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Herpes Simplex Virus Infections [keywords]
- Purification and characterization of a novel anti-HSV-2 protein with antiproliferative and peroxidase activities from Stellaria media. [JOURNAL ARTICLE]
- Acta Biochim Biophys Sin (Shanghai) 2013 Jun 11.
A novel antiviral protein, designated as Stellarmedin A, was purified from Stellaria media (L.) Vill. (Caryophyllaceae) by using ammonium sulfate precipitation, cation-exchange chromatography system. Gel electrophoresis analysis showed that Stellarmedin A is a highly basic glycoprotein with a molecular weight of 35.1 kDa and an isoelectric point of ∼8.7. The N-terminal 14-amino acid sequence, MGNTGVLTGERNDR, is similar to those of other plant peroxidases. This protein inhibited herpes simplex virus type 2 (HSV-2) replication in vitro with an IC50 of 13.18 µg/ml and a therapeutic index exceeding 75.9. It was demonstrated that Stellarmedin A affects the initial stage of HSV-2 infection and is able to inhibit the proliferation of promyelocytic leukemia HL-60 and colon carcinoma LoVo cells with an IC50 of 9.09 and 12.32 µM, respectively. Moreover, Stellarmedin A has a peroxidase activity of 36.6 µmol/min/mg protein, when guaiacol was used as substrate. To our knowledge, this is the first report about an anti-HSV-2 protein with antiproliferative and peroxidase activities from S. media.
- Glial fibrillary acidic protein expression during HSV-1 infection in mouse cornea. [JOURNAL ARTICLE]
- APMIS 2013 Jun 12.
This study aimed to investigate the dynamic expression of glial fibrillary acidic protein (GFAP), a common neural factor, in cornea and stromal cells during herpes simplex virus-1 (HSV-1) infection. For each anesthetized BALB/c mouse, the cornea in one eye was inoculated with 1 × 10(5) plaque forming unit (PFU) of HSV-1, while the contralateral cornea was mock-infected as the control. At different timepoints post-infection, corneal lesion examination by slit-lamp biomicroscopy, corneal histology and HSV-1 DNA detection by real-time PCR were performed to estimate the different stage of HSV-1 infection. The expression of GFAP was examined using real-time PCR, western blotting and immunofluorescence staining. After infected with HSV-1 for 15 days, the mouse corneas began to become clear, the corneal pathology recovered to normal, and HSV-1 DNA almost could not be detected, indicating that HSV-1 was entering a relative quiescent state from the acute infection. The expression of GFAP in HSV-1-infected corneas was comparatively low on day 3, increased slightly on day 7, and further increased thereafter, higher than that in mock-infected corneas on day 15. GFAP detection on the cellular level also indicated that the expression was downregulated in acute HSV-1 infection. GFAP was found to be downregulated in HSV-1 acute infection in cornea and upregulated in late stage, suggesting that GFAP might play some role during HSV-1 infection in cornea.
- Exploiting herpes simplex virus entry for novel therapeutics. [Journal Article]
- Viruses 2013; 5(6):1447-65.
Herpes Simplex virus (HSV) is associated with a variety of diseases such as genital herpes and numerous ocular diseases. At the global level, high prevalence of individuals who are seropositive for HSV, combined with its inconspicuous infection, remains a cause for major concern. At the molecular level, HSV entry into a host cell involves multiple steps, primarily the interaction of viral glycoproteins with various cell surface receptors, many of which have alternate substitutes. The molecular complexity of the virus to enter a cell is also enhanced by the existence of different modes of viral entry. The availability of many entry receptors, along with a variety of entry mechanisms, has resulted in a virus that is capable of infecting virtually all cell types. While HSV uses a wide repertoire of viral and host factors in establishing infection, current therapeutics aimed against the virus are not as diversified. In this particular review, we will focus on the initial entry of the virus into the cell, while highlighting potential novel therapeutics that can control this process. Virus entry is a decisive step and effective therapeutics can translate to less virus replication, reduced cell death, and detrimental symptoms.
- The Utility of a Composite Biological Endpoint in HIV/STI Prevention Trials. [JOURNAL ARTICLE]
- AIDS Behav 2013 Jun 9.
A human immunodeficiency virus (HIV) as a biological endpoint in HIV prevention trials may not be feasible, so investigators have used surrogate biological outcomes. In a multisite trial, the epidemiology of STIs may be different across sites and preclude using one STI as the outcome. This study explored using a composite STI outcome to address that problem. The combined biological endpoint was the incidence of any of six new STIs (chlamydia, gonorrhea, trichomonas (women only), syphilis, herpes simplex virus type 2 infection and HIV) during a 24-month follow up period. We investigated how a composite STI outcome would perform compared to single and dual STI outcomes under various conditions. We simulated outcomes for four populations that represented a wide range of sex and age distributions, and STI prevalences. The simulations demonstrated that a combined biologic outcome was superior to single and dual STI outcomes in assessing intervention effects in 82 % of the cases. A composite biological outcome was effective in detecting intervention effects and might allow more investigations to incorporate multiple biological outcomes in the assessment of behavioral intervention trials for HIV prevention.
- Modulation of neural stem/progenitor cell proliferation during experimental Herpes Simplex encephalitis is mediated by differential FGF-2 expression in the adult brain. [JOURNAL ARTICLE]
- Neurobiol Dis 2013 Jun 5.
Neural stem cells (NSCs) respond to inflammatory cues induced during brain injury and are thought to be involved in recovery from brain damage. Little is known about NSC response during brain infections. The present study evaluated NