (oHSV), M002, had a significant increase in survival. M002 has deletions in both copies of the γ134.5 gene, enabling replication in tumor cells but precluding infection of normal neural cells. We hypothesized that M002 would also be effective in the neural crest tumor, neuroblastoma. We showed that M002 infected, replicated, and decreased survival in neuroblastoma cell lines. In addition, we showed that in murine xenografts, treatment with M002 significantly decreased tumor growth, and that this effect was augmented with the addition of ionizing radiation. Importantly, survival could be increased by subsequent doses of radiation without re-dosing of the virus. Finally, these studies showed that the primary entry protein for oHSV, CD111 was expressed by numerous neuroblastoma cell lines and was also present in human neuroblastoma specimens. We concluded that M002 effectively targeted neuroblastoma and that this oHSV may have potential for use in children with unresponsive or relapsed neuroblastoma. PMID:24130898

Protection From Varicella Zoster in Solid Organ Transplant Recipients Carrying Killer Cell Immunoglobulin-Like Receptor B Haplotypes.

PubMed

Schmied, Laurent; Terszowski, Grzegorz; Gonzalez, Asensio; Schmitter, Karin; Hirsch, Hans H; Garzoni, Christian; van Delden, Christian; Boggian, Katia; Mueller, Nicolas J; Berger, Christoph; Villard, Jean; Manuel, Oriol; Meylan, Pascal; Hess, Christoph; Stern, Martin

2015-12-01

Natural killer cell function is regulated by inhibitory and activating killer cell immunoglobulin-like receptors (KIR). Previous studies have documented associations of KIR genotype with the risk of cytomegalovirus (CMV) replication after solid organ transplantation. In this study of 649 solid organ transplant recipients, followed prospectively for infectious disease events within the Swiss Transplant Cohort Study, we were interested to see if KIR genotype associated with virus infections other than CMV. We found that KIR B haplotypes (which have previously been linked to protection from CMV replication) were associated with protection from varicella zoster virus infection (hazard ratio, 0.43; 95% confidence interval, 0.21-0.91; P = 0.03). No significant associations were detected regarding the risk of herpes simplex, Epstein-Barr virus or BK polyomavirus infections. In conclusion, these data provide evidence that the relative protection of KIR haplotype B from viral replication after solid organ transplantation may extend beyond CMV to other herpes viruses, such as varicella zoster virus and possibly Epstein-Barr virus.

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

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

ERIC Educational Resources Information Center

McNab, Warren L.

1979-01-01

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

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.

SR proteins SRp20 and 9G8 contribute to efficient export of herpes simplex virus 1 mRNAs

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

Escudero-Paunetto, Laurimar; Li Ling; Hernandez, Felicia P.

2010-06-05

Herpes simplex virus 1 (HSV-1) mRNAs are exported to the cytoplasm through the export receptor TAP/NFX1. HSV-1 multifunctional protein ICP27 interacts with TAP/NXF1, binds viral RNAs, and is required for efficient viral RNA export. In ICP27 mutant infections, viral RNA export is reduced but not ablated, indicating that other export adaptors can aid in viral RNA export. Export adaptor protein Aly/REF is recruited to viral replication compartments, however, Aly/REF knockdown has little effect on viral RNA export. SR proteins SRp20 and 9G8 interact with TAP/NXF1 and mediate export of some cellular RNAs. We report that siRNA knockdown of SRp20 ormore » 9G8 resulted in about a 10 fold decrease in virus yields and in nuclear accumulation of poly(A+) RNA. In infected cells depleted of SRp20, newly transcribed Bromouridine-labeled RNA also accumulated in the nucleus. We conclude that SRp20 and 9G8 contribute to HSV-1 RNA export.« less

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

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

Release of the herpes simplex virus 1 protease by self cleavage is required for proper conformation of the portal vertex

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

Yang, Kui; Wills, Elizabeth G.; Baines, Joel D., E-mail: jdb11@cornell.edu

2012-07-20

We identify an NLS within herpes simplex virus scaffold proteins that is required for optimal nuclear import of these proteins into infected or uninfected nuclei, and is sufficient to mediate nuclear import of GFP. A virus lacking this NLS replicated to titers reduced by 1000-fold, but was able to make capsids containing both scaffold and portal proteins suggesting that other functions can complement the NLS in infected cells. We also show that Vp22a, the major scaffold protein, is sufficient to mediate the incorporation of portal protein into capsids, whereas proper portal immunoreactivity in the capsid requires the larger scaffold proteinmore » pU{sub L}26. Finally, capsid angularization in infected cells did not require the HSV-1 protease unless full length pU{sub L}26 was expressed. These data suggest that the HSV-1 portal undergoes conformational changes during capsid maturation, and reveal that full length pU{sub L}26 is required for this conformational change.« less

Rapid localized spread and immunologic containment define Herpes simplex virus-2 reactivation in the human genital tract.

PubMed

Schiffer, Joshua T; Swan, David; Al Sallaq, Ramzi; Magaret, Amalia; Johnston, Christine; Mark, Karen E; Selke, Stacy; Ocbamichael, Negusse; Kuntz, Steve; Zhu, Jia; Robinson, Barry; Huang, Meei-Li; Jerome, Keith R; Wald, Anna; Corey, Lawrence

2013-04-16

Herpes simplex virus-2 (HSV-2) is shed episodically, leading to occasional genital ulcers and efficient transmission. The biology explaining highly variable shedding patterns, in an infected person over time, is poorly understood. We sampled the genital tract for HSV DNA at several time intervals and concurrently at multiple sites, and derived a spatial mathematical model to characterize dynamics of HSV-2 reactivation. The model reproduced heterogeneity in shedding episode duration and viral production, and predicted rapid early viral expansion, rapid late decay, and wide spatial dispersion of HSV replication during episodes. In simulations, HSV-2 spread locally within single ulcers to thousands of epithelial cells in <12 hr, but host immune responses eliminated infected cells in <24 hr; secondary ulcers formed following spatial propagation of cell-free HSV-2, allowing for episode prolongation. We conclude that HSV-2 infection is characterized by extremely rapid virological growth and containment at multiple contemporaneous sites within genital epithelium. DOI:http://dx.doi.org/10.7554/eLife.00288.001.

Rapid localized spread and immunologic containment define Herpes simplex virus-2 reactivation in the human genital tract

PubMed Central

Schiffer, Joshua T; Swan, David; Al Sallaq, Ramzi; Magaret, Amalia; Johnston, Christine; Mark, Karen E; Selke, Stacy; Ocbamichael, Negusse; Kuntz, Steve; Zhu, Jia; Robinson, Barry; Huang, Meei-Li; Jerome, Keith R; Wald, Anna; Corey, Lawrence

2013-01-01

Herpes simplex virus-2 (HSV-2) is shed episodically, leading to occasional genital ulcers and efficient transmission. The biology explaining highly variable shedding patterns, in an infected person over time, is poorly understood. We sampled the genital tract for HSV DNA at several time intervals and concurrently at multiple sites, and derived a spatial mathematical model to characterize dynamics of HSV-2 reactivation. The model reproduced heterogeneity in shedding episode duration and viral production, and predicted rapid early viral expansion, rapid late decay, and wide spatial dispersion of HSV replication during episodes. In simulations, HSV-2 spread locally within single ulcers to thousands of epithelial cells in <12 hr, but host immune responses eliminated infected cells in <24 hr; secondary ulcers formed following spatial propagation of cell-free HSV-2, allowing for episode prolongation. We conclude that HSV-2 infection is characterized by extremely rapid virological growth and containment at multiple contemporaneous sites within genital epithelium. DOI: http://dx.doi.org/10.7554/eLife.00288.001 PMID:23606943

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.

Immunity to herpes simplex virus type 2. Suppression of virus-induced immune responses in ultraviolet B-irradiated mice

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

Yasumoto, S.; Hayashi, Y.; Aurelian, L.

1987-10-15

Ultraviolet B irradiation (280 to 320 nm) of mice at the site of intradermal infection with herpes simplex virus type 2 increased the severity of the herpes simplex virus type 2 disease and decreased delayed-type hypersensitivity (DTH) responses to viral antigen. Decrease in DTH resulted from the induction of suppressor T cells, as evidenced by the ability of spleen cells from UV-irradiated mice to inhibit DTH and proliferative responses after adoptive transfer. Lymph node cells from UV-irradiated animals did not transfer suppression. DTH was suppressed at the induction but not the expression phase. Suppressor T cells were Lyt-1+, L3T4+, andmore » their activity was antigen-specific. However, after in vitro culture of spleen cells from UV-irradiated mice with herpes simplex virus type 2 antigen, suppressor activity was mediated by Lyt-2+ cells. Culture supernatants contained soluble nonantigen-specific suppressive factors.« less

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.

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.

Herpes simplex type 2 encephalitis and methotrexate medication: a fortuitous or causative association in a patient with spondyloarthritis?

PubMed

Lupo, Julien; Dos Santos, Ophélie; Germi, Raphaele; Baccard-Longère, Monique; Stahl, Jean-Paul; Epaulard, Olivier; Morand, Patrice

2017-01-01

It is unclear whether immunosuppression is a risk factor for herpes encephalitis. Herein, we describe a rare case of herpes simplex virus type 2 encephalitis in a patient treated with low-dose methotrexate for HLA-B27-associated spondyloarthritis. The patient was successfully treated with acyclovir but presented sequelae of encephalitis. Here we discuss the possible role of low-dose methotrexate therapy as a risk factor of neurological herpes reactivation and severe disease. The host-related and viral risk factors are also addressed.

Genital herpes simplex virus infections in adults.

PubMed

Mertz, G; Corey, L

1984-02-01

With the decline in prevalence of childhood-acquired oral-labial herpes simplex type 1 infections in some populations and the increasing incidence of genital herpes infections in adults, clinicians are more likely to see patients with severe primary, first-episode genital herpes infections. Complications of these primary infections may include aseptic meningitis and urine retention secondary to sacral radiculopathy or autonomic dysfunction. Presented are the clinical course of first-episode and recurrent infections, complications, diagnostic laboratory methods, and results of controlled clinical trials evaluating the efficacy of topical, intravenous, and oral preparations of acyclovir.

Radionuclide imaging in herpes simplex encephalitis. [/sup 99m/Tc tracer techniques

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

Karlin, C.A.; Robinson, R.G.; Hinthorn, D.R.

1978-01-01

Eight patients with herpes simplex encephalitis among the 10 cases diagnosed at the University of Kansas Medical Center from 1966 to 1976 were studied with /sup 99m/Tc early in their diagnostic work-up. The images were unilaterally positive in the temporal lobe area in all 8 patients. Radionuclide studies can suggest herpes simplex as the specific etiology in cases of encephalitis and can also indicate the best site for brain biopsy to confirm the diagnosis by fluorescent antibody techniques. Appropriate antiviral therapy should be instituted as soon as possible to alter the course of this destructive form of viral encephalitis.

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.

Molecular requirement for sterols in herpes simplex virus entry and infectivity

USDA-ARS?s Scientific Manuscript database

Herpes simplex virus 1 (HSV-1) required cholesterol for virion-induced membrane fusion. HSV successfully entered DHCR24-/-cells, which lack a desmosterol-to-cholesterol conversion enzyme, indicating entry can occur independently of cholesterol. Depletion of desmosterol from these cells resulted in d...

RESEARCH PROGRAM FOR ALERTING, DETECTION AND IDENTIFICATION OF PATHOGENES.

DTIC Science & Technology

characteristic products. BHK-21 and RK-13 tissue cultures infected with NDV, influenza, YFV , Sendai, Vaccinia, and Herpes simplex showed a depletion of...infected and control serum could be detected in mice infected with YFV , influenza, Herpes simplex, and LDV superinfected with YFV . Several methods of

Genital Herpes

MedlinePlus

Genital herpes is a sexually transmitted disease (STD) caused by a herpes simplex virus (HSV). It can cause sores on ... also infect their babies during childbirth. Symptoms of herpes are called outbreaks. You usually get sores near ...

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.

Human Asymptomatic Epitope Peptide/CXCL10-Based Prime/Pull Vaccine Induces Herpes Simplex Virus-Specific Gamma Interferon-Positive CD107+ CD8+ T Cells That Infiltrate the Cornea and Trigeminal Ganglia of Humanized HLA Transgenic Rabbits and Protect against Ocular Herpes Challenge.

PubMed

Khan, Arif A; Srivastava, Ruchi; Vahed, Hawa; Roy, Soumyabrata; Walia, Sager S; Kim, Grace J; Fouladi, Mona A; Yamada, Taikun; Ly, Vincent T; Lam, Cynthia; Lou, Anthony; Nguyen, Vivianna; Boldbaatar, Undariya; Geertsema, Roger; Fraser, Nigel W; BenMohamed, Lbachir

2018-06-13

Herpes simplex virus 1 (HSV-1) is a prevalent human pathogen that infects the cornea causing potentially blinding herpetic disease. A clinical herpes vaccine is still lacking. In the present study, a novel prime/pull vaccine was tested in Human Leukocyte Antigen- (HLA-) transgenic rabbit model of ocular herpes (HLA Tg rabbit). Three asymptomatic (ASYMP) peptide epitopes were selected from the HSV-1 membrane glycoprotein C (UL44 400-408 ), the DNA replication binding helicase (UL9 196-204 ), and the tegument protein (UL25 572-580 ), all preferentially recognized by CD8 + T cells from "naturally protected" HSV-1-seropositive healthy ASYMP individuals (who never had recurrent corneal herpetic disease). HLA Tg rabbits were immunized with a mixture of these three ASYMP CD8 + T cell peptide epitopes (UL44 400-408 , UL9 196-204 and UL25 572-580 ), delivered subcutaneously with CpG 2007 adjuvant (prime). Fifteen days later, half of the rabbits received a topical ocular treatment with a recombinant neurotropic AAV8 vector, expressing the T cell-attracting CXCL10 chemokine (pull). The frequency, function of HSV-specific CD8 + T cells induced by the prime/pull vaccine were assessed in peripheral blood, cornea, and trigeminal ganglia (TG). Compared to peptides alone, the peptides/CXCL10 prime/pull vaccine generated frequent polyfunctional gamma interferon-positive (IFN-γ + ) CD107 + CD8 + T cells that infiltrated both the cornea and TG. CD8 + T cells mobilization into cornea and TG of prime/pull- vaccinated rabbits was associated with a significant reduction in corneal herpes infection and disease following an ocular HSV-1 challenge (McKrae). These findings draw attention to the novel prime/pull vaccine strategy to mobilize anti-viral CD8 + T cells into tissues protecting them against herpes infection and disease. IMPORTANCE There is an urgent need for a vaccine against widespread herpes simplex virus infections. The present study demonstrates that immunization of HLA transgenic rabbits with a peptide/CXCL10 prime/pull vaccine triggered mobilization of HSV-specific CD8 + T cells locally in the cornea and TG, the sites of acute and latent herpes infections. Mobilization of antiviral CD8 + T cells into cornea and TG of rabbits that received the prime/pull vaccine was associated with protection against ocular herpes infection and disease following an ocular HSV-1 challenge. These results highlight the importance of the prime/pull vaccine strategy to bolster the number and function of protective CD8 + T cells within infected tissues. Copyright © 2018 American Society for Microbiology.

Herpes: a dilemma for client and clinician.

PubMed

Edlund, B J; Poteet, G W

1987-01-01

In the last 10 years genital herpes simplex has reached epidemic proportions, affecting 5 million Americans, with 500,000 new cases yearly. The incidence is highest among middle and upper socioeconomic groups and among whites. There are 2 antigenically distinct strains of the herpes simplex virus, and type II is the cause of 85% of the genital infections. The virus has an affinity for tissues derived from the embryonic ectoderm -- skin, mucous membranes, eye, and central nervous system. Transmission is by personal contact with an infected area. The clinical course of the disease involves 4 stages. In the primary stage the typical lesions are vesicles, which rupture, leaving painful shallow ulcerations. The primary stage lasts from 2 to 4 weeks with approximately 10 days of viral shedding. In the latent stage the virus lies dormant in the sacral ganglion and is noninfectious. In the shedding stage the virus replicates and sheds in genital secretions. The recurrent stage is characterized by prodromal itching or tingling sensations prior to the eruption of the vesicles and by neuralgia. Recurrence occurs as often as 4 to 7 times a year and lasts from 7 to 10 days, with viral shedding for 4 or 5 days. Definitive diagnosis can be made from viral tissue culture or the Tzanck and Papanicolaou smears. There is no cure for herpes although acyclovir has been found to shorten the duration of the episodes. Except for pregnancy complications, the most serious complications of recurrent genital herpes are psychological. The disease is socially stigmatizing and inhibits sexual activity. The nurse should provide supportive care, information about the transmission and symptoms of the disease, and counseling as to precautions to take, such as condom and spermicide use, avoidance of oral sex, abstention when lesions are present, and limiting sex to one partner.

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…

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)

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.

Herpes simplex virus meningitis complicated by ascending paralysis

PubMed Central

Benjamin, Mina M.; Gummelt, Kyle L.; Zaki, Rabeea; Afzal, Aasim; Sloan, Louis

2013-01-01

A case of herpes simplex virus (HSV) meningitis complicated by ascending paralysis with almost complete recovery following antiviral treatment is reported. We present this case to illustrate the importance of including HSV-induced neuropathy in the differential diagnosis of acute neurologic symptoms following the viral illness. PMID:23814385

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.

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.

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.

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.

An antivirally active sulfated polysaccharide from Sargassum horneri (TURNER) C. AGARDH.

PubMed

Hoshino, T; Hayashi, T; Hayashi, K; Hamada, J; Lee, J B; Sankawa, U

1998-07-01

A sulfated polysaccharide was isolated from the hot water extract of a brown alga, Sargassum horneri (TURNER) C. AGARDH. Fucose was detected as the main component sugar of this polysaccharide. This compound showed potent antiviral activity against herpes simplex virus type 1, human cytomegalovirus and human immunodeficiency virus type 1. Time-of-addition experiments suggested that it inhibited not only the initial stages of viral infection, such as attachment to and penetration into host cells, but also later replication stages after virus penetration.

Loss of the Type I Interferon Pathway Increases Vulnerability of Mice to Genital Herpes Simplex Virus 2 Infection ▿

PubMed Central

Conrady, Christopher D.; Halford, William P.; Carr, Daniel J. J.

2011-01-01

The mouse model of genital herpes relies on medoxyprogesterone treatment of female mice to render the vaginal lumen susceptible to inoculation with herpes simplex virus 2 (HSV-2). In the present study, we report that mice deficient in the A1 chain of the type I interferon receptor (CD118−/−) are susceptible to HSV-2 in the absence of medroxyprogesterone preconditioning. In the absence of hormone pretreatment, 2,000 PFU of a clinical isolate of HSV-2 was sufficient to establish a productive infection in the vagina of 75% ± 17% and in the spinal cord of 71% ± 14% of CD118−/− mice, whereas the same dose of HSV-2 replicated to detectable levels in only 13% ± 13% of vaginal samples and 0% of spinal cord samples from wild-type mice, as determined at day 5 postinfection. The susceptibility to HSV-2 infection in the CD118−/− mice was associated with a significant reduction in the infiltration of HSV-specific cytotoxic T lymphocytes into the vaginal tissue, the local production of gamma interferon (IFN-γ), and the expression of T cell-recruiting chemokines CCL5, CXCL9, and CXCL10. Collectively, the results underscore the significant contribution of type I IFNs in resistance to genital HSV-2 infection. PMID:21147921

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

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.

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:…

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.

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.

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.

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.

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.

Vesicles

MedlinePlus

... herpetiformis Chickenpox Contact dermatitis (may be caused by poison ivy) Herpes simplex (cold sores, genital herpes ) Herpes zoster ( ... available for certain conditions that cause vesicles, including poison ivy and cold sores. When to Contact a Medical ...

Oncolytic herpes viruses, chemotherapeutics, and other cancer drugs

PubMed Central

Braidwood, Lynne; Graham, Sheila V; Graham, Alex; Conner, Joe

2013-01-01

Oncolytic viruses are emerging as a potential new way of treating cancers. They are selectively replication-competent viruses that propagate only in actively dividing tumor cells but not in normal cells and, as a result, destroy the tumor cells by consequence of lytic infection. At least six different oncolytic herpes simplex viruses (oHSVs) have undergone clinical trials worldwide to date, and they have demonstrated an excellent safety profile and intimations of efficacy. The first pivotal Phase III trial with an oHSV, talimogene laherparepvec (T-Vec [OncoVexGM-CSF]), is almost complete, with extremely positive early results reported. Intuitively, therapeutically beneficial interactions between oHSV and chemotherapeutic and targeted therapeutic drugs would be limited as the virus requires actively dividing cells for maximum replication efficiency and most anticancer agents are cytotoxic or cytostatic. However, combinations of such agents display a range of responses, with antagonistic, additive, or, perhaps most surprisingly, synergistic enhancement of antitumor activity. When synergistic interactions in cancer cell killing are observed, chemotherapy dose reductions that achieve the same overall efficacy may be possible, resulting in a valuable reduction of adverse side effects. Therefore, the combination of an oHSV with “standard-of-care” drugs makes a logical and reasonable approach to improved therapy, and the addition of a targeted oncolytic therapy with “standard-of-care” drugs merits further investigation, both preclinically and in the clinic. Numerous publications report such studies of oncolytic HSV in combination with other drugs, and we review their findings here. Viral interactions with cellular hosts are complex and frequently involve intracellular signaling networks, thus creating diverse opportunities for synergistic or additive combinations with many anticancer drugs. We discuss potential mechanisms that may lead to synergistic interactions. PMID:27512658

Inhibition of herpes simplex virus type 1 by the CDK6 inhibitor PD-0332991 (palbociclib) through the control of SAMHD1.

PubMed

Badia, Roger; Angulo, Guillem; Riveira-Muñoz, Eva; Pujantell, Maria; Puig, Teresa; Ramirez, Cristina; Torres-Torronteras, Javier; Martí, Ramón; Pauls, Eduardo; Clotet, Bonaventura; Ballana, Ester; Esté, José A

2016-02-01

Sterile α motif and histidine-aspartate domain-containing protein 1 (SAMHD1) has been shown to restrict retroviruses and DNA viruses by decreasing the pool of intracellular deoxynucleotides. In turn, SAMHD1 is controlled by cyclin-dependent kinases (CDK) that regulate the cell cycle and cell proliferation. Here, we explore the effect of CDK6 inhibitors on the replication of herpes simplex virus type 1 (HSV-1) in primary monocyte-derived macrophages (MDM). MDM were treated with palbociclib, a selective CDK4/6 inhibitor, and then infected with a GFP-expressing HSV-1. Intracellular deoxynucleotide triphosphate (dNTP) content was determined using a polymerase-based method. CDK6 inhibitor palbociclib blocked SAMHD1 phosphorylation, intracellular dNTP levels and HSV-1 replication in MDM at subtoxic concentrations. Treatment of MDM with palbociclib reduced CDK2 activation, measured as the phosphorylation of the T-loop at Thr160. The antiviral activity of palbociclib was lost when SAMHD1 was degraded by viral protein X. Similarly, palbociclib did not block HSV-1 replication in SAMHD1-negative Vero cells at subtoxic concentrations, providing further evidence for a role of SAMHD1 in mediating the antiviral effect. SAMHD1-mediated HSV-1 restriction is controlled by CDK and points to a preferential role for CDK6 and CDK2 as mediators of SAMHD1 activation. Similarly, the restricting activity of SAMHD1 against DNA viruses suggests that control of dNTP availability is the major determinant of its antiviral activity. This is the first study describing the anti-HSV-1 activity of palbociclib. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

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

[Study on the inhibition effect of siRNA on herpes simplex virus type 2 ICP4 gene].

PubMed

Liu, Ji-feng; Guan, Cui-ping; Tang, Xu; Xu, Ai-e

2010-06-01

To explore the inhibition effect of RNA interference on the ICP4 expression and DNA replication of herpes simplex virus type 2 (HSV2). Four pairs of siRNA targeted to HSV2 ICP4 gene and negative control siRNA were synthetized by chemical method, named as siRNA-1, siRNA-2, siRNA-3, siRNA-4 and siRNA-N respecticely. HSV2 HG52 was used to attack Vero cell after transfection overnight. Vero cell and supernatant were collected at 1d, 2d, 3d, 4d and 5d after virus attacking. Flurogenic quantitative reverse transcription polymerase chain reaction (FQ-RT-PCR)was used to detect the expression of HSV2 ICP4 mRNA, flurogenic quantitative polymerase chain reaction(FG-PCR) was used to detect the expression of HSV2 DNA and Western-Blot was used to detect the expression of HSV2 ICP4 protein. All the four pairs of siRNA could significantly inhibit the expression of HSV2 ICP4 mRNA and protein, especially siRNA-2. The above siRNAs could significantly decrease HSV2 DNA copy number,too. siRNAs targeted to HSV2 ICP4 gene could significantly inhibit expression of HSV2 ICP4 mRNA and protein, and decrease HSV2 DNA copy number, suggesting that siRNA can inhibit HSV2 DNA replication through silencing ICP4 gene.

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

Critical role of microRNA-155 in herpes simplex encephalitis.

PubMed

Bhela, Siddheshvar; Mulik, Sachin; Reddy, Pradeep B J; Richardson, Raphael L; Gimenez, Fernanda; Rajasagi, Naveen K; Veiga-Parga, Tamara; Osmand, Alexander P; Rouse, Barry T

2014-03-15

HSV infection of adult humans occasionally results in life-threatening herpes simplex encephalitis (HSE) for reasons that remain to be defined. An animal system that could prove useful to model HSE could be microRNA-155 knockout (miR-155KO) mice. Thus, we observe that mice with a deficiency of miR-155 are highly susceptible to HSE with a majority of animals (75-80%) experiencing development of HSE after ocular infection with HSV-1. The lesions appeared to primarily represent the destructive consequences of viral replication, and animals could be protected from HSE by acyclovir treatment provided 4 d after ocular infection. The miR-155KO animals were also more susceptible to development of zosteriform lesions, a reflection of viral replication and dissemination within the nervous system. One explanation for the heightened susceptibility to HSE and zosteriform lesions could be because miR-155KO animals develop diminished CD8 T cell responses when the numbers, functionality, and homing capacity of effector CD8 T cell responses were compared. Indeed, adoptive transfer of HSV-immune CD8 T cells to infected miR-155KO mice at 24 h postinfection provided protection from HSE. Deficiencies in CD8 T cell numbers and function also explained the observation that miR-155KO animals were less able than control animals to maintain HSV latency. To our knowledge, our observations may be the first to link miR-155 expression with increased susceptibility of the nervous system to virus infection.

Interplay between Herpesvirus Infection and Host Defense by PML Nuclear Bodies.

PubMed

Tavalai, Nina; Stamminger, Thomas

2009-12-01

In recent studies we and others have identified the cellular proteins PML, hDaxx, and Sp100, which form a subnuclear structure known as nuclear domain 10 (ND10) or PML nuclear bodies (PML-NBs), as host restriction factors that counteract herpesviral infections by inhibiting viral replication at different stages. The antiviral function of ND10, however, is antagonized by viral regulatory proteins (e.g., ICP0 of herpes simplex virus; IE1 of human cytomegalovirus) which induce either a modification or disruption of ND10. This review will summarize the current knowledge on how viral replication is inhibited by ND10 proteins. Furthermore, herpesviral strategies to defeat this host defense mechanism are discussed.

[Folliculitis barbae in herpes simplex infection].

PubMed

Löhrer, R; Rübben, A

2004-01-01

A 60-year-old male athlete developed a folliculitis in the beard region after several competitions. After identification of herpes simplex antigen within the lesions, systemic therapy with acyclovir led to rapid improvement. In folliculitis resistant to antibiotic and anti-inflammatory therapy, viral and mycotic infections as well as eosinophilic folliculitis should be considered as differential diagnostic possibilities.

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.

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

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.

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.

Novel Role for Protein Inhibitor of Activated STAT 4 (PIAS4) in the Restriction of Herpes Simplex Virus 1 by the Cellular Intrinsic Antiviral Immune Response.

PubMed

Conn, Kristen L; Wasson, Peter; McFarlane, Steven; Tong, Lily; Brown, James R; Grant, Kyle G; Domingues, Patricia; Boutell, Chris

2016-05-01

Small ubiquitin-like modifier (SUMO) is used by the intrinsic antiviral immune response to restrict viral pathogens, such as herpes simplex virus 1 (HSV-1). Despite characterization of the host factors that rely on SUMOylation to exert their antiviral effects, the enzymes that mediate these SUMOylation events remain to be defined. We show that unconjugated SUMO levels are largely maintained throughout infection regardless of the presence of ICP0, the HSV-1 SUMO-targeted ubiquitin ligase. Moreover, in the absence of ICP0, high-molecular-weight SUMO-conjugated proteins do not accumulate if HSV-1 DNA does not replicate. These data highlight the continued importance for SUMO signaling throughout infection. We show that the SUMO ligase protein inhibitor of activated STAT 4 (PIAS4) is upregulated during HSV-1 infection and localizes to nuclear domains that contain viral DNA. PIAS4 is recruited to sites associated with HSV-1 genome entry through SUMO interaction motif (SIM)-dependent mechanisms that are destabilized by ICP0. In contrast, PIAS4 accumulates in replication compartments through SIM-independent mechanisms irrespective of ICP0 expression. Depletion of PIAS4 enhances the replication of ICP0-null mutant HSV-1, which is susceptible to restriction by the intrinsic antiviral immune response. The mechanisms of PIAS4-mediated restriction are synergistic with the restriction mechanisms of a characterized intrinsic antiviral factor, promyelocytic leukemia protein, and are antagonized by ICP0. We provide the first evidence that PIAS4 is an intrinsic antiviral factor. This novel role for PIAS4 in intrinsic antiviral immunity contrasts with the known roles of PIAS proteins as suppressors of innate immunity. Posttranslational modifications with small ubiquitin-like modifier (SUMO) proteins regulate multiple aspects of host immunity and viral replication. The protein inhibitor of activated STAT (PIAS) family of SUMO ligases is predominantly associated with the suppression of innate immune signaling. We now identify a unique and contrasting role for PIAS proteins as positive regulators of the intrinsic antiviral immune response to herpes simplex virus 1 (HSV-1) infection. We show that PIAS4 relocalizes to nuclear domains that contain viral DNA throughout infection. Depletion of PIAS4, either alone or in combination with the intrinsic antiviral factor promyelocytic leukemia protein, significantly impairs the intrinsic antiviral immune response to HSV-1 infection. Our data reveal a novel and dynamic role for PIAS4 in the cellular-mediated restriction of herpesviruses and establish a new functional role for the PIAS family of SUMO ligases in the intrinsic antiviral immune response to DNA virus infection. Copyright © 2016 Conn et al.

Novel Role for Protein Inhibitor of Activated STAT 4 (PIAS4) in the Restriction of Herpes Simplex Virus 1 by the Cellular Intrinsic Antiviral Immune Response

PubMed Central

Conn, Kristen L.; Wasson, Peter; McFarlane, Steven; Tong, Lily; Brown, James R.; Grant, Kyle G.; Domingues, Patricia

2016-01-01

ABSTRACT Small ubiquitin-like modifier (SUMO) is used by the intrinsic antiviral immune response to restrict viral pathogens, such as herpes simplex virus 1 (HSV-1). Despite characterization of the host factors that rely on SUMOylation to exert their antiviral effects, the enzymes that mediate these SUMOylation events remain to be defined. We show that unconjugated SUMO levels are largely maintained throughout infection regardless of the presence of ICP0, the HSV-1 SUMO-targeted ubiquitin ligase. Moreover, in the absence of ICP0, high-molecular-weight SUMO-conjugated proteins do not accumulate if HSV-1 DNA does not replicate. These data highlight the continued importance for SUMO signaling throughout infection. We show that the SUMO ligase protein inhibitor of activated STAT 4 (PIAS4) is upregulated during HSV-1 infection and localizes to nuclear domains that contain viral DNA. PIAS4 is recruited to sites associated with HSV-1 genome entry through SUMO interaction motif (SIM)-dependent mechanisms that are destabilized by ICP0. In contrast, PIAS4 accumulates in replication compartments through SIM-independent mechanisms irrespective of ICP0 expression. Depletion of PIAS4 enhances the replication of ICP0-null mutant HSV-1, which is susceptible to restriction by the intrinsic antiviral immune response. The mechanisms of PIAS4-mediated restriction are synergistic with the restriction mechanisms of a characterized intrinsic antiviral factor, promyelocytic leukemia protein, and are antagonized by ICP0. We provide the first evidence that PIAS4 is an intrinsic antiviral factor. This novel role for PIAS4 in intrinsic antiviral immunity contrasts with the known roles of PIAS proteins as suppressors of innate immunity. IMPORTANCE Posttranslational modifications with small ubiquitin-like modifier (SUMO) proteins regulate multiple aspects of host immunity and viral replication. The protein inhibitor of activated STAT (PIAS) family of SUMO ligases is predominantly associated with the suppression of innate immune signaling. We now identify a unique and contrasting role for PIAS proteins as positive regulators of the intrinsic antiviral immune response to herpes simplex virus 1 (HSV-1) infection. We show that PIAS4 relocalizes to nuclear domains that contain viral DNA throughout infection. Depletion of PIAS4, either alone or in combination with the intrinsic antiviral factor promyelocytic leukemia protein, significantly impairs the intrinsic antiviral immune response to HSV-1 infection. Our data reveal a novel and dynamic role for PIAS4 in the cellular-mediated restriction of herpesviruses and establish a new functional role for the PIAS family of SUMO ligases in the intrinsic antiviral immune response to DNA virus infection. PMID:26937035

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

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.

High conservation of herpes simplex virus UL5/UL52 helicase-primase complex in the era of new antiviral therapies.

PubMed

Collot, Marianne; Rouard, Caroline; Brunet, Christel; Agut, Henri; Boutolleau, David; Burrel, Sonia

2016-04-01

The emergence of herpes simplex virus (HSV) resistance to current antiviral drugs, that all target the viral DNA polymerase, constitutes a major obstacle to antiviral treatment effectiveness of HSV infections, especially in immunocompromised patients. A novel and promising class of inhibitors of the HSV UL5/UL52 helicase-primase (HP) complex has been reported to hinder viral replication with a high potency. In this study, we describe the low natural polymorphism (interstrain identity >99.1% at both nucleotide and amino acid levels) of HSV HP complex subunits pUL5 and pUL52 among 64 HSV (32 HSV-1 and 32 HSV-2) clinical isolates, and we show that the HSV resistance profile to the first-line antiviral drug acyclovir (ACV) does not impact on the natural polymorphism of HSV HP complex. Genotypic tools and polymorphism data concerning HSV HP complex provided herein will be useful to detect drug resistance mutations in a relevant time frame when HP inhibitors (HPIs), i.e., amenamevir and pritelivir, will be available in medical practice. Copyright © 2016 Elsevier B.V. All rights reserved.

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.

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.

Houttuynia cordata Targets the Beginning Stage of Herpes Simplex Virus Infection

PubMed Central

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

2015-01-01

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

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

PubMed

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

2015-01-01

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

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.

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 ...

Aerophagia and belching after herpes simplex encephalitis.

PubMed

Scheid, Rainer; Teich, Niels; Schroeter, Matthias L

2008-03-01

The etiology of abnormal belching is not known. Currently, it is being subsumed under "functional gastroduodenal disorders." Here, we report the unusual case history of a patient who developed aerophagia and consecutive excessive belching in association with herpes simplex encephalitis. The case report adds to the limited information about potential organic geneses of belching. Implications for possible medical therapies are discussed.

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.

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.

Deletion of the S component inverted repeat sequence c' and the nonessential genes U(S)1 through U(S)5 from the herpes simplex virus type 1 genome substantially impairs productive viral infection in cell culture and pathogenesis in the rat central nervous system.

PubMed

Rasty, S; Poliani, P L; Fink, D J; Glorioso, J C

1997-08-01

A distinctive feature of the genetic make-up of herpes simplex virus type 1 (HSV-1), a human neurotropic virus, is that approximately half of the 81 known viral genes are not absolutely required for productive infection in Vero cells, and most can be individually deleted without substantially impairing viral replication in cell culture. If large blocks of contiguous viral genes could be replaced with foreign DNA sequences, it would be possible to engineer highly attenuated recombinant HSV-1 gene transfer vectors capable of carrying large cellular genes or multiple genes having related functions. We report the isolation and characterization of an HSV-1 mutant, designated d311, containing a 12 kb deletion of viral DNA located between the L-S Junction a sequence and the U(S)6 gene, spanning the S component inverted repeat sequence c' and the nonessential genes U(S)1 through U(S)5. Replication of d311 was totally inhibited in rat B103 and mouse Neuro-2A neuroblastoma cell lines, and was reduced by over three orders of magnitude in human SK-N-SH neuroblastoma cells compared to wild-type (wt) HSV-1 KOS. This suggested that the deleted genes, while nonessential for replication in Vero cells, play an important role in HSV replication in neuronal cells, particularly those of rodent origin. Unlike wt KOS which replicated locally and spread to other regions of brain following stereotactic inoculation into rat hippocampus, d311 was unable to replicate and spread within the brain, and did not cause any apparent local neuronal cell damage. These results demonstrate that d311 is highly attenuated for the rat central nervous system. d311 and other mutants of HSV containing major deletions of the nonessential genes within U(S) have the potential to serve as useful tools for gene transfer applications to brain.

Demonstration of the oncogenic potential of Herpes simplex viruses and human cytomegalovirus. [UV radiation

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

Rapp, F.; Li, J.L.H.

1975-01-01

The following topics are reviewed: transformation of hamster embryo cells by herpes simplex viruses and human cytomegalovirus; the use of uv radiation and photodynamic action to inactivate virus infectivity while retaining the transformation potential of the virus; detection of virus-specific antigens in transformed cells; oncogenicity of HSV- and CMV-transformed cells in vivo; immunological studies of metastases induced by herpes virus-transformed cells; resistance of transformed cells to superinfection; maintenance of the virus genome in the transformed state; and stimulation of cellular DNA synthesis by human cytomegalovirus. (HLW)

Antiviral activity of 2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl-5-iodocytosine against human cytomegalovirus in human skin fibroblasts.

PubMed Central

Colacino, J M; Lopez, C

1985-01-01

2'-Deoxy-2'-fluoro-beta-D-arabinofuranosyl-5-iodocytosine (FIAC) was shown to be a selective anti-human cytomegalovirus agent in vitro with a 50% antiviral effective dose of 0.6 microM (J. M. Colacino and C. Lopez, Antimicrob. Agents Chemother. 26:505-508, 1983) and a 50% cell growth inhibitory dose of 8 microM. Antiviral activity was more readily reversed with 10-fold excess thymidine, whereby the 50% effective dose was increased to 11.3 microM. FIAC-induced cytotoxicity was more readily reversed with 10-fold excess of deoxycytidine, whereby the 50% inhibitory dose was increased to greater than 100 microM. Thymidine was unable to reverse completely the antiviral activity of FIAC. Although, the extent of phosphorylation of thymidine, deoxycytidine, and deoxyuridine was 6-, 4-, and 4-fold greater, respectively, in human cytomegalovirus-infected cell lysates than in uninfected cell lysates, the extent of phosphorylation of FIAC was only 1.3-fold greater in human cytomegalovirus-infected cell lysates than in uninfected cell lysates. By comparison, the extent of FIAC phosphorylation was 500 times greater in herpes simplex virus type 1-infected cells than in uninfected cell lysates. Methotrexate was 400 times more effective against human cytomegalovirus replication than it was against herpes simplex virus type 1 replication, indicating that thymidylate synthetase may be important for human cytomegalovirus replication. However, 10 microM FIAC did not inhibit thymidylate synthetase activity in uninfected or virus-infected cells as determined by their metabolism of [6-3H]deoxyuridine in the presence or absence of drug. FIAC at 1 microM suppresses and FIAC at 10 microM completely inhibits human cytomegalovirus DNA replication as indicated by Southern blot analysis. This inhibition was reversible. FIAC incorporation into the DNA of human cytomegalovirus strain AD169-infected cells was stimulated relative to that in nondividing, uninfected cells. Images PMID:3010842

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.

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(®).

An HSV-2 Trivalent Vaccine Is Immunogenic in Rhesus Macaques and Highly Efficacious in Guinea Pigs.

PubMed

Awasthi, Sita; Hook, Lauren M; Shaw, Carolyn E; Pahar, Bapi; Stagray, Jacob A; Liu, David; Veazey, Ronald S; Friedman, Harvey M

2017-01-01

A genital herpes vaccine is urgently needed to prevent pain and suffering, reduce the incidence of neonatal herpes, and decrease the risk of HIV acquisition and transmission that accompanies genital infection. We evaluated a trivalent HSV-2 subunit antigen vaccine administered with CpG and alum in rhesus macaques and guinea pigs. The vaccine contains glycoproteins C, D and E (gC2, gD2, gE2) to block virus entry by gD2 and immune evasion by gC2 and gE2. In rhesus macaques, the trivalent vaccine induced plasma and mucosa neutralizing antibodies, antibodies that block gC2 and gE2 immune evasion activities, and stimulated CD4 T cell responses. After intravaginal challenge, a self-limited vaginal infection of brief duration was detected by histopathology and immunohistochemistry in naïve, but not in trivalent immunized macaques. Vaccine efficacy was evaluated in female guinea pigs. Animals were mock immunized, or immunized with gD2, the trivalent vaccine or the trivalent vaccine followed by a booster dose of gD2 (trivalent + gD2). The trivalent and trivalent + gD2 groups were 97% and 99% efficacious, respectively in preventing genital lesions and both outperformed gD2 alone. As a marker of transmission risk, vaginal swabs were evaluated daily for HSV-2 DNA and replication competent virus between five and seven weeks after challenge. HSV-2 DNA shedding was reduced in all groups compared with mock. Shedding of replication competent virus occurred on fewer days in the trivalent than gD2 immunized animals while the trivalent + gD2 group had no shedding of replication competent virus. Overall, the trivalent group had genital lesions on < 1% days and shedding of replication competent virus on 0.2% days. The vaccine has outstanding potential for prevention of genital herpes in humans.

Genital herpes - self-care

MedlinePlus

Herpes - genital - self-care; Herpes simplex - genital - self-care; Herpesvirus 2 - self-care; HSV-2 - self-care ... Call your health care provider if you have any of the following: Symptoms of an outbreak that worsen despite medicine and self-care ...

Isolation of herpes simplex virus from the genital tract during symptomatic recurrence on the buttocks.

PubMed

Kerkering, Katrina; Gardella, Carolyn; Selke, Stacy; Krantz, Elizabeth; Corey, Lawrence; Wald, Anna

2006-10-01

To estimate the frequency of isolation of herpes simplex virus (HSV) from the genital tract when recurrent herpes lesions were present on the buttocks. Data were extracted from a prospectively observed cohort attending a research clinic for genital herpes infections between 1975 and 2001. All patients with a documented herpes lesion on the buttocks, upper thigh or gluteal cleft ("buttock recurrence") and concomitant viral cultures from genital sites including the perianal region were eligible. We reviewed records of 237 subjects, 151 women and 86 men, with a total of 572 buttock recurrences. Of the 1,592 days with genital culture information during a buttock recurrence, participants had concurrent genital lesions on 311 (20%, 95% confidence interval [CI] 14-27%) of these days. Overall, HSV was isolated from the genital region on 12% (95% CI 8-17%) of days during a buttock recurrence. In the absence of genital lesions, HSV was isolated from the genital area on 7% (95% CI 4%-11%) of days during a buttock recurrence and, among women, from the vulvar or cervical sites on 1% of days. Viral shedding of herpes simplex virus from the genital area is a relatively common occurrence during a buttock recurrence of genital herpes, even without concurrent genital lesions, reflecting perhaps reactivation from concomitant regions of the sacral neural ganglia. Patients with buttock herpes recurrences should be instructed about the risk of genital shedding during such recurrences. II-2.

Inhibitors of signal peptide peptidase (SPP) affect HSV-1 infectivity in vitro and in vivo

PubMed Central

Allen, Sariah J.; Mott, Kevin R.; Ghiasi, Homayon

2014-01-01

Recently we have shown that the highly conserved herpes simplex virus glycoprotein K (gK) binds to signal peptide peptidase (SPP), also known as minor histocompatibility antigen H13. In this study we have demonstrated for the first time that inhibitors of SPP, such as L685,458, (Z-LL)2 ketone, aspirin, ibuprofen and DAPT, significantly reduced HSV-1 replication in tissue culture. Inhibition of SPP activity via (Z-LL)2 ketone significantly reduced viral transcripts in the nucleus of infected cells. Finally, when administered during primary infection, (Z-LL)2 ketone inhibitor reduced HSV-1 replication in the eyes of ocularly infected mice. Thus, blocking SPP activity may represent a clinically effective and expedient approach to the reduction of viral replication and the resulting pathology. PMID:24768597

Identification of interaction domains within the UL37 tegument protein of herpes simplex virus type 1.

PubMed

Bucks, Michelle A; Murphy, Michael A; O'Regan, Kevin J; Courtney, Richard J

2011-07-20

Herpes simplex virus type 1 (HSV-1) UL37 is a 1123 amino acid tegument protein that self-associates and binds to the tegument protein UL36 (VP1/2). Studies were undertaken to identify regions of UL37 involved in these protein-protein interactions. Coimmunoprecipitation assays showed that residues within the carboxy-terminal half of UL37, amino acids 568-1123, are important for interaction with UL36. Coimmunoprecipitation assays also revealed that amino acids 1-300 and 568-1123 of UL37 are capable of self-association. UL37 appears to self-associate only under conditions when UL36 is not present or is present in low amounts, suggesting UL36 and UL37 may compete for binding. Transfection-infection experiments were performed to identify domains of UL37 that complement the UL37 deletion virus, K∆UL37. The carboxy-terminal region of UL37 (residues 568-1123) partially rescues the K∆UL37 infection. These results suggest the C-terminus of UL37 may contribute to its essential functional role within the virus-infected cell. Copyright © 2011 Elsevier Inc. All rights reserved.

Psychosocial Treatment for Recurrent Genital Herpes.

ERIC Educational Resources Information Center

Longo, David J.; And Others

1988-01-01

Assigned 21 individuals with recurrent genital herpes to psychosocial intervention, social support, or waiting-list control conditions. Those receiving psychosocial intervention (herpes simplex virus information, relaxation training, stress management instructions, and an imagery technique) reported significantly greater reductions in herpes…

Urinary retention due to herpes virus infections.

PubMed

Yamanishi, T; Yasuda, K; Sakakibara, R; Hattori, T; Uchiyama, T; Minamide, M; Ito, H

1998-01-01

Urinary retention is uncommon in patients with herpes zoster and anogenital herpes simplex. Seven patients (four men, three women) with a mean age of 68.1 years (range, 35-84) with urinary retention due to herpes zoster (n = 6) or anogenital herpes simplex (n = 1) were studied. Six patients had unilateral skin eruption in the saddle area (S2-4 dermatome) and one patient with herpes zoster had a skin lesion in the L4-5 dermatome. All patients had detrusor areflexia without bladder sensation, and two of them had inactive external sphincter on electromyography at presentation. Clean intermittent catheterization was performed, and voiding function was recovered in 4-6 weeks (average, 5.4) in all patients. Urodynamic study was repeated after recovery of micturition in three patients, and they returned to normal on cystometrography and external sphincter electromyography. Acute urinary retention associated with anogenital herpes infection has been thought to occur when the meninges or sacral spinal ganglia were involved, and, in conclusion, this condition may be considered to be reversible.

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.

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome mimicking herpes simplex encephalitis on imaging studies.

PubMed

Gieraerts, Christopher; Demaerel, Philippe; Van Damme, Philip; Wilms, Guido

2013-01-01

We present a case in which mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome mimicked the clinical and radiological signs of herpes simplex encephalitis. In a patient with subacute encephalopathy, on computed tomography and magnetic resonance imaging, lesions were present in both temporal lobes extending to both insular regions with sparing of the lentiform nuclei and in both posterior straight and cingulate gyri. Final diagnosis of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome was based on biochemical investigations on cerebrospinal fluid, electromyogram, muscle biopsy, and genetic analysis. On diffusion-weighted imaging, diffusion restriction was present in some parts of the lesions but not throughout the entire lesions. We suggest that this could be an important sign in the differential diagnosis with herpes simplex encephalitis.

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.

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.

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.

The Challenges and Opportunities for Development of a T-Cell Epitope-Based Herpes Simplex Vaccine

PubMed Central

Kuo, Tiffany; Wang, Christine; Badakhshan, Tina; Chilukuri, Sravya; BenMohamed, Lbachir

2014-01-01

The infections with herpes simplex virus type 1 and type 2 (HSV-1 & HSV-2) have been prevalent since the ancient Greek times. To this day, they still affect a staggering number of over a half billion individuals worldwide. HSV-2 infections cause painful genital herpes, encephalitis, and death in newborns. HSV-1 infections are more prevalent than HSV-2 infections and cause potentially blinding ocular herpes, oro-facial herpes and encephalitis. While genital herpes in mainly caused by HSV-2 infections, in recent years, there is an increase in the proportion of genital herpes caused by HSV-1 infections in young adults, which reach 50% in some western societies. While prophylactic and therapeutic HSV vaccines remain urgently needed for centuries their development has been notoriously difficult. During the most recent National Institute of Health (NIH) workshop titled "Next Generation Herpes Simplex Virus Vaccines: The Challenges and Opportunities", basic researchers, funding agencies, and pharmaceutical representatives gathered: (i) to assess the status of herpes vaccine research; and (ii) to identify the gaps and propose alternative approaches in developing a safe and efficient herpes vaccine. One “common denominator” among previously failed clinical herpes vaccine trials is that they either used a whole virus or whole viral proteins, which contain both pathogenic “symptomatic” and protective “asymptomatic” antigens/epitopes. In this report, we continue to advocate that using an “asymptomatic” epitope-based vaccine strategy that selectively incorporates protective epitopes which: (i) are exclusively recognized, in vitro, by effector memory CD4+ and CD8+ TEM cells from “naturally” protected seropositive asymptomatic individuals; and (ii) protect, in vivo, human leukocyte antigen (HLA) transgenic animal models from ocular and genital herpes infections and diseases, could be the answer to many of the scientific challenges facing HSV vaccine development. We review the role of animal models in herpes vaccine development and discuss its current status, challenges, and prospects. PMID:25446827

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.

Fatal Neonatal Herpes Simplex Infection Likely from Unrecognized Breast Lesions.

PubMed

Field, Scott S

2016-02-01

Type 1 herpes simplex virus (HSV-1) is very prevalent yet in rare circumstances can lead to fatal neonatal disease. Genital acquisition of type 2 HSV is the usual mode for neonatal herpes, but HSV-1 transmission by genital or extragenital means may result in greater mortality rates. A very rare scenario is presented in which the mode of transmission was likely through breast lesions. The lesions were seen by nurses as well as the lactation consultant and obstetrician in the hospital after delivery of the affected baby but not recognized as possibly being caused by herpes. The baby died 9 days after birth with hepatic failure and disseminated intravascular coagulation. Peripartum health care workers need to be aware of potential nongenital (including from the breast[s]) neonatal herpes acquisition, which can be lethal. © The Author(s) 2015.

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

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.

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

Combination of a fusogenic glycoprotein, prodrug activation, and oncolytic herpes simplex virus for enhanced local tumor control.

PubMed

Simpson, Guy R; Han, Ziqun; Liu, Binlei; Wang, Yibing; Campbell, Gregor; Coffin, Robert S

2006-05-01

We have previously developed an oncolytic herpes simplex virus-1 based on a clinical virus isolate, which was deleted for ICP34.5 to provide tumor selected replication and ICP47 to increase antigen presentation as well as tumor selective virus replication. A phase I/II clinical trial using a version of this virus expressing granulocyte macrophage colony-stimulating factor has shown promising results. The work reported here aimed to develop a version of this virus in which local tumor control was further increased through the combined expression of a highly potent prodrug activating gene [yeast cytosine deaminase/uracil phospho-ribosyltransferase fusion (Fcy::Fur)] and the fusogenic glycoprotein from gibbon ape leukemia virus (GALV), which it was hoped would aid the spread of the activated prodrug through the tumor. Viruses expressing the two genes individually or in combination were constructed and tested, showing (a) GALV and/or Fcy::Fur expression did not affect virus growth; (b) GALV expression causes cell fusion and increases the tumor cell killing at least 30-fold in vitro and tumor shrinkage 5- to 10-fold in vivo; (c) additional expression of Fcy::Fur combined with 5-fluorocytosine administration improves tumor shrinkage further. These results indicate, therefore, that the combined expression of the GALV protein and Fcy::Fur provides a highly potent oncolytic virus with improved capabilities for local tumor control. It is intended to enter the GALV/Fcy::Fur expressing virus into clinical development for the treatment of tumor types, such as pancreatic or lung cancer, where local control would be anticipated to be clinically advantageous.

Innate immune response during herpes simplex virus encephalitis and development of immunomodulatory strategies.

PubMed

Piret, Jocelyne; Boivin, Guy

2015-09-01

Herpes simplex viruses are large double-stranded DNA viruses. These viruses have the ability to establish a lifelong latency in sensory ganglia and to invade and replicate in the CNS. Apart from relatively benign mucosal infections, HSV is responsible for severe illnesses including HSV encephalitis (HSE). HSE is the most common cause of sporadic, potentially fatal viral encephalitis in Western countries. If left untreated, the mortality rate associated with HSE is approximately 70%. Despite antiviral therapy, the mortality is still higher than 30%, and almost 60% of surviving individuals develop neurological sequelae. It is suggested that direct virus-related and indirect immune-mediated mechanisms contribute to the damages occurring in the CNS during HSE. In this manuscript, we describe the innate immune response to HSV, the development of HSE in mice knock-out for proteins of the innate immune system as well as inherited deficiencies in key components of the signaling pathways involved in the production of type I interferon that could predispose individuals to develop HSE. Finally, we review several immunomodulatory strategies aimed at modulating the innate immune response at a critical time after infection that were evaluated in mouse models and could be combined with antiviral therapy to improve the prognosis of HSE. In conclusion, the cerebral innate immune response that develops during HSE is a "double-edged sword" as it is critical to control viral replication in the brain early after infection, but, if left uncontrolled, may also result in an exaggerated inflammatory response that could be detrimental to the host. Copyright © 2015 John Wiley & Sons, Ltd.

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

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

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

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

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.

Analysis of Select Herpes Simplex Virus 1 (HSV-1) Proteins for Restriction of Human Immunodeficiency Virus Type 1 (HIV-1): HSV-1 gM Protein Potently Restricts HIV-1 by Preventing Intracellular Transport and Processing of Env gp160.

PubMed

Polpitiya Arachchige, Sachith; Henke, Wyatt; Pramanik, Ankita; Kalamvoki, Maria; Stephens, Edward B

2018-01-15

Virus-encoded proteins that impair or shut down specific host cell functions during replication can be used as probes to identify potential proteins/pathways used in the replication of viruses from other families. We screened nine proteins from herpes simplex virus 1 (HSV-1) for the ability to enhance or restrict human immunodeficiency virus type 1 (HIV-1) replication. We show that several HSV-1 proteins (glycoprotein M [gM], US3, and UL24) potently restricted the replication of HIV-1. Unlike UL24 and US3, which reduced viral protein synthesis, we observed that gM restriction of HIV-1 occurred through interference with the processing and transport of gp160, resulting in a significantly reduced level of mature gp120/gp41 released from cells. Finally, we show that an HSV-1 gM mutant lacking the majority of the C-terminal domain (HA-gM[Δ345-473]) restricted neither gp160 processing nor the release of infectious virus. These studies identify proteins from heterologous viruses that can restrict viruses through novel pathways. IMPORTANCE HIV-1 infection of humans results in AIDS, characterized by the loss of CD4 + T cells and increased susceptibility to opportunistic infections. Both HIV-1 and HSV-1 can infect astrocytes and microglia of the central nervous system (CNS). Thus, the identification of HSV-1 proteins that directly restrict HIV-1 or interfere with pathways required for HIV-1 replication could lead to novel antiretroviral strategies. The results of this study show that select viral proteins from HSV-1 can potently restrict HIV-1. Further, our results indicate that the gM protein of HSV-1 restricts HIV-1 through a novel pathway by interfering with the processing of gp160 and its incorporation into virus maturing from the cell. Copyright © 2018 American Society for Microbiology.

SUMO Ligase Protein Inhibitor of Activated STAT1 (PIAS1) Is a Constituent Promyelocytic Leukemia Nuclear Body Protein That Contributes to the Intrinsic Antiviral Immune Response to Herpes Simplex Virus 1

PubMed Central

Brown, James R.; Conn, Kristen L.; Wasson, Peter; Charman, Matthew; Tong, Lily; Grant, Kyle; McFarlane, Steven

2016-01-01

ABSTRACT Aspects of intrinsic antiviral immunity are mediated by promyelocytic leukemia nuclear body (PML-NB) constituent proteins. During herpesvirus infection, these antiviral proteins are independently recruited to nuclear domains that contain infecting viral genomes to cooperatively promote viral genome silencing. Central to the execution of this particular antiviral response is the small ubiquitin-like modifier (SUMO) signaling pathway. However, the participating SUMOylation enzymes are not fully characterized. We identify the SUMO ligase protein inhibitor of activated STAT1 (PIAS1) as a constituent PML-NB protein. We show that PIAS1 localizes at PML-NBs in a SUMO interaction motif (SIM)-dependent manner that requires SUMOylated or SUMOylation-competent PML. Following infection with herpes simplex virus 1 (HSV-1), PIAS1 is recruited to nuclear sites associated with viral genome entry in a SIM-dependent manner, consistent with the SIM-dependent recruitment mechanisms of other well-characterized PML-NB proteins. In contrast to that of Daxx and Sp100, however, the recruitment of PIAS1 is enhanced by PML. PIAS1 promotes the stable accumulation of SUMO1 at nuclear sites associated with HSV-1 genome entry, whereas the accumulation of other evaluated PML-NB proteins occurs independently of PIAS1. We show that PIAS1 cooperatively contributes to HSV-1 restriction through mechanisms that are additive to those of PML and cooperative with those of PIAS4. The antiviral mechanisms of PIAS1 are counteracted by ICP0, the HSV-1 SUMO-targeted ubiquitin ligase, which disrupts the recruitment of PIAS1 to nuclear domains that contain infecting HSV-1 genomes through mechanisms that do not directly result in PIAS1 degradation. IMPORTANCE Adaptive, innate, and intrinsic immunity cooperatively and efficiently restrict the propagation of viral pathogens. Intrinsic immunity mediated by constitutively expressed cellular proteins represents the first line of intracellular defense against infection. PML-NB constituent proteins mediate aspects of intrinsic immunity to restrict herpes simplex virus 1 (HSV-1) as well as other viruses. These proteins repress viral replication through mechanisms that rely on SUMO signaling. However, the participating SUMOylation enzymes are not known. We identify the SUMO ligase PIAS1 as a constituent PML-NB antiviral protein. This finding distinguishes a SUMO ligase that may mediate signaling events important in PML-NB-mediated intrinsic immunity. Moreover, this research complements the recent identification of PIAS4 as an intrinsic antiviral factor, supporting a role for PIAS proteins as both positive and negative regulators of host immunity to virus infection. PMID:27099310

SUMO Ligase Protein Inhibitor of Activated STAT1 (PIAS1) Is a Constituent Promyelocytic Leukemia Nuclear Body Protein That Contributes to the Intrinsic Antiviral Immune Response to Herpes Simplex Virus 1.

PubMed

Brown, James R; Conn, Kristen L; Wasson, Peter; Charman, Matthew; Tong, Lily; Grant, Kyle; McFarlane, Steven; Boutell, Chris

2016-07-01

Aspects of intrinsic antiviral immunity are mediated by promyelocytic leukemia nuclear body (PML-NB) constituent proteins. During herpesvirus infection, these antiviral proteins are independently recruited to nuclear domains that contain infecting viral genomes to cooperatively promote viral genome silencing. Central to the execution of this particular antiviral response is the small ubiquitin-like modifier (SUMO) signaling pathway. However, the participating SUMOylation enzymes are not fully characterized. We identify the SUMO ligase protein inhibitor of activated STAT1 (PIAS1) as a constituent PML-NB protein. We show that PIAS1 localizes at PML-NBs in a SUMO interaction motif (SIM)-dependent manner that requires SUMOylated or SUMOylation-competent PML. Following infection with herpes simplex virus 1 (HSV-1), PIAS1 is recruited to nuclear sites associated with viral genome entry in a SIM-dependent manner, consistent with the SIM-dependent recruitment mechanisms of other well-characterized PML-NB proteins. In contrast to that of Daxx and Sp100, however, the recruitment of PIAS1 is enhanced by PML. PIAS1 promotes the stable accumulation of SUMO1 at nuclear sites associated with HSV-1 genome entry, whereas the accumulation of other evaluated PML-NB proteins occurs independently of PIAS1. We show that PIAS1 cooperatively contributes to HSV-1 restriction through mechanisms that are additive to those of PML and cooperative with those of PIAS4. The antiviral mechanisms of PIAS1 are counteracted by ICP0, the HSV-1 SUMO-targeted ubiquitin ligase, which disrupts the recruitment of PIAS1 to nuclear domains that contain infecting HSV-1 genomes through mechanisms that do not directly result in PIAS1 degradation. Adaptive, innate, and intrinsic immunity cooperatively and efficiently restrict the propagation of viral pathogens. Intrinsic immunity mediated by constitutively expressed cellular proteins represents the first line of intracellular defense against infection. PML-NB constituent proteins mediate aspects of intrinsic immunity to restrict herpes simplex virus 1 (HSV-1) as well as other viruses. These proteins repress viral replication through mechanisms that rely on SUMO signaling. However, the participating SUMOylation enzymes are not known. We identify the SUMO ligase PIAS1 as a constituent PML-NB antiviral protein. This finding distinguishes a SUMO ligase that may mediate signaling events important in PML-NB-mediated intrinsic immunity. Moreover, this research complements the recent identification of PIAS4 as an intrinsic antiviral factor, supporting a role for PIAS proteins as both positive and negative regulators of host immunity to virus infection. Copyright © 2016 Brown et al.

Autism and Herpes Simplex Encephalitis. Brief Report.

ERIC Educational Resources Information Center

Ghaziuddin, Mohammad; And Others

1992-01-01

This paper presents two case studies of children who developed herpes virus infection in the intrauterine or early postnatal period and presented with features of autism around two years of age. Other research suggesting a link between herpes and autism is reviewed. (DB)

Designing herpes viruses as oncolytics

PubMed Central

Peters, Cole; Rabkin, Samuel D

2015-01-01

Oncolytic herpes simplex virus (oHSV) was one of the first genetically-engineered oncolytic viruses. Because HSV is a natural human pathogen that can cause serious disease, it is incumbent that it can be genetically-engineered or significantly attenuated for safety. Here, we present a detailed explanation of the functions of HSV-1 genes frequently mutated to endow oncolytic activity. These genes are nonessential for growth in tissue culture cells but are important for growth in postmitotic cells, interfering with intrinsic antiviral and innate immune responses or causing pathology, functions dispensable for replication in cancer cells. Understanding the function of these genes leads to informed creation of new oHSVs with better therapeutic efficacy. Virus infection and replication can also be directed to cancer cells through tumor-selective receptor binding and transcriptional- or post-transcriptional miRNA-targeting, respectively. In addition to the direct effects of oHSV on infected cancer cells and tumors, oHSV can be “armed” with transgenes that are: reporters, to track virus replication and spread; cytotoxic, to kill uninfected tumor cells; immune modulatory, to stimulate antitumor immunity; or tumor microenvironment altering, to enhance virus spread or to inhibit tumor growth. In addition to HSV-1, other alphaherpesviruses are also discussed for their oncolytic activity. PMID:26462293

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

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…

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.

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.

"Am not was": cognitive-behavioural therapy for adjustment and identity change following herpes simplex encephalitis.

PubMed

Dewar, Bonnie-Kate; Gracey, Fergus

2007-01-01

The cognitive sequelae of encephalitis are well documented, and it is increasingly recognised that disorders of mood and anxiety can accompany these sequelae. Loss of identity is emerging as a key theme in psychotherapeutic interventions in adjustment following acquired brain injury (ABI). Cognitive-behavioural therapy can be applied to construct a new model of the self in the context of behavioural, cognitive and social sequelae of the ABI, with consideration of pre-illness identity. Behavioural experiments, in particular, may be an effective means of redefining the meaning of current situations to create a positive sense of self. In the current paper we describe the therapeutic intervention to address anxiety and changes in identity in a woman recovering from herpes simplex viral encephalitis. The intervention highlights the need to take into account the interplay between cognitive changes, such as memory and executive function, with emotion in adjustment following herpes simplex viral encephalitis.

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.

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.

Anti-herpes simplex virus 1 and immunomodulatory activities of a poly-γ- glutamic acid from Bacillus horneckiae strain APA of shallow vent origin.

PubMed

Marino-Merlo, Francesca; Papaianni, Emanuela; Maugeri, Teresa L; Zammuto, Vincenzo; Spanò, Antonio; Nicolaus, Barbara; Poli, Annarita; Di Donato, Paola; Mosca, Claudia; Mastino, Antonio; Gugliandolo, Concetta

2017-10-01

Herpes simplex virus type 1 (HSV-1) is responsible of common and widespread viral infections in humans through the world, and of rare, but extremely severe, clinical syndromes in the central nervous system. The emergence of resistant strains to drugs actually in use encourages the searching for novel antiviral compounds, including those of natural origin. In this study, the recently described poly-γ-glutamic acid (γ-PGA-APA), produced by the marine thermotolerant Bacillus horneckiae strain APA, and previously shown to possess biological and antiviral activity, was evaluated for its anti-HSV-1 and immunomodulatory properties. The biopolymer hindered the HSV-1 infection in the very early phase of virus replication. In addition, the γ-PGA-APA was shown to exert low cytotoxicity and noticeable immunomodulatory activities towards TNF-α and IL-1β gene expression. Moreover, the capacity to positively modulate the transcriptional activity of the cytokine genes was paired with increased level of activation of the transcription factor NF-kB by γ-PGA-APA. Overall, as non-cytotoxic biopolymer able to contribute in the antiviral defense against HSV-1, γ-PGA-APA could lead to the development of novel natural drugs for alternative therapies.

Unequal homologous recombination between tandemly arranged sequences stably incorporated into cultured rat cells.

PubMed Central

Stringer, J R; Kuhn, R M; Newman, J L; Meade, J C

1985-01-01

Cultured rat cells deficient in endogenous thymidine kinase activity (tk) were stably transformed with a recombination-indicator DNA substrate constructed in vitro by rearrangement of the herpes simplex virus tk gene sequences into a partially redundant permutation of the functional gene. The recombination-indicator DNA did not express tk, but was designed to allow formation of a functional tk gene via homologous recombination. A clonal cell line (519) was isolated that harbored several permuted herpes simplex virus tk genes. 519 cells spontaneously produced progeny that survived in medium containing hypoxanthine, aminopterin, and thymidine. Acquisition of resistance to hypoxanthine, aminopterin, and thymidine was accompanied by the rearrangement of the defective tk gene to functional configuration. The rearrangement apparently occurred by unequal exchange between one permuted tk gene and a replicated copy of itself. Recombination was between 500-base-pair tracts of DNA sequence homology that were separated by 3.4 kilobases. Exchanges occurred spontaneously at a frequency of approximately 5 X 10(-6) events per cell per generation. Recombination also mediated reversion to the tk- phenotype; however, the predominant mechanism by which cells escaped death in the presence of drugs rendered toxic by thymidine kinase was not recombination, but rather inactivation of the intact tk gene. Images PMID:3016511

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.

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

Tolerance and immunity in mice infected with herpes simplex virus: simultaneous induction of protective immunity and tolerance to delayed-type hypersensitivity.

PubMed

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

1981-05-01

Unresponsiveness to delayed type hypersensitivity was induced in mice following an intravenous injection of herpes simplex virus. The principal tolerogens used were thymidine kinase-deficient virus mutants which grow poorly in vivo; u.v.-inactivated and to a lesser extent formalin-inactivated virus were also tolerogenic. The tolerance induced was specific for the virus type. Despite the tolerance to delayed hypersensitivity, anti-viral immunity is present as determined by the rapid inactivation of infectious virus. The mechanism of tolerance to herpes virus and the importance of these observations for the pathogenesis of viral disease is discussed.

Tolerance and immunity in mice infected with herpes simplex virus: simultaneous induction of protective immunity and tolerance to delayed-type hypersensitivity.

PubMed Central

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

1981-01-01

Unresponsiveness to delayed type hypersensitivity was induced in mice following an intravenous injection of herpes simplex virus. The principal tolerogens used were thymidine kinase-deficient virus mutants which grow poorly in vivo; u.v.-inactivated and to a lesser extent formalin-inactivated virus were also tolerogenic. The tolerance induced was specific for the virus type. Despite the tolerance to delayed hypersensitivity, anti-viral immunity is present as determined by the rapid inactivation of infectious virus. The mechanism of tolerance to herpes virus and the importance of these observations for the pathogenesis of viral disease is discussed. PMID:7251047

Analysis of HSV viral reactivation in explants of sensory neurons

PubMed Central

Turner, Anne-Marie W.; Kristie, Thomas M.

2014-01-01

As with all Herpesviruses, Herpes simplex virus (HSV) has both a lytic replication phase and a latency-reactivation cycle. During lytic replication, there is an ordered cascade of viral gene expression that leads to the synthesis of infectious viral progeny. In contrast, latency is characterized by the lack of significant lytic gene expression and the absence of infectious virus. Reactivation from latency is characterized by the re-entry of the virus into the lytic replication cycle and the production of recurrent disease. This unit describes the establishment of the mouse sensory neuron model of HSV-1 latency-reactivation as a useful in vivo system for the analysis of mechanisms involved in latency and reactivation. Assays including the determination of viral yields, immunohistochemical/immunofluorescent detection of viral antigens, and mRNA quantitation are used in experiments designed to investigate the network of cellular and viral proteins regulating HSV-1 lytic infection, latency, and reactivation. PMID:25367271

Dual Function of the pUL7-pUL51 Tegument Protein Complex in Herpes Simplex Virus 1 Infection.

PubMed

Albecka, Anna; Owen, Danielle J; Ivanova, Lyudmila; Brun, Juliane; Liman, Rukayya; Davies, Laura; Ahmed, M Firoz; Colaco, Susanna; Hollinshead, Michael; Graham, Stephen C; Crump, Colin M

2017-01-15

The tegument of herpesviruses is a highly complex structural layer between the nucleocapsid and the envelope of virions. Tegument proteins play both structural and regulatory functions during replication and spread, but the interactions and functions of many of these proteins are poorly understood. Here we focus on two tegument proteins from herpes simplex virus 1 (HSV-1), pUL7 and pUL51, which have homologues in all other herpesviruses. We have now identified that HSV-1 pUL7 and pUL51 form a stable and direct protein-protein interaction, their expression levels rely on the presence of each other, and they function as a complex in infected cells. We demonstrate that expression of the pUL7-pUL51 complex is important for efficient HSV-1 assembly and plaque formation. Furthermore, we also discovered that the pUL7-pUL51 complex localizes to focal adhesions at the plasma membrane in both infected cells and in the absence of other viral proteins. The expression of pUL7-pUL51 is important to stabilize focal adhesions and maintain cell morphology in infected cells and cells infected with viruses lacking pUL7 and/or pUL51 round up more rapidly than cells infected with wild-type HSV-1. Our data suggest that, in addition to the previously reported functions in virus assembly and spread for pUL51, the pUL7-pUL51 complex is important for maintaining the attachment of infected cells to their surroundings through modulating the activity of focal adhesion complexes. Herpesviridae is a large family of highly successful human and animal pathogens. Virions of these viruses are composed of many different proteins, most of which are contained within the tegument, a complex structural layer between the nucleocapsid and the envelope within virus particles. Tegument proteins have important roles in assembling virus particles as well as modifying host cells to promote virus replication and spread. However, little is known about the function of many tegument proteins during virus replication. Our study focuses on two tegument proteins from herpes simplex virus 1 that are conserved in all herpesviruses: pUL7 and pUL51. We demonstrate that these proteins directly interact and form a functional complex that is important for both virus assembly and modulation of host cell morphology. Further, we identify for the first time that these conserved herpesvirus tegument proteins localize to focal adhesions in addition to cytoplasmic juxtanuclear membranes within infected cells. Copyright © 2017 Albecka et al.

[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.

Protection from genital herpes disease, seroconversion and latent infection in a non-lethal murine genital infection model by immunization with an HSV-2 replication-defective mutant virus.

PubMed

Diaz, Fernando M; Knipe, David M

2016-01-15

Viral vaccines have traditionally protected against disease, but for viruses that establish latent infection, it is desirable for the vaccine to reduce infection to reduce latent infection and reactivation. While seroconversion has been used in clinical trials of herpes simplex virus (HSV) vaccines to measure protection from infection, this has not been modeled in animal infection systems. To measure the ability of a genital herpes vaccine candidate to protect against various aspects of infection, we established a non-lethal murine model of genital HSV-2 infection, an ELISA assay to measure antibodies specific for infected cell protein 8 (ICP8), and a very sensitive qPCR assay. Using these assays, we observed that immunization with HSV-2 dl5-29 virus reduced disease, viral shedding, seroconversion, and latent infection by the HSV-2 challenge virus. Therefore, it may be feasible to obtain protection against genital disease, seroconversion and latent infection by immunization, even if sterilizing immunity is not achieved. Copyright © 2015 Elsevier Inc. All rights reserved.

Epidemiology of orofacial herpes simplex virus infections in the general population in France: results of the HERPIMAX study.

PubMed

Malvy, D; Ezzedine, K; Lançon, F; Halioua, B; Rezvani, A; Bertrais, S; Chanzy, B; Malkin, J-E; Morand, P; De Labareyre, C; Hercberg, S; El Hasnaoui, A

2007-11-01

Prevalence of clinically manifest orofacial herpes in the general population is poorly characterized. Objectives To establish the lifetime prevalence of clinically manifest orofacial herpes and its relationship with herpes simplex virus (HSV) serotype in the French general population. Subjects (N = 2796) were serotyped for HSV1 and HSV2 and provided data on herpetic symptoms by questionnaire. Subjects reporting at least one episode of orobuccal ulcerative mucosal lesions were classified as clinically manifest orofacial herpes. Lifetime prevalence of clinically manifest orofacial herpes was 38.3% (42.1% in women, 32.4% in men). Prevalence in subjects seropositive for HSV1 was 50.3%. This prevalence rate was independent of HSV2 serotype. Prevalence in subjects infected with HSV2 alone was similar to that in subjects seronegative for HSV. Lack of case ascertainment limits precision of the data. Clinically manifest orofacial herpes was reported in one third of the sample, principally associated with HSV1 infection. HSV2 infection did not produce orofacial lesions nor influence clinical manifestations of HSV1 infection.

Mucosal Herpes Immunity and Immunopathology to Ocular and Genital Herpes Simplex Virus Infections

PubMed Central

Chentoufi, Aziz Alami; BenMohamed, Lbachir

2012-01-01

Herpes simplex viruses type 1 and type 2 (HSV-1 and HSV-2) are amongst the most common human infectious viral pathogens capable of causing serious clinical diseases at every stage of life, from fatal disseminated disease in newborns to cold sores genital ulcerations and blinding eye disease. Primary mucocutaneous infection with HSV-1 & HSV-2 is followed by a lifelong viral latency in the sensory ganglia. In the majority of cases, herpes infections are clinically asymptomatic. However, in symptomatic individuals, the latent HSV can spontaneously and frequently reactivate, reinfecting the muco-cutaneous surfaces and causing painful recurrent diseases. The innate and adaptive mucosal immunities to herpes infections and disease remain to be fully characterized. The understanding of innate and adaptive immune mechanisms operating at muco-cutaneous surfaces is fundamental to the design of next-generation herpes vaccines. In this paper, the phenotypic and functional properties of innate and adaptive mucosal immune cells, their role in antiherpes immunity, and immunopathology are reviewed. The progress and limitations in developing a safe and efficient mucosal herpes vaccine are discussed. PMID:23320014

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.

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).

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

Two-dimensional ultrasonography of the brain: its diagnostic usefullness in herpes simplex encephalitis and cytomegalic inclusion disease.

PubMed

Matsumoto, N; Yano, S; Miyao, M; Kamoshita, S; Itoh, K

1983-01-01

We have used brain ultrasonography in diagnosing and following up two infants, one with herpes simplex encephalitis and the other with cytomegalic inclusion disease. It was found that this technique was very useful to observe the changes of the brain parenchyma such as cystic degeneration and periventricular calcification. Also because it is non-invasive and an easy procedure, ultrasonography can be applied even for infants in critical condition when needed.

Herpetiform keratitis and palmoplantar hyperkeratosis: warning signs for Richner-Hanhart syndrome.

PubMed

Soares, Diogo C; Stroparo, Mariana N; Lian, Yu C; Takakura, Cristina Y; Wolf, Sabrina; Betz, Regina; Kim, Chong A

2017-05-01

Richner-Hanhart syndrome (RHS, tyrosinemia type II) is a rare, autosomal recessive inborn error of tyrosine metabolism caused by tyrosine aminotransferase deficiency. It is characterized by photophobia due to keratitis, painful palmoplantar hyperkeratosis, variable mental retardation, and elevated serum tyrosine levels. Patients are often misdiagnosed with herpes simplex keratitis. We report on a a boy from Brazil who presented with bilateral keratitis secondary to RHS, which had earlier been misdiagnosed as herpes simplex keratitis.

Herpes simplex encephalitis presenting as stroke-like symptoms with atypical MRI findings and lacking cerebrospinal fluid pleocytosis.

PubMed

Tsuboguchi, Shintaro; Wakasugi, Takahiro; Umeda, Yoshitaka; Umeda, Maiko; Oyake, Mutsuo; Fujita, Nobuya

2017-07-29

A 73-year-old woman presented with sudden onset of right hemiparesis and was diagnosed as having cerebral infarction on the basis of diffusion-weighted brain MRI, which demonstrated lesions in the left parietal cortex. On the 3rd day, the patient developed right upper limb myoclonus, aphasia, and disturbance of consciousness with high fever. On the 6th day, she was transferred to our hospital with suspected viral encephalitis, and treatment with acyclovir was started. By the 6th day, the lesions detected by MRI had expanded to the gyrus cinguli, insula and thalamus, but not to the temporal lobe. At that time, the CSF cell count was 8/μl, and this later increased to 17/μl by the 13th day. Although herpes simplex virus DNA was detected in the CSF on the 6th day, there was no evidence of CSF pleocytosis or temporal lobe abnormalities demonstrable by brain MRI throughout the whole follow-up period. This was very atypical case of herpes simplex encephalitis characterized by a stroke-like episode, atypical MRI findings, and absence of cerebrospinal fluid pleocytosis. It is important to be mindful that herpes simplex encephalitis (HSE) can have an atypical presentation, and that sufficient acyclovir treatment should be initiated until HSE can be ruled out.

Cell lines that support replication of a novel herpes simplex virus 1 U{sub L}31 deletion mutant can properly target U{sub L}34 protein to the nuclear rim in the absence of U{sub L}31

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

Liang Li; Tanaka, Michiko; Kawaguchi, Yasushi

2004-11-10

Previous results indicated that the herpes simplex virus 1 (HSV-1) U{sub L}31 gene is necessary and sufficient for localization of the U{sub L}34 protein exclusively to the nuclear membrane of infected Hep2 cells. In the current studies, a bacterial artificial chromosome containing the entire HSV-1 strain F genome was used to construct a recombinant viral genome in which a gene encoding kanamycin resistance was inserted in place of 262 codons of the 306 codon U{sub L}31 open reading frame. The deletion virus produced virus titers approximately 10- to 50-fold lower in rabbit skin cells, more than 2000-fold lower in Veromore » cells, and more than 1500-fold lower in CV1 cells, compared to a virus bearing a restored U{sub L}31 gene. The replication of the U{sub L}31 deletion virus was restored on U{sub L}31-complementing cell lines derived either from rabbit skin cells or CV1 cells. Confocal microscopy indicated that the majority of U{sub L}34 protein localized aberrantly in the cytoplasm and nucleoplasm of Vero cells and CV1 cells, whereas U{sub L}34 protein localized at the nuclear membrane in rabbit skin cells, and U{sub L}31 complementing CV1 cells infected with the U{sub L}31 deletion virus. We conclude that rabbit skin cells encode a function that allows proper localization of U{sub L}34 protein to the nuclear membrane. We speculate that this function partially complements that of U{sub L}31 and may explain why U{sub L}31 is less critical for replication in rabbit skin cells as opposed to Vero and CV1 cells.« less

Activation of Herpes Simplex Infection after Tattoo.

PubMed

Begolli Gerqari, Antigona; Ferizi, Mybera; Kotori, Merita; Daka, Aferdita; Hapciu, Syzana; Begolli, Ilir; Begolli, Mirije; Gerqari, Idriz

2018-04-01

Tattooing is a procedure where ink is applied to an area of the skin, mostly intraepidermally (1). This procedure is carried out mainly for aesthetic purposes. Lately, it has been used as a corrective medical procedure following amputation of mammilla. The procedure is aggressive (2), and the fact that skin is punctured many times with the same needle which cannot be fully sterilized may cause infection of the treated area with bacterial, fungal, or viral agents that may lead to health consequences manifesting in the form of verrucae vulgaris, molluscum contagiosum, and herpes simplex. On the other hand, complications such as granulomas, allergic reactions, Koebner phenomenon, lupus erythematosus, psoriasis, lichen ruber planus, hepatitis C, and HIV infections should also be considered as potential consequences of tattooing (3-7). Even systemic reactions have been reported. Herein we describe a case of herpes infection activation after tattooing. Herein we present the case of a 46-year-old woman, employed in the medical sector, with a two-day history of herpes simplex in the labial area that manifested following application of a cosmetic tattoo meant to outline the lips (Figure 1). Two days after tattoo application, the vesicular lesions appeared along the area that was filled with ink, followed by sub-febrile temperature and fever and a subjective feeling of itching initially, followed by burning sensation and pain. The skin signs located on erythematous base were mainly grouped vesicles with sharply demarcated borders. Regional lymphatic nodes, mainly retro auricular, were enlarged. Within 48 hours, the patient was treated with acyclovir tablets in a dose of 800 mg three times a day and an antipyretic. Acyclovir ointment was administered during the first two days, as well as tetracycline ointment after the second day of the eruption. On the fifth day, we observed regression of the skin changes (Figure 2), and complete healing was achieved after one week. We assessed the medical history of the patient, which revealed the following: hypothyreosis due to lobectomy performed for the treatment of toxic adenoma. The patient was under substitutional therapy with 75 mg levothyroxine. The patient had herpes simplex before, and this was the second herpetic eruption. Herpes simplex is caused by a herpes simplex virus (HSV) type-1 infection that is transmitted through droplets of saliva or direct contact with the affected area, for example during kissing (8-10). Histology reveals intraepidermal blisters, degeneration in epidermal cells at the base of the vesicle, and multilocular eosinophilic inclusional bodies inside cells. Infection is usually more pronounced in the initial phase of disease, where the symptoms are also more intense. Activation of the infection occurs when the body undergoes a decrease in immunity (1), in situations of extensive exposure to the sun, and also in some other circumstances, such as the application of a tattoo as described herein. Tattooing can inoculate the virus or trigger the activation of the herpes virus and other viruses (1,8-10). Tattooing, apart from bringing social stigma in some cases, which is one of the major issues for persons who undergo the procedure, may also cause injuries, contact dermatitis, foreign body granuloma, infections, and allergic reactions including anaphylaxis. Herpes simplex infections are also possible, either by inoculation or reactivation of the HSV. Except in situations where the tattoo is performed for medicinal purposes, tattooing is not a procedure that is supported by dermatologists. Furthermore, tattooing also causes a number of side effects. Allergic reactions (3,4), anaphylactic shock, foreign body granuloma, lichen ruber planus (5), granuloma pyogenes (5), verruca vulgaris, molluscum contagiosum, herpes simplex, and some other bacterial and viral infections.

A role for the JAK-STAT1 pathway in blocking replication of HSV-1 in dendritic cells and macrophages

PubMed Central

Mott, Kevin R; UnderHill, David; Wechsler, Steven L; Town, Terrence; Ghiasi, Homayon

2009-01-01

Background Macrophages and dendritic cells (DCs) play key roles in host defense against HSV-1 infection. Although macrophages and DCs can be infected by herpes simplex virus type 1 (HSV-1), both cell types are resistant to HSV-1 replication. The aim of our study was to determine factor (s) that are involved in the resistance of DCs and macrophages to productive HSV-1 infection. Results We report here that, in contrast to bone marrow-derived DCs and macrophages from wild type mice, DCs and macrophages isolated from signal transducers and activators of transcription-1 deficient (STAT1-/-) mice were susceptible to HSV-1 replication and the production of viral mRNAs and DNA. There were differences in expression of immediate early, early, and late gene transcripts between STAT1+/+ and STAT1-/- infected APCs. Conclusion These results suggest for the first time that the JAK-STAT1 pathway is involved in blocking replication of HSV-1 in DCs and macrophages. PMID:19439086

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

Evaluation of mixed infection cases with both herpes simplex virus types 1 and 2.

PubMed

Kaneko, Hisatoshi; Kawana, Takashi; Ishioka, Ken; Ohno, Shigeaki; Aoki, Koki; Suzutani, Tatsuo

2008-05-01

Herpes simplex virus type 1 (HSV-1) is isolated principally from the upper half of the body innervated by the trigeminal ganglia whereas herpes simplex virus type 2 (HSV-2) is generally isolated from the lower half of the body innervated by the sacral ganglia. However, recent reports suggest that HSV-1 and HSV-2 can each infect both the upper and lower half of the body causing a variety of symptoms and there is a possibility that HSV-1 and HSV-2 infections can occur simultaneously with both causing symptoms. HSV type in clinical isolates from 87 patients with genital herpes and 57 with ocular herpes was determined by the polymerase chain reaction (PCR), and six cases of mixed infection with both HSV-1 and HSV-2 were identified. Of the six cases, three were patients with genital herpes and three were ocular herpes patients. Analysis of the copy number of the HSV-1 and HSV-2 genome by a quantitative real time PCR demonstrated that HSV-1 was dominant at a ratio of approximately 100:1 in the ocular infections. In contrast, the HSV-2 genome was present at a 4-40 times higher frequency in isolates from genital herpes patients. There was no obvious difference between the clinical course of mixed infection and those of single HSV-1 or HSV-2 infections. This study indicated that the frequency of mixed infection with both HSV-1 and HSV-2 is comparatively higher than those of previous reports. The genome ratio of HSV-1 and HSV-2 reflects the preference of each HSV type for the target organ.

Seroprevalence of HSV-1 and HSV-2 antibodies in Canadian women screened for enrolment in a herpes simplex virus vaccine trial.

PubMed

Gorfinkel, I S; Aoki, F; McNeil, S; Dionne, M; Shafran, S D; Zickler, P; Halperin, S; Langley, J; Bellamy, A; Schulte, J; Heineman, T; Belshe, R

2013-05-01

Herpes simplex virus 1 and 2 (HSV-1 and HSV-2) infections continue to be among the most common and unrecognized sexually transmitted infections in the world. Although treatable, HSV-1 and HSV-2 infections remain incurable. Hence, there is interest in the development of a vaccine to prevent genital herpes. As part of a multicentre, randomized, placebo-controlled trial to test such a vaccine, healthy women 18-30 years were enrolled as volunteers in several Canadian centres between 2005 and 2007. This study reports the seroprevalence of HSV-1 and HSV-2 antibodies in this group. A total of 2694 adult female volunteers in Canada with no known history of herpes simplex were screened for HSV antibodies using Western blot assay (the gold standard for diagnosis of HSV) for potential participation in a randomized, double-blind efficacy field trial of a herpes simplex vaccine. This trial provides a unique opportunity to examine the prevalence of antibodies to HSV-1 and of antibodies to HSV-2 in women with no known history of herpes simplex infection. The prevalence of antibodies to HSV-1 and to HSV-2 is compared with that found in previous Canadian studies that focused on a more general population. The overall seroprevalence of antibody to HSV-1 was 43%; that of HSV-2 was 2.5% and seropositivity to both was 2%. The prevalence of antibody to both HSV-1 and to HSV-2 increased with age. Seronegativity to both HSV-1 and HSV-2 was 56% in participating centres with populations under 250,000 and 46% in participating centres with populations over 250,000. Significant racial differences in seropositivity to HSV-1 and to HSV-2 were noted. The likelihood of participants being seropositive to HSV-1 and to HSV-2 was found to increase with age and to positively correlate with the population of the city in which they resided. Hypotheses are proposed to account for differences in racial seropositivity to HSV-1 and to HSV-2.

Validity of the coding for herpes simplex encephalitis in the Danish National Patient Registry

PubMed Central

Jørgensen, Laura Krogh; Dalgaard, Lars Skov; Østergaard, Lars Jørgen; Andersen, Nanna Skaarup; Nørgaard, Mette; Mogensen, Trine Hyrup

2016-01-01

Background 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). Methods 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. Results 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%. Conclusion 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. PMID:27330328

Research on Skin Diseases - USSR -

DTIC Science & Technology

1960-09-28

Psoriasis 1.8 5. Pyoderma (without •25. Lichen ruber planus U& .L specifying) 20.8 26. Rose herpes 2.0 6. Erysipelas 0.55 27. Herpes simplex 3.0 7...herpes) 5>«U 9*h b) Chronic inflammatory (psoriasis, lichen planus , lupus erythema- tosus, vesicular dermatites) 2.6 5.1 c) Non

Development of a Glycoprotein D-Expressing Dominant-Negative and Replication-Defective Herpes Simplex Virus 2 (HSV-2) Recombinant Viral Vaccine against HSV-2 Infection in Mice ▿

PubMed Central

Akhrameyeva, Natalie V.; Zhang, Pengwei; Sugiyama, Nao; Behar, Samuel M.; Yao, Feng

2011-01-01

Using the T-REx (Invitrogen, California) gene switch technology and a dominant-negative mutant polypeptide of herpes simplex virus 1 (HSV-1)-origin binding protein UL9, we previously constructed a glycoprotein D-expressing replication-defective and dominant-negative HSV-1 recombinant viral vaccine, CJ9-gD, for protection against HSV infection and disease. It was demonstrated that CJ9-gD is avirulent following intracerebral inoculation in mice, cannot establish detectable latent infection following different routes of infection, and offers highly effective protective immunity against primary HSV-1 and HSV-2 infection and disease in mouse and guinea pig models of HSV infections. Given these favorable safety and immunological profiles of CJ9-gD, aiming to maximize levels of HSV-2 glycoprotein D (gD2) expression, we have constructed an ICP0 null mutant-based dominant-negative and replication-defective HSV-2 recombinant, CJ2-gD2, that contains 2 copies of the gD2 gene driven by the tetracycline operator (tetO)-bearing HSV-1 major immediate-early ICP4 promoter. CJ2-gD2 expresses gD2 as efficiently as wild-type HSV-2 infection and can lead to a 150-fold reduction in wild-type HSV-2 viral replication in cells coinfected with CJ2-gD2 and wild-type HSV-2 at the same multiplicity of infection. CJ2-gD2 is avirulent following intracerebral injection and cannot establish a detectable latent infection following subcutaneous (s.c.) immunization. CJ2-gD2 is a more effective vaccine than HSV-1 CJ9-gD and a non-gD2-expressing dominant-negative and replication-defective HSV-2 recombinant in protection against wild-type HSV-2 genital disease. Using recall response, we showed that immunization with CJ2-gD2 elicited strong HSV-2-specific memory CD4+ and CD8+ T-cell responses. Collectively, given the demonstrated preclinical immunogenicity and its unique safety profiles, CJ2-gD2 represents a new class of HSV-2 replication-defective recombinant viral vaccines in protection against HSV-2 genital infection and disease. PMID:21389121

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.

Cold Sores (HSV-1)

MedlinePlus

... Cold Sores Diagnosed and Treated? Print en español Herpes labial Neal knew something weird was going on. ... or around a person's lips, are caused by herpes simplex virus-1 (HSV-1) . But they don' ...

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.

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.

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.

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

Proton MR spectroscopy in herpes simplex encephalitis: Assessment of neuronal loss

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

Menon, D.K.; Sargentoni, J.; Peden, C.J.

1990-05-01

We present here the case of an 11-year-old boy with herpes simplex encephalitis diagnosed on the basis of clinical features, serology, and response to acyclovir, who relapsed after 3 weeks of therapy. In vivo proton magnetic resonance spectroscopy (1H MRS) of the brain, at 8 and 16 weeks after the onset of symptoms, showed abnormalities, most prominently a reduction in the N-acetylaspartate/choline ratio. The role of 1H MRS in assessing disease activity is discussed.

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

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.

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

IFN-ε protects primary macrophages against HIV infection.

PubMed

Tasker, Carley; Subbian, Selvakumar; Gao, Pan; Couret, Jennifer; Levine, Carly; Ghanny, Saleena; Soteropoulos, Patricia; Zhao, Xilin; Landau, Nathaniel; Lu, Wuyuan; Chang, Theresa L

2016-12-08

IFN-ε is a unique type I IFN that is not induced by pattern recognition response elements. IFN-ε is constitutively expressed in mucosal tissues, including the female genital mucosa. Although the direct antiviral activity of IFN-ε was thought to be weak compared with IFN-α, IFN-ε controls Chlamydia muridarum and herpes simplex virus 2 in mice, possibly through modulation of immune response. We show here that IFN-ε induces an antiviral state in human macrophages that blocks HIV-1 replication. IFN-ε had little or no protective effect in activated CD4 + T cells or transformed cell lines unless activated CD4 + T cells were infected with replication-competent HIV-1 at a low MOI. The block to HIV infection of macrophages was maximal after 24 hours of treatment and was reversible. IFN-ε acted on early stages of the HIV life cycle, including viral entry, reverse transcription, and nuclear import. The protection did not appear to operate through known type I IFN-induced HIV host restriction factors, such as APOBEC3A and SAMHD1. IFN-ε-stimulated immune mediators and pathways had the signature of type I IFNs but were distinct from IFN-α in macrophages. IFN-ε induced significant phagocytosis and ROS, which contributed to the block to HIV replication. These findings indicate that IFN-ε induces an antiviral state in macrophages that is mediated by different factors than those induced by IFN-α. Understanding the mechanism of IFN-ε-mediated HIV inhibition through immune modulation has implications for prevention.

IFN-ε protects primary macrophages against HIV infection

PubMed Central

Tasker, Carley; Subbian, Selvakumar; Gao, Pan; Couret, Jennifer; Levine, Carly; Ghanny, Saleena; Soteropoulos, Patricia; Zhao, Xilin; Landau, Nathaniel; Lu, Wuyuan

2016-01-01

IFN-ε is a unique type I IFN that is not induced by pattern recognition response elements. IFN-ε is constitutively expressed in mucosal tissues, including the female genital mucosa. Although the direct antiviral activity of IFN-ε was thought to be weak compared with IFN-α, IFN-ε controls Chlamydia muridarum and herpes simplex virus 2 in mice, possibly through modulation of immune response. We show here that IFN-ε induces an antiviral state in human macrophages that blocks HIV-1 replication. IFN-ε had little or no protective effect in activated CD4+ T cells or transformed cell lines unless activated CD4+ T cells were infected with replication-competent HIV-1 at a low MOI. The block to HIV infection of macrophages was maximal after 24 hours of treatment and was reversible. IFN-ε acted on early stages of the HIV life cycle, including viral entry, reverse transcription, and nuclear import. The protection did not appear to operate through known type I IFN-induced HIV host restriction factors, such as APOBEC3A and SAMHD1. IFN-ε–stimulated immune mediators and pathways had the signature of type I IFNs but were distinct from IFN-α in macrophages. IFN-ε induced significant phagocytosis and ROS, which contributed to the block to HIV replication. These findings indicate that IFN-ε induces an antiviral state in macrophages that is mediated by different factors than those induced by IFN-α. Understanding the mechanism of IFN-ε–mediated HIV inhibition through immune modulation has implications for prevention. PMID:27942584

Cellular Protein WDR11 Interacts with Specific Herpes Simplex Virus Proteins at the trans-Golgi Network To Promote Virus Replication

PubMed Central

Taylor, Kathryne E.

2015-01-01

ABSTRACT It has recently been proposed that the herpes simplex virus (HSV) protein ICP0 has cytoplasmic roles in blocking antiviral signaling and in promoting viral replication in addition to its well-known proteasome-dependent functions in the nucleus. However, the mechanisms through which it produces these effects remain unclear. While investigating this further, we identified a novel cytoplasmic interaction between ICP0 and the poorly characterized cellular protein WDR11. During an HSV infection, WDR11 undergoes a dramatic change in localization at late times in the viral replication cycle, moving from defined perinuclear structures to a dispersed cytoplasmic distribution. While this relocation was not observed during infection with viruses other than HSV-1 and correlated with efficient HSV-1 replication, the redistribution was found to occur independently of ICP0 expression, instead requiring viral late gene expression. We demonstrate for the first time that WDR11 is localized to the trans-Golgi network (TGN), where it interacts specifically with some, but not all, HSV virion components, in addition to ICP0. Knockdown of WDR11 in cultured human cells resulted in a modest but consistent decrease in yields of both wild-type and ICP0-null viruses, in the supernatant and cell-associated fractions, without affecting viral gene expression. Although further study is required, we propose that WDR11 participates in viral assembly and/or secondary envelopment. IMPORTANCE While the TGN has been proposed to be the major site of HSV-1 secondary envelopment, this process is incompletely understood, and in particular, the role of cellular TGN components in this pathway is unknown. Additionally, little is known about the cellular functions of WDR11, although the disruption of this protein has been implicated in multiple human diseases. Therefore, our finding that WDR11 is a TGN-resident protein that interacts with specific viral proteins to enhance viral yields improves both our understanding of basic cellular biology as well as how this protein is co-opted by HSV. PMID:26178983

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

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.

Genital herpes simplex virus infections: clinical manifestations, course, and complications.

PubMed

Corey, L; Adams, H G; Brown, Z A; Holmes, K K

1983-06-01

The clinical course and complications of 268 patients with first episodes and 362 with recurrent episodes of genital herpes infection were reviewed. Symptoms of genital herpes were more severe in women than in men. Primary first-episode genital herpes was accompanied by systemic symptoms (67%), local pain and itching (98%), dysuria (63%), and tender adenopathy (80%). Patients presented with several bilaterally distributed postular ulcerative lesions that lasted a mean of 19.0 days. Herpes simplex virus was isolated from the urethra, cervix, and pharynx of 82%, 88%, and 13% of women with first-episode primary genital herpes, and the urethra and pharynx of 28% and 7% of men. Complications included aseptic meningitis (8%), sacral autonomic nervous system dysfunction (2%), development of extragenital lesions (20%), and secondary yeast infections (11%). Recurrent episodes were characterized by small vesicular or ulcerative unilaterally distributed lesions that lasted a mean of 10.1 days. Systemic symptoms were uncommon and 25% of recurrent episodes were asymptomatic. The major concerns of patients were the frequency of recurrences and fear of transmitting infection to partners or infants.

Which plant for which skin disease? Part 1: Atopic dermatitis, psoriasis, acne, condyloma and herpes simplex.

PubMed

Reuter, Juliane; Wölfle, Ute; Weckesser, Steffi; Schempp, Christoph

2010-10-01

Plant extracts and isolated compounds are increasingly used in cosmetics and food supplements to improve skin conditions. We first introduce the positive plant monographs with dermatological relevance of the former German Commission E. Subsequently clinical studies with botanicals for atopic dermatitis, psoriasis, acne, condylomata acuminata and herpes simplex are discussed. The best studies have been conducted with atopic dermatitis and psoriasis patients. Mahonia aquifolium, Hypericum perforatum, Glycyrrhiza glabra and certain traditional Chinese therapies have been shown to be effective in the treatment of atopic dermatitis. Mahonia aquifolium, Indigo naturalis and Capsicum frutescens are effective treatments for psoriasis. Green tea extract and tea tree oil have been investigated in the treatment of acne. Podophyllin and green tea extract are effective treatments for condylomata acuminata. Balm mint and a combination of sage and rhubarb have been shown to be effective in the treatment of herpes simplex in proof of concept studies. © The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin.

Application of low-intensity laser in the treatment of Herpes simplex recidivans

NASA Astrophysics Data System (ADS)

Uzunov, Tzonko T.; Uzunov, T.; Grozdanova, R.

2004-06-01

We made our aim to investigate the effect of the low intensive laser with λ=630 nm in the visible red spectrum of light at Herpes simplex treatment. For this purpose we carried out a clinical research upon 62 persons with Herpes simplex lesions which have been divided into two groups of 31 persons. At the first group the effect of laser with power density 100 mW/cm2 +/- 5 mW/cm2 and time of exposure 3 min. on field was traced out. At the second group the low intensive laser with the same characteristics has been used but in combination with the patent medicine Granofurin H as a photosensibilizer. The clinical approbations of this method showed high therapeutical effectiveness. The obtained results showed that at both groups there is an expressed anaesthetic, anti-inflammatory and regeneration stimulating effect and at the second group with the use of Granofurin H the reconvalescent period is shorter.

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

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

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.

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.

[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.

The Calcitonin Receptor Gene Is a Candidate for Regulation of Susceptibility to Herpes simplex Type 1 Neuronal Infection Leading to Encephalitis in Rat

PubMed Central

Abdelmagid, Nada; Bereczky-Veress, Biborka; Guerreiro-Cacais, André Ortlieb; Bergman, Petra; Luhr, Katarina M.; Bergström, Tomas; Sköldenberg, Birgit; Piehl, Fredrik

2012-01-01

Herpes simplex encephalitis (HSE) is a fatal infection of the central nervous system (CNS) predominantly caused by Herpes simplex virus type 1. Factors regulating the susceptibility to HSE are still largely unknown. To identify host gene(s) regulating HSE susceptibility we performed a genome-wide linkage scan in an intercross between the susceptible DA and the resistant PVG rat. We found one major quantitative trait locus (QTL), Hse1, on rat chromosome 4 (confidence interval 24.3–31 Mb; LOD score 29.5) governing disease susceptibility. Fine mapping of Hse1 using recombinants, haplotype mapping and sequencing, as well as expression analysis of all genes in the interval identified the calcitonin receptor gene (Calcr) as the main candidate, which also is supported by functional studies. Thus, using unbiased genetic approach variability in Calcr was identified as potentially critical for infection and viral spread to the CNS and subsequent HSE development. PMID:22761571

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 internalization into epithelial cells requires Na+/H+ exchangers and p21-activated kinases but neither clathrin- nor caveolin-mediated endocytosis.

PubMed

Devadas, Deepika; Koithan, Thalea; Diestel, Randi; Prank, Ute; Sodeik, Beate; Döhner, Katinka

2014-11-01

Herpes simplex virus 1 (HSV-1) is an alphaherpesvirus that has been reported to infect some epithelial cell types by fusion at the plasma membrane but others by endocytosis. To determine the molecular mechanisms of productive HSV-1 cell entry, we perturbed key endocytosis host factors using specific inhibitors, RNA interference (RNAi), or overexpression of dominant negative proteins and investigated their effects on HSV-1 infection in the permissive epithelial cell lines Vero, HeLa, HEp-2, and PtK2. HSV-1 internalization required neither endosomal acidification nor clathrin- or caveolin-mediated endocytosis. In contrast, HSV-1 gene expression and internalization were significantly reduced after treatment with 5-(N-ethyl-N-isopropyl)amiloride (EIPA). EIPA blocks the activity of Na(+)/H(+) exchangers, which are plasma membrane proteins implicated in all forms of macropinocytosis. HSV-1 internalization furthermore required the function of p21-activated kinases that contribute to macropinosome formation. However, in contrast to some forms of macropinocytosis, HSV-1 did not enlist the activities of protein kinase C (PKC), tyrosine kinases, C-terminal binding protein 1, or dynamin to activate its internalization. These data suggest that HSV-1 depends on Na(+)/H(+) exchangers and p21-activated kinases either for macropinocytosis or for local actin rearrangements required for fusion at the plasma membrane or subsequent passage through the actin cortex underneath the plasma membrane. After initial replication in epithelial cells, herpes simplex viruses (HSVs) establish latent infections in neurons innervating these regions. Upon primary infection and reactivation from latency, HSVs cause many human skin and neurological diseases, particularly in immunocompromised hosts, despite the availability of effective antiviral drugs. Many viruses use macropinocytosis for virus internalization, and many host factors mediating this entry route have been identified, although the specific perturbation profiles vary for different host and viral cargo. In addition to an established entry pathway via acidic endosomes, we show here that HSV-1 internalization depended on sodium-proton exchangers at the plasma membrane and p21-activated kinases. These results suggest that HSV-1 requires a reorganization of the cortical actin cytoskeleton, either for productive cell entry via pH-independent fusion from macropinosomes or for fusion at the plasma membrane, and subsequent cytosolic passage to microtubules that mediate capsid transport to the nucleus for genome uncoating and replication. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Cutaneous Infections in Wrestlers

PubMed Central

Wilson, Eugene K.; deWeber, Kevin; Berry, James W.; Wilckens, John H.

2013-01-01

Context: Cutaneous infections are common in wrestlers. Although many are simply a nuisance in the everyday population, they can be problematic to wrestlers because such infections may result in disqualification from practice or competition. Prompt diagnosis and treatment are therefore important. Evidence Acquisition: Medline and PubMed databases, the Cochrane Database of Systematic Reviews, and UpToDate were searched through 2012 with the following keywords in various combinations: skin infections, cutaneous infections, wrestlers, athletes, methicillin-resistant Staphylococcus aureus, skin and soft tissue infections, tinea corporis, tinea capitis, herpes simplex, varicella zoster, molluscum contagiosum, verruca vulgaris, warts, scabies, and pediculosis. Relevant articles found in the primary search, and selected references from those articles were reviewed for pertinent clinical information. Results: The most commonly reported cutaneous infections in wrestlers are herpes simplex virus infections (herpes gladiatorum), bacterial skin and soft tissue infections, and dermatophyte infections (tinea gladiatorum). The clinical appearance of these infections can be different in wrestlers than in the community at large. Conclusion: For most cutaneous infections, diagnosis and management options in wrestlers are similar to those in the community at large. With atypical presentations, testing methods are recommended to confirm the diagnosis of herpes gladiatorum and tinea gladiatorum. There is evidence to support the use of prophylactic medications to prevent recurrence of herpes simplex virus and reduce the incidence of dermatophyte infections in wrestlers. PMID:24427413

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.

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

DNA vaccine expressing herpes simplex virus 1 glycoprotein C and D protects mice against herpes simplex keratitis

PubMed Central

Dong, Li-Li; Tang, Ru; Zhai, Yu-Jia; Malla, Tejsu; Hu, Kai

2017-01-01

AIM To investigate whether DNA vaccine encoding herpes simplex virus 1 (HSV-1) glycoprotein C (gC) and glycoprotein D (gD) will achieve better protective effect against herpes simplex keratitis (HSK) than DNA vaccine encoding gD alone. METHODS DNA vaccine expressing gD or gC combined gD (gD.gC) were constructed and carried by chitosan nanoparticle. The expression of fusion protein gD and gC were detected in DNA/nanoparticle transfected 293T cells by Western-blot. For immunization, mice were inoculated with DNA/nanoparticle for 3 times with 2wk interval, and two weeks after the final immunization, the specific immune responses and clinical degrees of primary HSK were evaluated. RESULTS Fusion protein gD.gC could be expressed successfully in cultured 293T cells. And, pRSC-gC.gD-IL21 DNA/chitosan nanoparticle could effectively elicit strongest humoral and cellular immune response in primary HSK mice evidenced by higher levels of specific neutralizing antibody and sIgA production, enhanced cytotoxicities of splenocytes and nature killer cells (NK), when compared with those of gD alone or mocked vaccine immunized mice. As a result, gC-based vaccine immunized mice showed least HSK disease. CONCLUSION gC-based DNA vaccine could effectively prevent the progress of primary HSK, suggesting that this DNA vaccine could be a promising vaccine for HSK treatment in the future. PMID:29181304

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.

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.

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

PubMed Central

Gu, Haidong

2016-01-01

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

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

[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.

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

Efficacy of N-methanocarbathymidine against genital herpes simplex virus type 2 shedding and infection in guinea pigs.

PubMed

Bernstein, David I; Bravo, Fernando J; Pullum, Derek A; Shen, Hui; Wang, Mei; Rahman, Aquilur; Glazer, Robert I; Cardin, Rhonda D

2015-02-01

Current approved nucleoside therapies for genital herpes simplex virus (HSV) infections are effective but improved therapies are needed for treatment of both acute and recurrent diseases. The effects of N-methanocarbathymidine were evaluated and compared to acyclovir using guinea pig models of acute and recurrent infection. For acute disease following intravaginal inoculation of 10(6 )pfu HSV-2 (MS strain), animals were treated intraperitoneally beginning 24 h post-infection, and the effects on disease severity, vaginal virus replication, subsequent recurrences, and latent virus loads were evaluated. For evaluation of recurrent infection, animals were treated for 21 days beginning 14 days after infection and disease recurrence and recurrent shedding were evaluated. Treatment of the acute disease with N-methanocarbathymidine significantly reduced the severity of acute disease and decreased acute vaginal virus shedding more effectively than acyclovir. Significantly, none of the animals developed visible disease in the high-dose N-methanocarbathymidine group and this was the only group in which the number of days with recurrent virus shedding was reduced. Treatment of recurrent disease was equivalent to acyclovir when acyclovir was continuously supplied in the drinking water. N-methanocarbathymidine was effective as therapy for acute and recurrent genital HSV-2 disease in the guinea pig models. © The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

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

Mechanism of herpes simplex virus type 2 suppression by propolis extracts.

PubMed

Nolkemper, Silke; Reichling, Jürgen; Sensch, Karl Heinz; Schnitzler, Paul

2010-02-01

Genital herpes caused by herpes simplex virus type 2 (HSV-2) is a chronic, persistent infection spreading efficiently and silently as sexually transmitted disease through the population. Antiviral agents currently applied for the treatment of herpesvirus infections include acyclovir and derivatives. Aqueous and ethanolic extracts of propolis were phytochemically analysed, different polyphenols, flavonoids and phenylcarboxylic acids were identified as major constituents. The aqueous propolis extract revealed a relatively high amount of phenylcarboxylic acids and low concentrations flavonoids when compared to the ethanolic special extract GH 2002. The cytotoxic and antiherpetic effect of propolis extracts against HSV-2 was analysed in cell culture, and revealed a moderate cytotoxicity on RC-37 cells. The 50% inhibitory concentration (IC(50)) of aqueous and ethanolic GH 2002 propolis extracts for HSV-2 plaque formation was determined at 0.0005% and 0.0004%, respectively. Both propolis extracts exhibited high levels of antiviral activity against HSV-2 in viral suspension tests, infectivity was significantly reduced by >99% and a direct concentration- and time-dependent antiherpetic activity could be demonstrated for both extracts. In order to determine the mode of virus suppression by propolis, the extracts were added at different times during the viral infection cycle. Addition of these drugs to uninfected cells prior to infection or to herpesvirus-infected cells during intracellular replication had no effect on virus multiplication. However both propolis extracts exhibited high anti-herpetic activity when viruses were pretreated with these drugs prior to infection. Selectivity indices were determined at 80 and 42.5 for the aqueous and ethanolic extract, respectively, thus propolis extracts might be suitable for topical therapy in recurrent herpetic infection. Copyright 2009 Elsevier GmbH. All rights reserved.

Elsberg syndrome: a neurologic basis for acute urinary retention in patients with genital herpes.

PubMed

Hemrika, D J; Schutte, M F; Bleker, O P

1986-09-01

Three patients with genital herpes simplex type II primoinfection and acute urinary retention are described. All patients showed pleocytosis of the cerebrospinal fluid, substantiating central nervous involvement. The association of genital herpes and sacral (myelo-) radiculitis has gained little attention in gynecologic literature, yet it is not an uncommon finding in female patients suffering from herpes. The present report emphasizes the importance of urinary symptoms in genital herpes and reviews the literature on similar cases.

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.

The ATM and Rad3-Related (ATR) Protein Kinase Pathway Is Activated by Herpes Simplex Virus 1 and Required for Efficient Viral Replication.

PubMed

Edwards, Terri G; Bloom, David C; Fisher, Chris

2018-03-15

The ATM and Rad3-related (ATR) protein kinase and its downstream effector Chk1 are key sensors and organizers of the DNA damage response (DDR) to a variety of insults. Previous studies of herpes simplex virus 1 (HSV-1) showed no evidence for activation of the ATR pathway. Here we demonstrate that both Chk1 and ATR were phosphorylated by 3 h postinfection (h.p.i.). Activation of ATR and Chk1 was observed using 4 different HSV-1 strains in multiple cell types, while a specific ATR inhibitor blocked activation. Mechanistic studies point to early viral gene expression as a key trigger for ATR activation. Both pATR and pChk1 localized to the nucleus within viral replication centers, or associated with their periphery, by 3 h.p.i. Significant levels of pATR and pChk1 were also detected in the cytoplasm, where they colocalized with ICP4 and ICP0. Proximity ligation assays confirmed that pATR and pChk1 were closely and specifically associated with ICP4 and ICP0 in both the nucleus and cytoplasm by 3 h.p.i., but not with ICP8 or ICP27, presumably in a multiprotein complex. Chemically distinct ATR and Chk1 inhibitors blocked HSV-1 replication and infectious virion production, while inhibitors of ATM, Chk2, and DNA-dependent protein kinase (DNA-PK) did not. Together our data show that HSV-1 activates the ATR pathway at early stages of infection and that ATR and Chk1 kinase activities play important roles in HSV-1 replication fitness. These findings indicate that the ATR pathway may provide insight for therapeutic approaches. IMPORTANCE Viruses have evolved complex associations with cellular DNA damage response (DDR) pathways, which sense troublesome DNA structures formed during infection. The first evidence for activation of the ATR pathway by HSV-1 is presented. ATR is activated, and its downstream target Chk1 is robustly phosphorylated, during early stages of infection. Both activated proteins are found in the nucleus associated with viral replication compartments and in the cytoplasm associated with viral proteins. We also demonstrate that both ATR and Chk1 kinase activities are important for viral replication. The findings suggest that HSV-1 activates ATR and Chk1 during early stages of infection and utilizes the enzymes to promote its own replication. The observation may be exploitable for antiviral approaches. Copyright © 2018 American Society for Microbiology.

Herpes simplex infection in a juvenile orangutan (Pongo pygmaeus pygmaeus).

PubMed

Kik, Maria J L; Bos, Jan H; Groen, Jan; Dorrestein, Gerry M

2005-03-01

A juvenile orangutan (Pongo pygmaeus pygmaeus) died after 8 days of diarrhea and vomiting. Necropsy showed petechial hemorrhages in the skin, the myocardium, and the peritoneal membranes. The lungs were hyperemic and edematous, and the liver and spleen were enlarged. Histologic changes consisted of interstitial pneumonia, hepatitis, and splenic hyperplasia. Numerous eosinophilic intranuclear inclusion bodies were visible in pulmonary epithelial cells, hepatocytes, and splenic endothelial cells. Electron microscopic examination revealed herpesvirus in hepatocyte nuclei. Polymerase chain reaction of liver tissue demonstrated the presence of a herpes simplex virus-1.

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.

2014 UK national guideline for the management of anogenital herpes.

PubMed

Patel, Raj; Green, John; Clarke, Emily; Seneviratne, Kanchana; Abbt, Naomi; Evans, Ceri; Bickford, Jane; Nicholson, Marian; O'Farrell, Nigel; Barton, Simon; FitzGerald, Mark; Foley, Elizabeth

2015-10-01

These guidelines concern the management of anogenital herpes simplex virus infections in adults and give advice on diagnosis, management, and counselling of patients. This guideline replaces the 2007 BASHH herpes guidelines and includes new sections on herpes proctitis, key points to cover with patients regarding transmission and removal of advice on the management of HSV in pregnancy which now has a separate joint BASHH/RCOG guideline. © The Author(s) 2015.

Potent Adjuvant Activity of Cationic Liposome-DNA Complexes for Genital Herpes Vaccines▿

PubMed Central

Bernstein, David I.; Cardin, Rhonda D.; Bravo, Fernando J.; Strasser, Jane E.; Farley, Nicholas; Chalk, Claudia; Lay, Marla; Fairman, Jeff

2009-01-01

Development of a herpes simplex virus (HSV) vaccine is a priority because these infections are common. It appears that potent adjuvants will be required to augment the immune response to subunit HSV vaccines. Therefore, we evaluated cationic liposome-DNA complexes (CLDC) as an adjuvant in a mouse model of genital herpes. Using a whole-virus vaccine (HVAC), we showed that the addition of CLDC improved antibody responses compared to vaccine alone. Most important, CLDC increased survival, reduced symptoms, and decreased vaginal virus replication compared to vaccine alone or vaccine administered with monophosphoryl lipid A (MPL) plus trehalose dicorynomycolate (TDM) following intravaginal challenge of mice. When CLDC was added to an HSV gD2 vaccine, it increased the amount of gamma interferon that was produced from splenocytes stimulated with gD2 compared to the amount produced with gD2 alone or with MPL-alum. The addition of CLDC to the gD2 vaccine also improved the outcome following vaginal HSV type 2 challenge compared to vaccine alone and was equivalent to vaccination with an MPL-alum adjuvant. CLDC appears to be a potent adjuvant for HSV vaccines and should be evaluated further. PMID:19279167

Maternal Immunoreactivity to Herpes Simplex Virus 2 and Risk of Autism Spectrum Disorder in Male Offspring

PubMed Central

Mahic, Milada; Mjaaland, Siri; Bøvelstad, Hege Marie; Gunnes, Nina; Susser, Ezra; Bresnahan, Michaeline; Øyen, Anne-Siri; Levin, Bruce; Che, Xiaoyu; Hirtz, Deborah; Reichborn-Kjennerud, Ted; Schjølberg, Synnve; Roth, Christine; Magnus, Per; Stoltenberg, Camilla; Surén, Pål; Hornig, Mady

2017-01-01

ABSTRACT Maternal infections during pregnancy are associated with risk of neurodevelopmental disorders, including autism spectrum disorders (ASDs). Proposed pathogenetic mechanisms include fetal infection, placental inflammation, and maternal cytokines or antibodies that cross the placenta. The Autism Birth Cohort comprises mothers, fathers, and offspring recruited in Norway in 1999 to 2008. Through questionnaire screening, referrals, and linkages to a national patient registry, 442 mothers of children with ASD were identified, and 464 frequency-matched controls were selected. Immunoglobulin G (IgG) antibodies to Toxoplasma gondii, rubella virus, cytomegalovirus (CMV), herpes simplex virus 1 (HSV-1), and HSV-2 in plasma collected at midpregnancy and after delivery were measured by multiplexed immunoassays. High levels of HSV-2 IgG antibodies in maternal midpregnancy plasma were associated with increased risk of ASD in male offspring (an increase in HSV-2 IgG levels from 240 to 640 arbitrary units/ml was associated with an odds ratio of 2.07; 95% confidence interval, 1.06 to 4.06; P = 0.03) when adjusted for parity and child’s birth year. No association was found between ASD and the presence of IgG antibodies to Toxoplasma gondii, rubella virus, CMV, or HSV-1. Additional studies are needed to test for replicability of risk and specificity of the sex effect and to examine risk associated with other infections. IMPORTANCE The cause (or causes) of most cases of autism spectrum disorder is unknown. Evidence from epidemiological studies and work in animal models of neurodevelopmental disorders suggest that both genetic and environmental factors may be implicated. The latter include gestational infection and immune activation. In our cohort, high levels of antibodies to herpes simplex virus 2 at midpregnancy were associated with an elevated risk of autism spectrum disorder in male offspring. These findings provide support for the hypothesis that gestational infection may contribute to the pathogenesis of autism spectrum disorder and have the potential to drive new efforts to monitor women more closely for cryptic gestational infection and to implement suppressive therapy during pregnancy. PMID:28251181

Maternal Immunoreactivity to Herpes Simplex Virus 2 and Risk of Autism Spectrum Disorder in Male Offspring.

PubMed

Mahic, Milada; Mjaaland, Siri; Bøvelstad, Hege Marie; Gunnes, Nina; Susser, Ezra; Bresnahan, Michaeline; Øyen, Anne-Siri; Levin, Bruce; Che, Xiaoyu; Hirtz, Deborah; Reichborn-Kjennerud, Ted; Schjølberg, Synnve; Roth, Christine; Magnus, Per; Stoltenberg, Camilla; Surén, Pål; Hornig, Mady; Lipkin, W Ian

2017-01-01

Maternal infections during pregnancy are associated with risk of neurodevelopmental disorders, including autism spectrum disorders (ASDs). Proposed pathogenetic mechanisms include fetal infection, placental inflammation, and maternal cytokines or antibodies that cross the placenta. The Autism Birth Cohort comprises mothers, fathers, and offspring recruited in Norway in 1999 to 2008. Through questionnaire screening, referrals, and linkages to a national patient registry, 442 mothers of children with ASD were identified, and 464 frequency-matched controls were selected. Immunoglobulin G (IgG) antibodies to Toxoplasma gondii , rubella virus, cytomegalovirus (CMV), herpes simplex virus 1 (HSV-1), and HSV-2 in plasma collected at midpregnancy and after delivery were measured by multiplexed immunoassays. High levels of HSV-2 IgG antibodies in maternal midpregnancy plasma were associated with increased risk of ASD in male offspring (an increase in HSV-2 IgG levels from 240 to 640 arbitrary units/ml was associated with an odds ratio of 2.07; 95% confidence interval, 1.06 to 4.06; P = 0.03) when adjusted for parity and child's birth year. No association was found between ASD and the presence of IgG antibodies to Toxoplasma gondii , rubella virus, CMV, or HSV-1. Additional studies are needed to test for replicability of risk and specificity of the sex effect and to examine risk associated with other infections. IMPORTANCE The cause (or causes) of most cases of autism spectrum disorder is unknown. Evidence from epidemiological studies and work in animal models of neurodevelopmental disorders suggest that both genetic and environmental factors may be implicated. The latter include gestational infection and immune activation. In our cohort, high levels of antibodies to herpes simplex virus 2 at midpregnancy were associated with an elevated risk of autism spectrum disorder in male offspring. These findings provide support for the hypothesis that gestational infection may contribute to the pathogenesis of autism spectrum disorder and have the potential to drive new efforts to monitor women more closely for cryptic gestational infection and to implement suppressive therapy during pregnancy.

Recombination Analysis of Herpes Simplex Virus 1 Reveals a Bias toward GC Content and the Inverted Repeat Regions

PubMed Central

Lee, Kyubin; Kolb, Aaron W.; Sverchkov, Yuriy; Cuellar, Jacqueline A.; Craven, Mark

2015-01-01

ABSTRACT Herpes simplex virus 1 (HSV-1) causes recurrent mucocutaneous ulcers and is the leading cause of infectious blindness and sporadic encephalitis in the United States. HSV-1 has been shown to be highly recombinogenic; however, to date, there has been no genome-wide analysis of recombination. To address this, we generated 40 HSV-1 recombinants derived from two parental strains, OD4 and CJ994. The 40 OD4-CJ994 HSV-1 recombinants were sequenced using the Illumina sequencing system, and recombination breakpoints were determined for each of the recombinants using the Bootscan program. Breakpoints occurring in the terminal inverted repeats were excluded from analysis to prevent double counting, resulting in a total of 272 breakpoints in the data set. By placing windows around the 272 breakpoints followed by Monte Carlo analysis comparing actual data to simulated data, we identified a recombination bias toward both high GC content and intergenic regions. A Monte Carlo analysis also suggested that recombination did not appear to be responsible for the generation of the spontaneous nucleotide mutations detected following sequencing. Additionally, kernel density estimation analysis across the genome found that the large, inverted repeats comprise a recombination hot spot. IMPORTANCE Herpes simplex virus 1 (HSV-1) virus is the leading cause of sporadic encephalitis and blinding keratitis in developed countries. HSV-1 has been shown to be highly recombinogenic, and recombination itself appears to be a significant component of genome replication. To date, there has been no genome-wide analysis of recombination. Here we present the findings of the first genome-wide study of recombination performed by generating and sequencing 40 HSV-1 recombinants derived from the OD4 and CJ994 parental strains, followed by bioinformatics analysis. Recombination breakpoints were determined, yielding 272 breakpoints in the full data set. Kernel density analysis determined that the large inverted repeats constitute a recombination hot spot. Additionally, Monte Carlo analyses found biases toward high GC content and intergenic and repetitive regions. PMID:25926637

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.

Early rehabilitation results in a child who developed herpes simplex encephalitis

PubMed Central

Toy, Seyma; Ozdemir, Filiz; Kızılay, Fatma; Ersoy, Yuksel; Apaydın, Hakan

2017-01-01

In this case, a 4-year-old girl was admitted to the emergency service with the complaints of a sudden onset of fever, shortness of breath, jerking motions of the hands and feet and a sliding mouth. Her condition deteriorated, and she was kept under observation in the intensive care unit for 6 days. The Glasgow Coma Score of the patient was 1. Lumbar puncture revealed a white blood cell count of 0 and cerebrospinal fluid was positive for herpes simplex virus 1 and 2. Antiviral therapy was administered for 14 days. One month earlier, the patient had experienced a herpes labialis infection, which suggested herpes simplex encephalitis (HSE). Cranial magnetic resonance imaging indicated significant bilateral cerebral ischemic changes, which also supported suspicion of HSE. After antiviral treatment, the patient was referred to the department of physical therapy and rehabilitation. The Functional Independence Measure for Children (WeeFIM) scale was used to evaluate the patient. A 30-session rehabilitation program based on the Bobath concept of neurodevelopmental therapy was implemented. Before the treatment, the WeeFIM score was 20 points, and at its conclusion, the score was 88 points. The patient began to walk without limitation and the choreoathetosis was almost completely corrected. The patient was discharged with medical treatment and a home-based exercise training program. PMID:29270579

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.

Database of Autotransplants for Breast Cancer.

DTIC Science & Technology

1996-12-01

Infections (Indicate code for atypical bacteria; 301 Herpes Simplex (HSV1, HSV2) list bacterium for non-atypical bacteria.) 302 Herpes Zoster ( Chicken pox ...for non-atypical bacteria.) 302 Herpes Zoster ( Chicken pox , Varicella) 303 Cytomegalovirus (CMV) 100 Atypical bacteria, not otherwise specified 304... Chicken pox , Varicella) 303 Cytomegalovirus (CMV) 100 Atypical bacteria, not otherwise specified 304 Adenovirus 101 Coxiella 305 Enterovirus (Coxsackie

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.

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.

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.

[Laboratory diagnosis of genital herpes--direct immunofluorescence method].

PubMed

Majewska, Anna; Romejko-Wolniewicz, Ewa; Zareba-Szczudlik, Julia; Kilijańczyk, Marek; Gajewska, Małgorzata; Młynarczyk, Grazyna

2013-07-01

Aim of the study was to determine clinical usefulness of direct immunofluorescence method in the laboratory diagnosis of genital herpes in women. Overall 187 anogenital swabs were collected from 120 women. Using a dacron-tipped applicator 83 swabs were collected from women suspected of genital herpes and 104 from patients with no signs of genital infection. All samples were tested using cell culture (Vero cell line) and then direct immunofluorescence method (DIF) for the identification of antigens of herpes simplex viruses: HSV-1 and HSV-2. Characteristic cytopathic effect (CPE), indicative of alphaherpesvirus infection, was observed in 43.4% of cultures with clinical specimens collected from women with suspected genital herpes and in 29.8% of cultures of clinical specimens taken from patients with no clinical symptoms of genital herpes. Herpes simplex viruses were determined in 73 samples by direct immunofluorescence method after amplification of the virus in cell culture. The DIF test confirmed the diagnosis based on the microscopic CPE observation in 85%. In 15% of samples (taken from pregnant women without clinical signs of infection) we reported positive immunofluorescence in the absence of CPE. The frequency of antigen detection was statistically significantly higher in samples that were positive by culture study (chi-square test with Yates's correction, p < 0.01). This method proved to be highly sensitive (97%) in women with clinically suspected infection. High negative predictive value (99%) proves the clinical utility of the DIF in these group of patients. In asymptomatic infections, viral antigens were detected most frequently in the swabs from the cervical canal, and in cases of suspected genital herpes in swabs taken from the vestibule of the vagina and the vulva. However, there was no statistically significant difference in the frequency of detection of Herpes Simplex Virus antigens in specimens from different parts of the genital tract in both groups of women (chi-square test, p > 0.05). In our study HHV-1 was the main causative agent of genital herpes. The growing worldwide prevalence of genital herpes, challenges with the clinical diagnosis, and availability of effective antiviral therapy are the main reasons for a growing interest in rapid, proper laboratory diagnosis of infected patients. Optimal testing diagnostic algorithm depends on patient population, clinical circumstances and availability. Our results indicated that combination of laboratory tests may help to establish the diagnosis if genital herpes is suspected but there are no typical signs.

[Update on congenital and neonatal herpes infections: infection due to cytomegalovirus and herpes simplex].

PubMed

Baquero-Artigao, F

2017-05-17

Newborn infants are a population which is especially susceptible to viral infections that frequently affect the central nervous system. Herpes infections can be transmitted to the foetus and to the newborn infant, and give rise to severe clinical conditions with long-term sensory and cognitive deficits. Two thirds of newborn infants with encephalitis due to herpes simplex virus and half of the children with symptomatic congenital infection by cytomegalovirus develop sequelae, which results in high community health costs in the long term. Fortunately, the better knowledge about these infections gained in recent years together with the development of effective antiviral treatments have improved the patients' prognosis. Valganciclovir (32 mg/kg/day in two doses for six months) prevents the development of hypoacusis and improves the neurological prognosis in symptomatic congenital infection due to cytomegalovirus. Acyclovir (60 mg/kg/day in three doses for 2-3 weeks) prevents the development of severe forms in skin-eyes-mouth herpes disease, and lowers the rate of mortality and sequelae when the disease has disseminated and is located in the central nervous system.

Herpes simplex virus type 2-associated recurrent aseptic meningitis (Mollaret's meningitis) with a recurrence after 11-year interval: a case report.

PubMed

Nakamura, Yoshitsugu; Nakajima, Hideto; Kano, Yosuke; Unoda, Kiichi; Ishida, Shimon; Kimura, Fumiharu

2016-11-29

A 55-year-old woman was diagnosed with aseptic meningitis at the age of 43 and 44. She developed sudden fever and headache, and she showed nuchal rigidity. Cerebrospinal fluid examination revealed pleocytosis (cell count 208/mm 3 ) and was positive for herpes simplex virus type 2 (HSV-2) DNA by PCR. Acyclovir was started on the first day of admission, and she was complete recovery. Preserved cerebrospinal fluid specimen from aseptic meningitis at the age of 44 was also positive for HSV-2 DNA by PCR. She was diagnosed with HSV-2 associated recurrent aseptic meningitis (Mollaret's meningitis) with a recurrence after 11-year interval. She repeatedly relapsed genital herpes after 44 years old and she was treated with valacyclovir whenever genital herpes relapses. But she showed no genital herpes at the onset of meningitis. Because HSV-2 is one of the most significant causes of recurrent meningitis, we would like to stress that HSV-2 infection and antiviral therapy should always be kept in mind for a recurrent meningitis case.

Relationship of herpes simplex encephalitis and transcranial direct current stimulation--a case report.

PubMed

Yang, Yuanbin; Xiao, Juan; Song, Haiqing; Wang, Ralph; Hussain, Mohammed; Song, Weiqun

2015-04-01

We report a rare case of relapsing herpes simplex encephalitis in a-37-year-old patient which was previously confirmed by positive polymerase chain reaction, herpes simplex virus (HSV) type1 IgG antibodies in cerebrospinal fluid and characterized on MRI. During the first admission, he was treated with continuous acyclovir treatment for one month with clinical improvement except for residual aphasia, for which he received a course of outpatient transcranial direct current stimulation (tDCS). A constant current of 1.2 mA was applied for 20 min twice daily. After the 4th day the patient was found to be irritable and uncooperative by staff and family members. A subsequent MRI showed significant deterioration of the lesion on comparison to the first MRI which led to discontinuation of tDCS.The relatively rapid exacerbation of HSV in only a few days is unusual. Our aim is to discuss if tDCS is related to HSV relapse and in doing so highlight possible mechanisms. Copyright © 2015. Published by Elsevier B.V.

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

Antiviral Action of Hydromethanolic Extract of Geopropolis from Scaptotrigona postica against Antiherpes Simplex Virus (HSV-1).

PubMed

Coelho, Guilherme Rabelo; Mendonça, Ronaldo Zucatelli; Vilar, Karina de Senna; Figueiredo, Cristina Adelaide; Badari, Juliana Cuoco; Taniwaki, Noemi; Namiyama, Gisleine; de Oliveira, Maria Isabel; Curti, Suely Pires; Evelyn Silva, Patricia; Negri, Giuseppina

2015-01-01

The studies on chemical composition and biological activity of propolis had focused mainly on species Apis mellifera L. (Hymenoptera: Apidae). There are few studies about the uncommon propolis collected by stingless bees of the Meliponini tribe known as geopropolis. The geopropolis from Scaptotrigona postica was collected in the region of Barra do Corda, Maranhão state, Brazil. The chemical analysis of hydromethanolic extract of this geopropolis (HMG) was carried out through HPLC-DAD-ESI-MS/MS and the main constituents found were pyrrolizidine alkaloids and C-glycosyl flavones. The presence of alkaloids in extracts of propolis is detected for the first time in this sample. The antiviral activity of HMG was evaluated through viral DNA quantification experiments and electron microscopy experiments. Quantification of viral DNA from herpes virus showed reduction of about 98% in all conditions and concentration tested of the HMG extract. The results obtained were corroborated by transmission electron microscopy, in which the images did not show particle or viral replication complex. The antiviral activity of C-glycosyl flavones was reported for a variety of viruses, being observed at different points in the viral replication. This work is the first report about the antiviral activity of geopropolis from Scaptotrigona postica, in vitro, against antiherpes simplex virus (HSV).

Antiviral Action of Hydromethanolic Extract of Geopropolis from Scaptotrigona postica against Antiherpes Simplex Virus (HSV-1)

PubMed Central

Coelho, Guilherme Rabelo; Mendonça, Ronaldo Zucatelli; Vilar, Karina de Senna; Figueiredo, Cristina Adelaide; Badari, Juliana Cuoco; Taniwaki, Noemi; Namiyama, Gisleine; de Oliveira, Maria Isabel; Curti, Suely Pires; Evelyn Silva, Patricia

2015-01-01

The studies on chemical composition and biological activity of propolis had focused mainly on species Apis mellifera L. (Hymenoptera: Apidae). There are few studies about the uncommon propolis collected by stingless bees of the Meliponini tribe known as geopropolis. The geopropolis from Scaptotrigona postica was collected in the region of Barra do Corda, Maranhão state, Brazil. The chemical analysis of hydromethanolic extract of this geopropolis (HMG) was carried out through HPLC-DAD-ESI-MS/MS and the main constituents found were pyrrolizidine alkaloids and C-glycosyl flavones. The presence of alkaloids in extracts of propolis is detected for the first time in this sample. The antiviral activity of HMG was evaluated through viral DNA quantification experiments and electron microscopy experiments. Quantification of viral DNA from herpes virus showed reduction of about 98% in all conditions and concentration tested of the HMG extract. The results obtained were corroborated by transmission electron microscopy, in which the images did not show particle or viral replication complex. The antiviral activity of C-glycosyl flavones was reported for a variety of viruses, being observed at different points in the viral replication. This work is the first report about the antiviral activity of geopropolis from Scaptotrigona postica, in vitro, against antiherpes simplex virus (HSV). PMID:25861357

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.

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.

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.

Acute hydrocephalus secondary to herpes simplex type II meningitis.

PubMed

Heppner, Peter A; Schweder, Patrick M; Monteith, Stephen J; Law, Andrew J J

2008-10-01

A 34-year-old woman presented with a rapid onset of meningitic symptoms. Cerebrospinal fluid (CSF) from a lumbar puncture revealed a leucocytosis with a preponderance of monocytes, elevated protein and reduced glucose. Herpes simplex virus (HSV) type II was subsequently confirmed by polymerase chain reaction (PCR) of CSF. The patient's level of consciousness deteriorated and a CT scan revealed hydrocephalus. The patient required placement of an external ventricular drain for 5 days; however, she made a full recovery without specific antiviral therapy. This is the first reported case of hydrocephalus secondary to isolated HSV type II meningitis.

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.

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.

Novel Structure and Unexpected RNA-Binding Ability of the C-Terminal Domain of Herpes Simplex Virus 1 Tegument Protein UL21

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

Metrick, Claire M.; Heldwein, Ekaterina E.; Sandri-Goldin, R. M.

Proteins forming the tegument layers of herpesviral virions mediate many essential processes in the viral replication cycle, yet few have been characterized in detail. UL21 is one such multifunctional tegument protein and is conserved among alphaherpesviruses. While UL21 has been implicated in many processes in viral replication, ranging from nuclear egress to virion morphogenesis to cell-cell spread, its precise roles remain unclear. Here we report the 2.7-Å crystal structure of the C-terminal domain of herpes simplex virus 1 (HSV-1) UL21 (UL21C), which has a unique α-helical fold resembling a dragonfly. Analysis of evolutionary conservation patterns and surface electrostatics pinpointed fourmore » regions of potential functional importance on the surface of UL21C to be pursued by mutagenesis. In combination with the previously determined structure of the N-terminal domain of UL21, the structure of UL21C provides a 3-dimensional framework for targeted exploration of the multiple roles of UL21 in the replication and pathogenesis of alphaherpesviruses. Additionally, we describe an unanticipated ability of UL21 to bind RNA, which may hint at a yet unexplored function. IMPORTANCEDue to the limited genomic coding capacity of viruses, viral proteins are often multifunctional, which makes them attractive antiviral targets. Such multifunctionality, however, complicates their study, which often involves constructing and characterizing null mutant viruses. Systematic exploration of these multifunctional proteins requires detailed road maps in the form of 3-dimensional structures. In this work, we determined the crystal structure of the C-terminal domain of UL21, a multifunctional tegument protein that is conserved among alphaherpesviruses. Structural analysis pinpointed surface areas of potential functional importance that provide a starting point for mutagenesis. In addition, the unexpected RNA-binding ability of UL21 may expand its functional repertoire. The structure of UL21C and the observation of its RNA-binding ability are the latest additions to the navigational chart that can guide the exploration of the multiple functions of UL21.« less

The Product of the Herpes Simplex Virus Type 1 UL25 Gene Is Required for Encapsidation but Not for Cleavage of Replicated Viral DNA

PubMed Central

McNab, Alistair R.; Desai, Prashant; Person, Stan; Roof, Lori L.; Thomsen, Darrell R.; Newcomb, William W.; Brown, Jay C.; Homa, Fred L.

1998-01-01

The herpes simplex virus type 1 (HSV-1) UL25 gene contains a 580-amino-acid open reading frame that codes for an essential protein. Previous studies have shown that the UL25 gene product is a virion component (M. A. Ali et al., Virology 216:278–283, 1996) involved in virus penetration and capsid assembly (C. Addison et al., Virology 138:246–259, 1984). In this study, we describe the isolation of a UL25 mutant (KUL25NS) that was constructed by insertion of an in-frame stop codon in the UL25 open reading frame and propagated on a complementing cell line. Although the mutant was capable of synthesis of viral DNA, it did not form plaques or produce infectious virus in noncomplementing cells. Antibodies specific for the UL25 protein were used to demonstrate that KUL25NS-infected Vero cells did not express the UL25 protein. Western immunoblotting showed that the UL25 protein was associated with purified, wild-type HSV A, B, and C capsids. Transmission electron microscopy indicated that the nucleus of Vero cells infected with KUL25NS contained large numbers of both A and B capsids but no C capsids. Analysis of infected cells by sucrose gradient sedimentation analysis confirmed that the ratio of A to B capsids was elevated in KUL25NS-infected Vero cells. Following restriction enzyme digestion, specific terminal fragments were observed in DNA isolated from KUL25NS-infected Vero cells, indicating that the UL25 gene was not required for cleavage of replicated viral DNA. The latter result was confirmed by pulsed-field gel electrophoresis (PFGE), which showed the presence of genome-size viral DNA in KUL25NS-infected Vero cells. DNase I treatment prior to PFGE demonstrated that monomeric HSV DNA was not packaged in the absence of the UL25 protein. Our results indicate that the product of the UL25 gene is required for packaging but not cleavage of replicated viral DNA. PMID:9445000

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 systematic analysis of host factors reveals a Med23-interferon-λ regulatory axis against herpes simplex virus type 1 replication.

PubMed

Griffiths, Samantha J; Koegl, Manfred; Boutell, Chris; Zenner, Helen L; Crump, Colin M; Pica, Francesca; Gonzalez, Orland; Friedel, Caroline C; Barry, Gerald; Martin, Kim; Craigon, Marie H; Chen, Rui; Kaza, Lakshmi N; Fossum, Even; Fazakerley, John K; Efstathiou, Stacey; Volpi, Antonio; Zimmer, Ralf; Ghazal, Peter; Haas, Jürgen

2013-01-01

Herpes simplex virus type 1 (HSV-1) is a neurotropic virus causing vesicular oral or genital skin lesions, meningitis and other diseases particularly harmful in immunocompromised individuals. To comprehensively investigate the complex interaction between HSV-1 and its host we combined two genome-scale screens for host factors (HFs) involved in virus replication. A yeast two-hybrid screen for protein interactions and a RNA interference (RNAi) screen with a druggable genome small interfering RNA (siRNA) library confirmed existing and identified novel HFs which functionally influence HSV-1 infection. Bioinformatic analyses found the 358 HFs were enriched for several pathways and multi-protein complexes. Of particular interest was the identification of Med23 as a strongly anti-viral component of the largely pro-viral Mediator complex, which links specific transcription factors to RNA polymerase II. The anti-viral effect of Med23 on HSV-1 replication was confirmed in gain-of-function gene overexpression experiments, and this inhibitory effect was specific to HSV-1, as a range of other viruses including Vaccinia virus and Semliki Forest virus were unaffected by Med23 depletion. We found Med23 significantly upregulated expression of the type III interferon family (IFN-λ) at the mRNA and protein level by directly interacting with the transcription factor IRF7. The synergistic effect of Med23 and IRF7 on IFN-λ induction suggests this is the major transcription factor for IFN-λ expression. Genotypic analysis of patients suffering recurrent orofacial HSV-1 outbreaks, previously shown to be deficient in IFN-λ secretion, found a significant correlation with a single nucleotide polymorphism in the IFN-λ3 (IL28b) promoter strongly linked to Hepatitis C disease and treatment outcome. This paper describes a link between Med23 and IFN-λ, provides evidence for the crucial role of IFN-λ in HSV-1 immune control, and highlights the power of integrative genome-scale approaches to identify HFs critical for disease progression and outcome.

A Domain of Herpes Simplex Virus pUL33 Required To Release Monomeric Viral Genomes from Cleaved Concatemeric DNA.

PubMed

Yang, Kui; Dang, Xiaoqun; Baines, Joel D

2017-10-15

Monomeric herpesvirus DNA is cleaved from concatemers and inserted into preformed capsids through the actions of the viral terminase. The terminase of herpes simplex virus (HSV) is composed of three subunits encoded by U L 15, U L 28, and U L 33. The U L 33-encoded protein (pU L 33) interacts with pU L 28, but its precise role in the DNA cleavage and packaging reaction is unclear. To investigate the function of pU L 33, we generated a panel of recombinant viruses with either deletions or substitutions in the most conserved regions of U L 33 using a bacterial artificial chromosome system. Deletion of 11 amino acids (residues 50 to 60 or residues 110 to 120) precluded viral replication, whereas the truncation of the last 10 amino acids from the pU L 33 C terminus did not affect viral replication or the interaction of pU L 33 with pU L 28. Mutations that replaced the lysine at codon 110 and the arginine at codon 111 with alanine codons failed to replicate, and the pU L 33 mutant interacted with pU L 28 less efficiently. Interestingly, genomic termini of the large (L) and small (S) components were detected readily in cells infected with these mutants, indicating that concatemeric DNA was cleaved efficiently. However, the release of monomeric genomes as assessed by pulsed-field gel electrophoresis was greatly diminished, and DNA-containing capsids were not observed. These results suggest that pU L 33 is necessary for one of the two viral DNA cleavage events required to release individual genomes from concatemeric viral DNA. IMPORTANCE This paper shows a role for pU L 33 in one of the two DNA cleavage events required to release monomeric genomes from concatemeric viral DNA. This is the first time that such a phenotype has been observed and is the first identification of a function of this protein relevant to DNA packaging other than its interaction with other terminase components. Copyright © 2017 Yang et al.

Latency Entry of Herpes Simplex Virus 1 Is Determined by the Interaction of Its Genome with the Nuclear Environment

PubMed Central

Cohen, Camille; Streichenberger, Nathalie; Texier, Pascale; Takissian, Julie; Rousseau, Antoine; Poccardi, Nolwenn; Welsch, Jérémy; Corpet, Armelle; Schaeffer, Laurent; Labetoulle, Marc; Lomonte, Patrick

2016-01-01

Herpes simplex virus 1 (HSV-1) establishes latency in trigeminal ganglia (TG) sensory neurons of infected individuals. The commitment of infected neurons toward the viral lytic or latent transcriptional program is likely to depend on both viral and cellular factors, and to differ among individual neurons. In this study, we used a mouse model of HSV-1 infection to investigate the relationship between viral genomes and the nuclear environment in terms of the establishment of latency. During acute infection, viral genomes show two major patterns: replication compartments or multiple spots distributed in the nucleoplasm (namely “multiple-acute”). Viral genomes in the “multiple-acute” pattern are systematically associated with the promyelocytic leukemia (PML) protein in structures designated viral DNA-containing PML nuclear bodies (vDCP-NBs). To investigate the viral and cellular features that favor the acquisition of the latency-associated viral genome patterns, we infected mouse primary TG neurons from wild type (wt) mice or knock-out mice for type 1 interferon (IFN) receptor with wt or a mutant HSV-1, which is unable to replicate due to the synthesis of a non-functional ICP4, the major virus transactivator. We found that the inability of the virus to initiate the lytic program combined to its inability to synthesize a functional ICP0, are the two viral features leading to the formation of vDCP-NBs. The formation of the “multiple-latency” pattern is favored by the type 1 IFN signaling pathway in the context of neurons infected by a virus able to replicate through the expression of a functional ICP4 but unable to express functional VP16 and ICP0. Analyses of TGs harvested from HSV-1 latently infected humans showed that viral genomes and PML occupy similar nuclear areas in infected neurons, eventually forming vDCP-NB-like structures. Overall our study designates PML protein and PML-NBs to be major cellular components involved in the control of HSV-1 latency, probably during the entire life of an individual. PMID:27618691

Accumulation of Herpes Simplex Virus Type 1 Early and Leaky-Late Proteins Correlates with Apoptosis Prevention in Infected Human HEp-2 Cells

PubMed Central

Aubert, Martine; Rice, Stephen A.; Blaho, John A.

2001-01-01

We previously reported that a recombinant ICP27-null virus stimulated, but did not prevent, apoptosis in human HEp-2 cells during infection (M. Aubert and J. A. Blaho, J. Virol. 73:2803–2813, 1999). In the present study, we used a panel of 15 recombinant ICP27 mutant viruses to determine which features of herpes simplex virus type 1 (HSV-1) replication are required for the apoptosis-inhibitory activity. Each virus was defined experimentally as either apoptotic, partially apoptotic, or nonapoptotic based on infected HEp-2 cell morphologies, percentages of infected cells with condensed chromatin, and patterns of specific cellular death factor processing. Viruses d27-1, d1-5, d1-2, M11, M15, M16, n504R, n406R, n263R, and n59R are apoptotic or partially apoptotic in HEp-2 cells and severely defective for growth in Vero cells. Viruses d2-3, d3-4, d4-5, d5-6, and d6-7 are nonapoptotic, demonstrating that ICP27 contains a large amino-terminal region, including its RGG box RNA binding domain, which is not essential for apoptosis prevention. Accumulations of viral TK, VP16, and gD but not gC, ICP22, or ICP4 proteins correlated with prevention of apoptosis during the replication of these viruses. Of the nonapoptotic viruses, d4-5 did not produce gC, indicating that accumulation of true late gene products is not necessary for the prevention process. Analyses of viral DNA synthesis in HEp-2 cells indicated that apoptosis prevention by HSV-1 requires that the infection proceeds to the stage in which viral DNA replication takes place. Infections performed in the presence of the drug phosphonoacetic acid confirmed that the process of viral DNA synthesis and the accumulation of true late (γ2) proteins are not required for apoptosis prevention. Based on our results, we conclude that the accumulation of HSV-1 early (β) and leaky-late (γ1) proteins correlates with the prevention of apoptosis in infected HEp-2 cells. PMID:11134315

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.

Transient urinary retention and chronic neuropathic pain associated with genital herpes simplex virus infection.

PubMed

Haanpää, Maija; Paavonen, Jorma

2004-10-01

Genital herpes (GH) causes genital ulcer disease, severe transient pain, and often paresthesias. Whether or not GH can cause urinary retention or chronic neuropathic pain is not well known. We present two immunocompetent patients with GH associated with neuropathic symptoms. We also review the literature on GH and associated neurologic problems. Patient 1 had primary herpes simplex virus (HSV)-2 infection with transient urinary retention and chronic bilateral neuropathic pain in the sacral area. Patient 2 had recurrent HSV-1 associated with unitaleral chronic neuropathic pain in the sacral area. Although transient urinary retention associated with GH is not uncommon, chronic neuropathic pain has not been reported previously. Our cases show that chronic neuropathic pain, that is "pain initiated or caused by a primary lesion or dysfunction in the nervous system," can follow genital HSV infection.

Acyclovir resistant acute herpes simplex encephalitis associated with acute retinal necrosis: A case report and review of the literature.

PubMed

Ogura, Haruchika; Fukae, Jiro; Kimura, Satoshi; Aoki, Mikiko; Nabeshima, Kazuki; Tsuboi, Yoshio

2017-05-27

A 55-year-old man was admitted to our hospital for investigation of high fever, decreased consciousness and bilateral visual impairment. His cerebrospinal fluid analysis revealed pleocytosis of mononuclear cells and an increased protein concentration. FLAIR images revealed multiple high-intensity lesions in the frontal lobe, part of which was enhanced with gadolinium. Despite initiating treatment with acyclovir and corticosteroids, his consciousness and visual acuity deteriorated. Immunopathological examination of brain biopsies showed numerous herpes simplex virus type 2-positive neurons and macrophages, leading to a diagnosis of herpes simplex encephalitis (HSE). Fundoscopic examination revealed multiple foci of retinitis with vasculopathies, and inflammation in the anterior chamber and vitreous, indicating acute retinal necrosis (ARN). Foscarnet treatment was initiated in place of acyclovir and his consciousness improved, with a slight improvement in visual acuity. ARN is typically caused by a herpes virus infection limited to the eyeball, and rarely in combination with HSE. In such cases, there is a latency of approximately 2-4 weeks between ARN and the onset of encephalitis. Our case is unique in that HSE and ARN developed simultaneously, and it highlights that there may not always be a latency between the onsets of the two disorders. Finally, foscarnet should be considered in cases of HSE and ARN with acyclovir resistance.

Genome-wide engineering of an infectious clone of herpes simplex virus type 1 using synthetic genomics assembly methods.

PubMed

Oldfield, Lauren M; Grzesik, Peter; Voorhies, Alexander A; Alperovich, Nina; MacMath, Derek; Najera, Claudia D; Chandra, Diya Sabrina; Prasad, Sanjana; Noskov, Vladimir N; Montague, Michael G; Friedman, Robert M; Desai, Prashant J; Vashee, Sanjay

2017-10-17

Here, we present a transformational approach to genome engineering of herpes simplex virus type 1 (HSV-1), which has a large DNA genome, using synthetic genomics tools. We believe this method will enable more rapid and complex modifications of HSV-1 and other large DNA viruses than previous technologies, facilitating many useful applications. Yeast transformation-associated recombination was used to clone 11 fragments comprising the HSV-1 strain KOS 152 kb genome. Using overlapping sequences between the adjacent pieces, we assembled the fragments into a complete virus genome in yeast, transferred it into an Escherichia coli host, and reconstituted infectious virus following transfection into mammalian cells. The virus derived from this yeast-assembled genome, KOS YA , replicated with kinetics similar to wild-type virus. We demonstrated the utility of this modular assembly technology by making numerous modifications to a single gene, making changes to two genes at the same time and, finally, generating individual and combinatorial deletions to a set of five conserved genes that encode virion structural proteins. While the ability to perform genome-wide editing through assembly methods in large DNA virus genomes raises dual-use concerns, we believe the incremental risks are outweighed by potential benefits. These include enhanced functional studies, generation of oncolytic virus vectors, development of delivery platforms of genes for vaccines or therapy, as well as more rapid development of countermeasures against potential biothreats.

Inhibition of herpes simplex type 1 and type 2 infections by Oximacro(®), a cranberry extract with a high content of A-type proanthocyanidins (PACs-A).

PubMed

Terlizzi, Maria Elena; Occhipinti, Andrea; Luganini, Anna; Maffei, Massimo E; Gribaudo, Giorgio

2016-08-01

In the absence of efficient preventive vaccines, topical microbicides offer an attractive alternative in the prevention of Herpes simplex type 1 (HSV-1) and type 2 (HSV-2) infections. Because of their recognized anti-adhesive activity against bacterial pathogens, cranberry (Vaccinium macrocarpon Ait.) extracts may represent a natural source of new antiviral microbicides. However, few studies have addressed the applications of cranberry extract as a direct-acting antiviral agent. Here, we report on the ability of the novel cranberry extract Oximacro(®) and its purified A-type proanthocyanidins (PACs-A), to inhibit HSV-1 and HSV-2 replication in vitro. Analysis of the mode of action revealed that Oximacro(®) prevents adsorption of HSV-1 and HSV-2 to target cells. Further mechanistic studies confirmed that Oximacro(®) and its PACs-A target the viral envelope glycoproteins gD and gB, thus resulting in the loss of infectivity of HSV particles. Moreover, Oximacro(®) completely retained its anti-HSV activity even at acidic pHs (3.0 and 4.0) and in the presence of 10% human serum proteins; conditions that mimic the physiological properties of the vagina - a potential therapeutic location for Oximacro(®). Taken together, these findings indicate Oximacro(®) as an attractive candidate for the development of novel microbicides of natural origin for the prevention of HSV infections. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

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

PubMed Central

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

2003-01-01

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

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

Genome-wide engineering of an infectious clone of herpes simplex virus type 1 using synthetic genomics assembly methods

PubMed Central

Grzesik, Peter; Voorhies, Alexander A.; Alperovich, Nina; MacMath, Derek; Najera, Claudia D.; Chandra, Diya Sabrina; Prasad, Sanjana; Noskov, Vladimir N.; Montague, Michael G.; Friedman, Robert M.; Desai, Prashant J.

2017-01-01

Here, we present a transformational approach to genome engineering of herpes simplex virus type 1 (HSV-1), which has a large DNA genome, using synthetic genomics tools. We believe this method will enable more rapid and complex modifications of HSV-1 and other large DNA viruses than previous technologies, facilitating many useful applications. Yeast transformation-associated recombination was used to clone 11 fragments comprising the HSV-1 strain KOS 152 kb genome. Using overlapping sequences between the adjacent pieces, we assembled the fragments into a complete virus genome in yeast, transferred it into an Escherichia coli host, and reconstituted infectious virus following transfection into mammalian cells. The virus derived from this yeast-assembled genome, KOSYA, replicated with kinetics similar to wild-type virus. We demonstrated the utility of this modular assembly technology by making numerous modifications to a single gene, making changes to two genes at the same time and, finally, generating individual and combinatorial deletions to a set of five conserved genes that encode virion structural proteins. While the ability to perform genome-wide editing through assembly methods in large DNA virus genomes raises dual-use concerns, we believe the incremental risks are outweighed by potential benefits. These include enhanced functional studies, generation of oncolytic virus vectors, development of delivery platforms of genes for vaccines or therapy, as well as more rapid development of countermeasures against potential biothreats. PMID:28928148

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

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.

Dendritiform Keratopathy Associated with Exposure to Polyquarternium-1, a Common Ophthalmic Preservative.

PubMed

Matoba, Alice Y; Peterson, Jeff R; Wilhelmus, Kirk R

2016-03-01

To describe dendritiform keratopathy associated with exposure to polyquaternium-1, a common preservative found in contact lens solutions and tear replacement products. Case series. Sixteen patients who demonstrated dendritiform keratopathy during topical ophthalmic exposure to polyquaternium-1. Records were reviewed of all patients diagnosed with dendritiform keratopathy between 1999 and 2014 who had documented exposure to contact lens care disinfecting solutions or artificial tear solutions containing polyquaternium-1. Patients were excluded who had coexisting potential causes for dendritiform keratopathy, such as prior herpes simplex keratitis, varicella-zoster viral keratitis, the linear form of Thygeson's superficial keratitis, epithelial regeneration line, Acanthamoeba keratitis, mucus plaque keratopathy, medication-related keratopathy, or limbal stem cell deficiency characterized by conjunctivalization of the corneal epithelium. Effect of discontinuation of exposure to polyquaternium-1 on the dendritiform keratopathy. Sixteen patients demonstrated dendritiform keratopathy after exposure to the preservative polyquaternium-1. Thirteen patients had a history of recent exposure to contact lens disinfecting solutions (Opti-Free, Equate) containing polyquaternium-1. Three patients used a tear replacement product (Systane) containing a polyquaternium-1 preservative. Four patients were treated with antiviral medications for presumed herpes simplex keratitis; 4 patients underwent diagnostic testing for Acanthamoeba keratitis. Two additional patients were diagnosed sequentially with herpes simplex keratitis, then Acanthamoeba keratitis before referral. All dendritiform lesions resolved within 2 to 6 weeks after elimination of exposure to polyquaternium-1. Ophthalmic products containing polyquaternium-1 may cause dendritiform keratopathy that may be confused with infections of the superficial cornea, such as herpes simplex virus keratitis or Acanthamoeba keratitis. Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Guidelines for the management of herpes simplex virus in pregnancy.

PubMed

Money, Deborah; Steben, Marc

2008-06-01

To provide recommendations for the management of genital herpes infection in women who want to get pregnant or are pregnant and for the management of genital herpes in pregnancy and strategies to prevent transmission to the infant. More effective management of complications of genital herpes in pregnancy and prevention of transmission of genital herpes from mother to infant. Medline was searched for articles published in French or English related to genital herpes and pregnancy. Additional articles were identified through the references of these articles. All study types and recommendation reports were reviewed. Recommendations were made according to the guidelines developed by the Canadian Task Force on Preventive Health Care.

Update on Neonatal Herpes Simplex Epidemiology in the Netherlands: A Health Problem of Increasing Concern?

PubMed

van Oeffelen, Louise; Biekram, Manisha; Poeran, Jashvant; Hukkelhoven, Chantal; Galjaard, Sander; van der Meijden, Wim; Op de Coul, Eline

2018-01-18

This paper provides an update on the incidence of neonatal herpes, guideline adherence by health care professionals (HCP), and trends in genital herpes simplex virus (HSV) infection during pregnancy in the Netherlands. Questionnaires were sent to all hospitals inquiring about numbers and characteristics of neonatal and maternal HSV infections, and guideline adherence between 2012 and 2015. Longitudinal trends were investigated from 1999 onwards using survey data and Perinatal Registry of the Netherlands data (Perined). Trends were smoothed with Poisson regression splines. Risk indicators for neonatal and maternal HSV infections were examined with Poisson regression analyses. Neonatal herpes incidence was 4.8/100,000 live births based on survey data (2012-2015) and 3.4/100,000 based on Perined (2012-2014). Mortality rate was 23% (7/30). Neonatal herpes incidence increased slightly over time as did the prevalence of genital HSV infection among pregnant women. Non-Western ethnicity (RR 1.9, 95%CI 1.5-2.5) and age <20 years (RR 2.3, 95%CI 1.2-4.7) were associated with genital herpes during pregnancy. In Perined, none of the neonatal herpes cases had a mother diagnosed with an active genital herpes infection during pregnancy. Preventive measures to reduce vertical herpes transmission (such as caesarean section) were less commonly reported by HCP in 2012-2015 compared to 2006-2011. Neonatal herpes incidence in the Netherlands slowly increased over the last 15 years. An increased genital HSV prevalence during pregnancy or, to lower extent, the decreased guideline adherence by HCP may be responsible. A rise in asymptomatic maternal HSV shedding is also plausible, emphasizing the challenges in preventing neonatal herpes.

Thymidine Kinase-Negative Herpes Simplex Virus 1 Can Efficiently Establish Persistent Infection in Neural Tissues of Nude Mice.

PubMed

Huang, Chih-Yu; Yao, Hui-Wen; Wang, Li-Chiu; Shen, Fang-Hsiu; Hsu, Sheng-Min; Chen, Shun-Hua

2017-02-15

Herpes simplex virus 1 (HSV-1) establishes latency in neural tissues of immunocompetent mice but persists in both peripheral and neural tissues of lymphocyte-deficient mice. Thymidine kinase (TK) is believed to be essential for HSV-1 to persist in neural tissues of immunocompromised mice, because infectious virus of a mutant with defects in both TK and UL24 is detected only in peripheral tissues, but not in neural tissues, of severe combined immunodeficiency mice (T. Valyi-Nagy, R. M. Gesser, B. Raengsakulrach, S. L. Deshmane, B. P. Randazzo, A. J. Dillner, and N. W. Fraser, Virology 199:484-490, 1994, https://doi.org/10.1006/viro.1994.1150). Here we find infiltration of CD4 and CD8 T cells in peripheral and neural tissues of mice infected with a TK-negative mutant. We therefore investigated the significance of viral TK and host T cells for HSV-1 to persist in neural tissues using three genetically engineered mutants with defects in only TK or in both TK and UL24 and two strains of nude mice. Surprisingly, all three mutants establish persistent infection in up to 100% of brain stems and 93% of trigeminal ganglia of adult nude mice at 28 days postinfection, as measured by the recovery of infectious virus. Thus, in mouse neural tissues, host T cells block persistent HSV-1 infection, and viral TK is dispensable for the virus to establish persistent infection. Furthermore, we found 30- to 200-fold more virus in neural tissues than in the eye and detected glycoprotein C, a true late viral antigen, in brainstem neurons of nude mice persistently infected with the TK-negative mutant, suggesting that adult mouse neurons can support the replication of TK-negative HSV-1. Acyclovir is used to treat herpes simplex virus 1 (HSV-1)-infected immunocompromised patients, but treatment is hindered by the emergence of drug-resistant viruses, mostly those with mutations in viral thymidine kinase (TK), which activates acyclovir. TK mutants are detected in brains of immunocompromised patients with persistent infection. However, answers to the questions as to whether TK-negative (TK - ) HSV-1 can establish persistent infection in brains of immunocompromised hosts and whether neurons in vivo are permissive for TK - HSV-1 remain elusive. Using three genetically engineered HSV-1 TK - mutants and two strains of nude mice deficient in T cells, we found that all three HSV-1 TK - mutants can efficiently establish persistent infection in the brain stem and trigeminal ganglion and detected glycoprotein C, a true late viral antigen, in brainstem neurons. Our study provides evidence that TK - HSV-1 can persist in neural tissues and replicate in brain neurons of immunocompromised hosts. Copyright © 2017 American Society for Microbiology.

Thymidine Kinase-Negative Herpes Simplex Virus 1 Can Efficiently Establish Persistent Infection in Neural Tissues of Nude Mice

PubMed Central

Huang, Chih-Yu; Yao, Hui-Wen; Wang, Li-Chiu; Shen, Fang-Hsiu

2016-01-01

ABSTRACT Herpes simplex virus 1 (HSV-1) establishes latency in neural tissues of immunocompetent mice but persists in both peripheral and neural tissues of lymphocyte-deficient mice. Thymidine kinase (TK) is believed to be essential for HSV-1 to persist in neural tissues of immunocompromised mice, because infectious virus of a mutant with defects in both TK and UL24 is detected only in peripheral tissues, but not in neural tissues, of severe combined immunodeficiency mice (T. Valyi-Nagy, R. M. Gesser, B. Raengsakulrach, S. L. Deshmane, B. P. Randazzo, A. J. Dillner, and N. W. Fraser, Virology 199:484–490, 1994, https://doi.org/10.1006/viro.1994.1150). Here we find infiltration of CD4 and CD8 T cells in peripheral and neural tissues of mice infected with a TK-negative mutant. We therefore investigated the significance of viral TK and host T cells for HSV-1 to persist in neural tissues using three genetically engineered mutants with defects in only TK or in both TK and UL24 and two strains of nude mice. Surprisingly, all three mutants establish persistent infection in up to 100% of brain stems and 93% of trigeminal ganglia of adult nude mice at 28 days postinfection, as measured by the recovery of infectious virus. Thus, in mouse neural tissues, host T cells block persistent HSV-1 infection, and viral TK is dispensable for the virus to establish persistent infection. Furthermore, we found 30- to 200-fold more virus in neural tissues than in the eye and detected glycoprotein C, a true late viral antigen, in brainstem neurons of nude mice persistently infected with the TK-negative mutant, suggesting that adult mouse neurons can support the replication of TK-negative HSV-1. IMPORTANCE Acyclovir is used to treat herpes simplex virus 1 (HSV-1)-infected immunocompromised patients, but treatment is hindered by the emergence of drug-resistant viruses, mostly those with mutations in viral thymidine kinase (TK), which activates acyclovir. TK mutants are detected in brains of immunocompromised patients with persistent infection. However, answers to the questions as to whether TK-negative (TK−) HSV-1 can establish persistent infection in brains of immunocompromised hosts and whether neurons in vivo are permissive for TK− HSV-1 remain elusive. Using three genetically engineered HSV-1 TK− mutants and two strains of nude mice deficient in T cells, we found that all three HSV-1 TK− mutants can efficiently establish persistent infection in the brain stem and trigeminal ganglion and detected glycoprotein C, a true late viral antigen, in brainstem neurons. Our study provides evidence that TK− HSV-1 can persist in neural tissues and replicate in brain neurons of immunocompromised hosts. PMID:27974554

Overexpression of Promyelocytic Leukemia Protein Precludes the Dispersal of ND10 Structures and Has No Effect on Accumulation of Infectious Herpes Simplex Virus 1 or Its Proteins

PubMed Central

Lopez, Pascal; Jacob, Robert J.; Roizman, Bernard

2002-01-01

A key early event in the replication of herpes simplex virus 1 (HSV-1) is the localization of infected-cell protein no. 0 (ICP0) in nuclear structures knows as ND10 or promyelocytic leukemia oncogenic domains (PODs). This is followed by dispersal of ND10 constituents such as the promyelocytic leukemia protein (PML), CREB-binding protein (CBP), and Daxx. Numerous experiments have shown that this dispersal is mediated by ICP0. PML is thought to be the organizing structural component of ND10. To determine whether the virus targets PML because it is inimical to viral replication, telomerase-immortalized human foreskin fibroblasts and HEp-2 cells were transduced with wild-type baculovirus or a baculovirus expressing the Mr 69,000 form of PML. The transduced cultures were examined for expression and localization of PML in mock-infected and HSV-1-infected cells. The results obtained from studies of cells overexpressing PML were as follows. (i) Transduced cells accumulate large amounts of unmodified and SUMO-I-modified PML. (ii) Mock-infected cells exhibited enlarged ND10 structures containing CBP and Daxx in addition to PML. (iii) In infected cells, ICP0 colocalized with PML in ND10 early in infection, but the two proteins did not overlap or were juxtaposed in orderly structures. (iv) The enlarged ND10 structures remained intact at least until 12 h after infection and retained CBP and Daxx in addition to PML. (v) Overexpression of PML had no effect on the accumulation of viral proteins representative of α, β, or γ groups and had no effect on the accumulation of infectious virus in cells infected with wild-type virus or a mutant (R7910) from which the α0 genes had been deleted. These results indicate the following: (i) PML overexpressed in transduced cells cannot be differentiated from endogenous PML with respect to sumoylation and localization in ND10 structures. (ii) PML does not affect viral replication or the changes in the localization of ICP0 through infection. (iii) Disaggregation of ND10 structures is not an obligatory event essential for viral replication. PMID:12186918

Nasal and skin delivery of IC31(®)-adjuvanted recombinant HSV-2 gD protein confers protection against genital herpes.

PubMed

Wizel, Benjamin; Persson, Josefine; Thörn, Karolina; Nagy, Eszter; Harandi, Ali M

2012-06-19

Genital herpes caused by herpes simplex virus type 2 (HSV-2) remains the leading cause of genital ulcers worldwide. Given the disappointing results of the recent genital herpes vaccine trials in humans, development of novel vaccine strategies capable of eliciting protective mucosal and systemic immune responses to HSV-2 is urgently required. Here we tested the ability of the adjuvant IC31(®) in combination with HSV-2 glycoprotein D (gD) used through intranasal (i.n.), intradermal (i.d.), or subcutaneous (s.c.) immunization routes for induction of protective immunity against genital herpes infection in C57BL/6 mice. Immunization with gD plus IC31(®) through all three routes of immunization developed elevated gD-specific serum antibody responses with HSV-2 neutralizing activity. Whereas the skin routes promoted the induction of a mixed IgG2c/IgG1 isotype profile, the i.n. route only elicited IgG1 antibodies. All immunization routes were able to induce gD-specific IgG antibody responses in the vaginas of mice immunized with IC31(®)-adjuvanted gD. Although specific lymphoproliferative responses were observed in splenocytes from mice of most groups vaccinated with IC31(®)-adjuvanted gD, only i.d. immunization resulted in a significant splenic IFN-γ response. Further, immunization with gD plus IC31(®) conferred 80-100% protection against an otherwise lethal vaginal HSV-2 challenge with amelioration of viral replication and disease severity in the vagina. These results warrant further exploration of IC31(®) for induction of protective immunity against genital herpes and other sexually transmitted infections. Copyright © 2012 Elsevier Ltd. All rights reserved.

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

Herpes Simplex Virus Type 1 Infects Enteric Neurons and Triggers Gut Dysfunction via Macrophage Recruitment.

PubMed

Brun, Paola; Qesari, Marsela; Marconi, Peggy C; Kotsafti, Andromachi; Porzionato, Andrea; Macchi, Veronica; Schwendener, Reto A; Scarpa, Marco; Giron, Maria C; Palù, Giorgio; Calistri, Arianna; Castagliuolo, Ignazio

2018-01-01

Herpes Simplex Virus type 1 (HSV-1), a neurotropic pathogen widespread in human population, infects the enteric nervous system (ENS) in humans and rodents and causes intestinal neuromuscular dysfunction in rats. Although infiltration of inflammatory cells in the myenteric plexus and neurodegeneration of enteric nerves are common features of patients suffering from functional intestinal disorders, the proof of a pathogenic link with HSV-1 is still unsettled mainly because the underlying mechanisms are largely unknown. In this study we demonstrated that following intragastrical administration HSV-1 infects neurons within the myenteric plexus resulting in functional and structural alterations of the ENS. By infecting mice with HSV-1 replication-defective strain we revealed that gastrointestinal neuromuscular anomalies were however independent of viral replication. Indeed, enteric neurons exposed to UV-inactivated HSV-1 produced monocyte chemoattractant protein-1 (MCP-1/CCL2) to recruit activated macrophages in the longitudinal muscle myenteric plexus. Infiltrating macrophages produced reactive oxygen and nitrogen species and directly harmed enteric neurons resulting in gastrointestinal dysmotility. In HSV-1 infected mice intestinal neuromuscular dysfunctions were ameliorated by in vivo administration of (i) liposomes containing dichloromethylene bisphosphonic acid (clodronate) to deplete tissue macrophages, (ii) CCR2 chemokine receptor antagonist RS504393 to block the CCL2/CCR2 pathway, (iii) Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) and AR-C 102222 to quench production of nitrogen reactive species produced via iNOS. Overall these data demonstrate that HSV-1 infection makes enteric neurons recruit macrophages via production of a specific chemoattractant factor. The resulting inflammatory reaction is mandatory for intestinal dysmotility. These findings provide insights into the neuro-immune communication that occurs in the ENS following HSV-1 infection and allow recognition of an original pathophysiologic mechanism underlying gastrointestinal diseases as well as identification of novel therapeutic targets.

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

PubMed

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

2015-09-01

Clinical and subclinical genital herpes simplex virus type 2 (HSV-2) reactivations have been associated with increases in human immunodeficiency virus (HIV)-1 genital shedding. Whether HSV-2 shedding contributes to the selection of specific genital HIV-1 variants remains unknown. We evaluated the genetic diversity of genital and blood HIV-1 RNA and DNA in 14 HIV-1/HSV-2-co-infected women, including seven with HSV-2 genital reactivation, and seven without as controls. HIV-1 DNA and HIV-1 RNA env V1-V3 sequences in paired blood and genital samples were compared. The HSV-2 selection pressure on HIV was estimated according to the number of synonymous substitutions (dS), the number of non-synonymous substitutions (dN) and the dS/dN ratio within HIV quasi-species. HIV-1 RNA levels in cervicovaginal secretions were higher in women with HSV-2 replication than in controls (p0.02). Plasma HIV-1 RNA and genital HIV-1 RNA and DNA were genetically compartmentalized. No differences in dS, dN and the dS/dN ratio were observed between the study groups for either genital HIV-1 RNA or plasma HIV-1 RNA. In contrast, dS and dN in genital HIV-1 DNA were significantly higher in patients with HSV-2 genital reactivation (p <0.01 and p <0.05, respectively). The mean of the dS/dN ratio in genital HIV-1 DNA was slightly higher in patients with HSV-2 genital replication, indicating a trend for purifying selection (p 0.056). HSV-2 increased the genetic diversity of genital HIV-1 DNA. These observations confirm molecular interactions between HSV-2 and HIV-1 at the genital tract level. Copyright © 2015 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Mutational Inactivation of Herpes Simplex Virus 1 MicroRNAs Identifies Viral mRNA Targets and Reveals Phenotypic Effects in Culture

PubMed Central

Flores, Omar; Nakayama, Sanae; Whisnant, Adam W.; Javanbakht, Hassan; Cullen, Bryan R.

2013-01-01

Herpes simplex virus 1 (HSV-1), a ubiquitous human pathogen, expresses several viral microRNAs (miRNAs). These, along with the latency-associated transcript, represent the only viral RNAs detectable in latently infected neuronal cells. Here, for the first time, we analyze which HSV-1 miRNAs are loaded into the RNA-induced silencing complex (RISC), the key effector of miRNA function. Only 9 of the 17 reported HSV-1 miRNAs, i.e., miR-H1 to miR-H8 plus miR-H11, were found to actually load into the RISC. Surprisingly, this analysis also revealed that HSV-1 miRNAs loaded into the RISC with efficiencies that differed widely; <1% of the miR-H1-3p miRNA detectable in HSV-1-infected cells was loaded into the RISC. Analysis of HSV-1 mutants individually lacking the viral miR-H2, miR-H3, or miR-H4 miRNA revealed that loss of these miRNAs affected the rate of replication of HSV-1 in neuronal cells but not in fibroblasts. Analysis of mRNA and protein expression, as well as assays mapping viral miRNA binding sites in infected cells, showed that endogenous HSV-1 miR-H2 binds to viral ICP0 mRNA and inhibits its expression, while endogenous miR-H4 inhibits the expression of the viral ICP34.5 gene. In contrast, no viral mRNA target for miR-H3 could be detected, even though miR-H3, like miR-H4, is perfectly complementary to ICP34.5 mRNA. Together, these data demonstrate that endogenous HSV-1 miRNA expression can significantly alter viral replication in culture, and they also identify two viral mRNA targets for miR-H2 and miR-H4 that can partially explain this phenotype. PMID:23536669

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.

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

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

Dense amnesia in a professional musician following herpes simplex virus encephalitis.

PubMed

Wilson, B A; Baddeley, A D; Kapur, N

1995-10-01

We describe the memory functioning of C, a professional musician who became amnesic following herpes simplex encephalitis in 1985. Although transient amnesia in a professional musician has previously been described, this is the first reported case of chronic amnesia in a highly talented professional musician. C is unusual in three respects. First, his amnesia is particularly severe. Second, his amnesia includes semantic as well as episodic memory deficits. Third, he believes he has just woken up and his preoccupation with this state of 'just wakening' has persisted for over 9 years. This appears to be the result of a delusion rather than the consequence of his amnesia.

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

PubMed Central

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

2015-01-01

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

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.

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

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

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

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.

The prevalence of human immunodeficiency virus and sexually transmitted infections among female sex workers in Shiraz, South of Iran: by respondent-driven sampling.

PubMed

Kazerooni, Parvin Afsar; Motazedian, Nasrin; Motamedifar, Mohammad; Sayadi, Mehrab; Sabet, Mojghan; Lari, Mahmood Amini; Kamali, Kianoush

2014-02-01

As a concentrated epidemic, human immunodeficiency virus (HIV) is spreading rapidly in one or more groups in Iran, but in the general population its prevalence is relatively low. Female sex workers (FSWs) and their partners are at greater risk for HIV infection. To determine the prevalence of HIV and sexually transmitted infections (STIs) including gonorrhoea, Chlamydia, herpes simplex type 2 and syphilis among FSWs. We conducted a cross-sectional study of 278 FSWs in Shiraz, by using respondent-driven sampling, from June to March 2010. The recruitment chain started with 14 seeds, and FSWs were tested for HIV, syphilis, herpes simplex type 2, gonorrhoea and Chlamydia. HIV prevalence was 4.7% (13/278); the most prevalent STI was herpes simplex type 2, 9.7% (27/278), followed by Chlamydia 9% (25/278), gonorrhoea 1.4% (4/278) and syphilis (0/278). The FSWs reported drug use (69.9%) of which 16.4% had history of injecting drug use. Unprotected sex in the past month was reported by 24.4% of FSWs. Urgent education and risk reduction programmes are needed in this population.

Herpes Simplex Type 2 Encephalitis After Craniotomy: Case Report and Literature Review.

PubMed

Berger, Assaf; Shahar, Tal; Margalit, Nevo

2016-04-01

Herpes simplex encephalitis (HSE) after neurosurgical procedures is extremely uncommon, and the few published case reports mainly described herpes simplex virus type 1 (HSV-1) as being culpable. We present a rare case of HSV-2 encephalitis after craniotomy and describe its pathophysiology and optimal management. A 70-year-old woman underwent an elective resection of a recurrent left sphenoid wing meningioma and clipping of a left middle cerebral artery aneurysm, the latter having been found incidentally. She returned to our department with clinical findings suggestive of meningitis 12 days after the operation. Her lack of response to empiric antibiotic treatment, taken together with the lymphocyte-predominant initial cerebrospinal fluid obtained by lumbar puncture and the electroencephalographic indications of encephalopathy, led to the suspicion of a diagnosis of HSE, which was later confirmed by a polymerase chain reaction test positive for HSV-2. The patient was then successfully treated with intravenous acyclovir for 2 weeks followed by another week of oral acyclovir treatment before being discharged. The present case stresses the importance of recognizing the relatively rare entity of HSE after craniotomy. Timely correct diagnosis will expedite the initiation of appropriate treatment. Copyright © 2016 Elsevier Inc. All rights reserved.

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.

[Update on Herpes Simplex Encephalitis].

PubMed

Kuroda, Hiroshi

2015-07-01

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

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 )

Bilateral Herpes Simplex Uveitis: Review of the Literature and Own Reports‏.

PubMed

de-la-Torre, Alejandra; Valdes-Camacho, Juanita; Foster, C Stephen

2017-08-01

Herpes simplex-associated uveitis is usually considered a unilateral eye disease, and rarely included in the differential diagnosis whenever there is bilateral involvement. We report three cases of bilateral herpetic anterior uveitis. We evaluated three patients who presented with clinical manifestations of bilateral uveitis suggestive of viral origin. We found intraocular hypertension, cells in the anterior chamber, paralytic mydriasis, iris atrophy with transillumination defects, and variable anterior vitreous cellularity. According to the clinical findings, supported with herpes-specific antibody titers and aqueous humor PCR results in two of them, they were diagnosed with bilateral anterior herpetic uveitis. Our patients were initially misdiagnosed as having non-infectious uveitis and were treated with immunomodulatory medications, which could have favored the extension of infection bilaterally. Although uncommon, bilateral herpetic uveitis should always be considered in the differential diagnoses, when patients present with hypertensive uveitis in both eyes.

Intratypic variability of a tandem repeat locus within the DNA polymerase gene of human herpes simplex virus type 2.

PubMed

Sun, Yongjiang; Chan, Roy Kum Wah; Tan, Suat Hoon

2004-01-01

In this study, the irntratypic variability of a tandem repeat locus within the DNA polymerase (pol) gene of human herpes simplex virus type 2 (HSV2) was uncovered. The locus contained variable numbers of tandem dodecanucleotide (5'-GAC GAG GAC GGG-3') repetitive units. Our result showed that approximately 95% of analyzed HSV2 clinical isolates and the current GenBank HSV2 strains contained two copies of the repetitive units. From genital herpes specimens, three new HSV2 strains, which respectively contained 1, 3, and 4 copies of the repetitive units, were identified. This variable number of tandem repeat (VNTR) locus is absent in HSV1, and thus it also contributes to the intertypic variability of HSV1 and HSV2. The intratypic variability of the locus may be useful for HSV2 strain genotyping and this application is discussed.

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 Case Study of the Cognitive and Behavioral Deficits of Temporal Lobe Damage in Herpes Simplex Encephalitis.

ERIC Educational Resources Information Center

Greer, Margaret K.; And Others

1989-01-01

This case study illustrates the highly significant language difficulties, marked memory deficits, and propensity for physical aggression following temporal lobe damage brought about by herpes encephalitis, and presents the usefulness of a new diagnostic measure in delineating such a variable cognitive pattern. (Author)

[The alpha-herpesviridae in dermatology : Herpes simplex virus types I and II. German version].

PubMed

El Hayderi, L; Rübben, A; Nikkels, A F

2017-03-01

This review on herpes simplex virus type I and type II (HSV-I, HSV-II) summarizes recent developments in clinical manifestations and treatment interventions for primary and recurrent orolabial and genital herpes, as well as those regarding vaccination issues. Among the clinical presentations, the relationship between pyogenic granuloma and chronic HSV-I infection; HSV-related folliculitis; verrucous HSV-I and HSV-II lesions; the role of recurrent HSV-I infection in burning mouth syndrome; HSV-I and HSV-II infection of the periareolar area; zosteriform HSV; the "knife-cut sign"; and the preferential colonization and infection of preexisting dermatoses by HSV-I or HSV-II are discussed. The usual antiviral treatment regimens for primary and recurrent orolabial and genital herpes are compared to short-term and one-day treatment options. New anti-HSV-I and anti-HSV-II agents include amenavir, pritelivir, brincidofovir, valomaciclovir, and FV-100. Therapeutic or preventive vaccination against HSV-I and HSV-II infections still remains a highly desirable treatment aim, which, unfortunately, has no clinically relevant applications to date.

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.

Diagnosis of genital herpes simplex virus infection in the clinical laboratory

PubMed Central

2014-01-01

Since the type of herpes simplex virus (HSV) infection affects prognosis and subsequent counseling, type-specific testing to distinguish HSV-1 from HSV-2 is always recommended. Although PCR has been the diagnostic standard method for HSV infections of the central nervous system, until now viral culture has been the test of choice for HSV genital infection. However, HSV PCR, with its consistently and substantially higher rate of HSV detection, could replace viral culture as the gold standard for the diagnosis of genital herpes in people with active mucocutaneous lesions, regardless of anatomic location or viral type. Alternatively, antigen detection—an immunofluorescence test or enzyme immunoassay from samples from symptomatic patients--could be employed, but HSV type determination is of importance. Type-specific serology based on glycoprotein G should be used for detecting asymptomatic individuals but widespread screening for HSV antibodies is not recommended. In conclusion, rapid and accurate laboratory diagnosis of HSV is now become a necessity, given the difficulty in making the clinical diagnosis of HSV, the growing worldwide prevalence of genital herpes and the availability of effective antiviral therapy. PMID:24885431

Antiviral activity of some South American medicinal plants.

PubMed

Abad, M J; Bermejo, P; Sanchez Palomino, S; Chiriboga, X; Carrasco, L

1999-03-01

Folk medicinal plants are potential sources of useful therapeutic compounds including some with antiviral activities. Extracts prepared from 10 South American medicinal plants (Baccharis trinervis, Baccharis teindalensis, Eupatorium articulatum, Eupatorium glutinosum, Tagetes pusilla, Neurolaena lobata, Conyza floribunda, Phytolacca bogotensis, Phytolacca rivinoides and Heisteria acuminata) were screened for in vitro antiviral activity against herpes simplex type I (HSV-1), vesicular stomatitis virus (VSV) and poliovirus type 1. The most potent inhibition was observed with an aqueous extract of B. trinervis, which inhibited HSV-1 replication by 100% at 50-200 micrograms/mL, without showing cytotoxic effects. Good activities were also found with the ethanol extract of H. acuminata and the aqueous extract of E. articulatum, which exhibited antiviral effects against both DNA and RNA viruses (HSV-1 and VSV, respectively) at 125-250 micrograms/mL. The aqueous extracts of T. pusilla (100-250 micrograms/mL), B. teindalensis (50-125 micrograms/mL) and E. glutinosum (50-125 micrograms/mL) also inhibited the replication of VSV, but none of the extracts tested had any effect on poliovirus replication.

Antiviral Activities of Sulfated Polysaccharides Isolated from Sphaerococcus coronopifolius (Rhodophytha, Gigartinales) and Boergeseniella thuyoides (Rhodophyta, Ceramiales)

PubMed Central

Bouhlal, Rhimou; Haslin, Camille; Chermann, Jean-Claude; Colliec-Jouault, Sylvia; Sinquin, Corinne; Simon, Gaelle; Cerantola, Stephane; Riadi, Hassane; Bourgougnon, Nathalie

2011-01-01

Water-soluble sulfated polysaccharides isolated from two red algae Sphaerococcus coronopifolius (Gigartinales, Sphaerococcaceae) and Boergeseniella thuyoides (Ceramiales, Rhodomelaceae) collected on the coast of Morocco inhibited in vitro replication of the Human Immunodeficiency Virus (HIV) at 12.5 μg/mL. In addition, polysaccharides were capable of inhibiting the in vitro replication of Herpes simplex virus type 1 (HSV-1) on Vero cells values of EC50 of 4.1 and 17.2 μg/mL, respectively. The adsorption step of HSV-1 to the host cell seems to be the specific target for polysaccharide action. While for HIV-1, these results suggest a direct inhibitory effect on HIV-1 replication by controlling the appearance of the new generations of virus and potential virucidal effect. The polysaccharides from S. coronopifolius (PSC) and B. thuyoides (PBT) were composed of galactose, 3,6-anhydrogalactose, uronics acids, sulfate in ratios of 33.1, 11.0, 7.7 and 24.0% (w/w) and 25.4, 16.0, 3.2, 7.6% (w/w), respectively. PMID:21822410

Generating protective immunity against genital herpes

PubMed Central

Shin, Haina; Iwasaki, Akiko

2013-01-01

Genital herpes is an incurable, chronic disease that affects millions of people worldwide. Not only does genital herpes cause painful, recurrent symptoms, it is also a significant risk factor for the acquisition of other sexually transmitted infections such as HIV-1. Antiviral drugs are used to treat herpes simplex virus (HSV) infection, but they cannot stop viral shedding and transmission. Thus, developing a vaccine that can prevent or clear infection will be critical in limiting the spread of disease. In this review, we outline recent studies that improve our understanding of host responses against HSV infection, discuss past clinical vaccine trials and highlight new strategies for vaccine design against genital herpes. PMID:24012144

Phase I study of replication-competent adenovirus-mediated double-suicide gene therapy in combination with conventional-dose three-dimensional conformal radiation therapy for the treatment of newly diagnosed, intermediate- to high-risk prostate cancer.

PubMed

Freytag, Svend O; Stricker, Hans; Pegg, Jan; Paielli, Dell; Pradhan, Deepak G; Peabody, James; DePeralta-Venturina, Mariza; Xia, Xueqing; Brown, Steve; Lu, Mei; Kim, Jae Ho

2003-11-01

The primary study objective was to determine the safety of intraprostatic administration of a replication-competent, oncolytic adenovirus containing a cytosine deaminase (CD)/herpes simplex virus thymidine kinase (HSV-1 TK) fusion gene concomitant with increasing durations of 5-fluorocytosine and valganciclovir prodrug therapy and conventional-dose three-dimensional conformal radiation therapy (3D-CRT) in patients with newly diagnosed, intermediate- to high-risk prostate cancer. Secondary objectives were to determine the persistence of therapeutic transgene expression in the prostate and to examine early posttreatment response. Fifteen patients in five cohorts received a single intraprostatic injection of 10(12) viral particles of the replication-competent Ad5-CD/TKrep adenovirus on day 1. Two days later, patients were administered 5-fluorocytosine and valganciclovir prodrug therapy for 1 (cohorts 1-3), 2 (cohort 4), or 3 (cohort 5) weeks along with 70-74 Gy 3D-CRT. Sextant needle biopsy of the prostate was obtained at 2 (cohort 1), 3 (cohort 2), and 4 (cohort 3) weeks for determination of the persistence of transgene expression. There were no dose-limiting toxicities and no significant treatment-related adverse events. Ninety-four percent of the adverse events observed were mild to moderate and self-limiting. Acute urinary and gastrointestinal toxicities were similar to those expected for conventional-dose 3D-CRT. Therapeutic transgene expression was found to persist in the prostate for up to 3 weeks after the adenovirus injection. As expected for patients receiving definitive radiation therapy, all patients experienced significant declines in prostate-specific antigen (PSA). The mean PSA half-life in patients administered more than 1 week of prodrug therapy was significantly shorter than that of patients receiving prodrugs for only 1 week (0.6 versus 2.0 months; P < 0.02) and markedly shorter than that reported previously for patients treated with conventional-dose 3D-CRT alone (2.4 months). With a median follow-up of only 9 months, 5 of 10 (50%) patients not treated with androgen-deprivation therapy achieved a serum PSA < or = 0.5 ng/ml. The results demonstrate that replication-competent adenovirus-mediated double-suicide gene therapy can be combined safely with conventional-dose 3D-CRT in patients with intermediate- to high-risk prostate cancer. The shorter than expected PSA half-life in patients receiving more than 1 week of prodrug therapy may suggest a possible interaction between the oncolytic adenovirus and/or double-suicide gene therapies and radiation therapy.

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.

Attitudes and Willingness to Assume Risk of Experimental Therapy to Eradicate Genital Herpes Simplex Virus Infection.

PubMed

Oseso, Linda; Magaret, Amalia S; Jerome, Keith R; Fox, Julie; Wald, Anna

2016-09-01

Current treatment of genital herpes is focused on ameliorating signs and symptoms but is not curative. However, as potential herpes simplex virus (HSV) cure approaches are tested in the laboratory, we aimed to assess the interest in such studies by persons with genital herpes and the willingness to assume risks associated with experimental therapy. We constructed an anonymous online questionnaire that was posted on websites that provide information regarding genital herpes. The questions collected demographic and clinical information on adults who self-reported as having genital herpes, and assessed attitudes toward and willingness to participate in HSV cure clinical research. Seven hundred eleven participants provided sufficient responses to be included in the analysis. Sixty-six percent were women; the median age was 37 years, and the median time since genital HSV diagnosis was 4.7 years. The willingness to participate in trials increased from 59.0% in phase 1 to 68.5% in phase 2, and 81.2% in phase 3 trials, and 40% reported willingness to participate even in the absence of immediate, personal benefits. The most desirable outcome was the elimination of risk for transmission to sex partner or neonate. The mean perceived severity of receiving a diagnosis of genital HSV-2 was 4.2 on a scale of 1 to 5. Despite suppressive therapy available, persons with genital herpes are interested in participating in clinical research aimed at curing HSV, especially in more advanced stages of development.

Potent virucidal effect of pheophorbide a and pyropheophorbide a on enveloped viruses.

PubMed

Bouslama, Lamjed; Hayashi, Kyoko; Lee, Jung-Bum; Ghorbel, Abdelwahed; Hayashi, Toshimitsu

2011-01-01

In this study, we evaluated the inhibitory effect of ethanol and aqueous extracts from a stem of Opuntia ficus indica on replication of three kinds of viruses: two enveloped viruses [herpes simplex virus type 2 (HSV-2), influenza A virus (IFV-A)], and one non-enveloped virus [poliovirus type 1 (PV-1)]. Only ethanol extract from the cactus stem showed significant antiviral activity in vitro. Two chlorophyll derivatives, pheophorbide a and pyropheophorbide a, were isolated as active substances exhibiting potent virucidal effects on HSV-2 and IFV-A, but no activity against PV-1 was observed. These findings suggest that these active compounds might recognize specific glycoproteins of enveloped viruses, precluding their binding to host cell receptors and inhibiting viral infections.

Inhibitory effects of lupene-derived pentacyclic triterpenoids from Bursera simaruba on HSV-1 and HSV-2 in vitro replication.

PubMed

Álvarez, Ángel L; Habtemariam, Solomon; Parra, Francisco

2015-01-01

The cytotoxicity and antiviral properties of Bursera simaruba against herpes simplex viruses (HSV-1 and HSV-2) were investigated through a bioactivity-guided isolation protocol. The plant material was fractionated using solvent-solvent partitioning, size-exclusion and thin-layer chromatography. The antiviral compounds present in the most active fractions were identified by means of LC-MS and NMR. Three different methods were compared during the evaluation of antiviral activity of samples. Four lupene-related pentacyclic triterpenes were found to be responsible for the anti-herpesvirus effects of B. simaruba and were isolated from this species for the first time. The selective indexes (SI) of B. simaruba-derived samples ranged from 7.7 to 201.9.

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

Genome Sequencing and Analysis of Geographically Diverse Clinical Isolates of Herpes Simplex Virus 2

PubMed Central

Lamers, Susanna L.; Weiner, Brian; Ray, Stuart C.; Colgrove, Robert C.; Diaz, Fernando; Jing, Lichen; Wang, Kening; Saif, Sakina; Young, Sarah; Henn, Matthew; Laeyendecker, Oliver; Tobian, Aaron A. R.; Cohen, Jeffrey I.; Koelle, David M.; Quinn, Thomas C.; Knipe, David M.

2015-01-01

ABSTRACT Herpes simplex virus 2 (HSV-2), the principal causative agent of recurrent genital herpes, is a highly prevalent viral infection worldwide. Limited information is available on the amount of genomic DNA variation between HSV-2 strains because only two genomes have been determined, the HG52 laboratory strain and the newly sequenced SD90e low-passage-number clinical isolate strain, each from a different geographical area. In this study, we report the nearly complete genome sequences of 34 HSV-2 low-passage-number and laboratory strains, 14 of which were collected in Uganda, 1 in South Africa, 11 in the United States, and 8 in Japan. Our analyses of these genomes demonstrated remarkable sequence conservation, regardless of geographic origin, with the maximum nucleotide divergence between strains being 0.4% across the genome. In contrast, prior studies indicated that HSV-1 genomes exhibit more sequence diversity, as well as geographical clustering. Additionally, unlike HSV-1, little viral recombination between HSV-2 strains could be substantiated. These results are interpreted in light of HSV-2 evolution, epidemiology, and pathogenesis. Finally, the newly generated sequences more closely resemble the low-passage-number SD90e than HG52, supporting the use of the former as the new reference genome of HSV-2. IMPORTANCE Herpes simplex virus 2 (HSV-2) is a causative agent of genital and neonatal herpes. Therefore, knowledge of its DNA genome and genetic variability is central to preventing and treating genital herpes. However, only two full-length HSV-2 genomes have been reported. In this study, we sequenced 34 additional HSV-2 low-passage-number and laboratory viral genomes and initiated analysis of the genetic diversity of HSV-2 strains from around the world. The analysis of these genomes will facilitate research aimed at vaccine development, diagnosis, and the evaluation of clinical manifestations and transmission of HSV-2. This information will also contribute to our understanding of HSV evolution. PMID:26018166

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 virus seroepidemiology in the adult Swedish population.

PubMed

Olsson, Jan; Kok, Eloise; Adolfsson, Rolf; Lövheim, Hugo; Elgh, Fredrik

2017-01-01

Herpes viruses establish a life-long latency and can cause symptoms during both first-time infection and later reactivation. The aim of the present study was to describe the seroepidemiology of Herpes simplex type 1 (HSV1), Herpes simplex type 2 (HSV2), Cytomegalovirus (CMV), Varicella Zoster virus (VZV) and Human herpes virus type 6 (HHV6) in an adult Swedish population (35-95 years of age). Presence of antibodies against the respective viruses in serum from individuals in the Betula study was determined with an enzyme-linked immunosorbent assay (ELISA). Singular samples from 535 persons (53.9% women, mean age at inclusion 62.7 ± 14.4 years) collected 2003-2005 were analyzed for the five HHVs mentioned above. In addition, samples including follow-up samples collected 1988-2010 from 3,444 persons were analyzed for HSV. Prevalence of HSV1 was 79.4%, HSV2 12.9%, CMV 83.2%, VZV 97.9%, and HHV6 97.5%. Herpes virus infections were more common among women ( p  = 0.010) and a lower age-adjusted HSV seroprevalence was found in later birth cohorts ( p  < 0.001). The yearly incidence of HSV infection was estimated at 14.0/1000. Women are more often seropositive for HHV, especially HSV2. Age-adjusted seroprevalence for HSV was lower in later birth cohorts indicating a decreasing childhood and adolescent risk of infection.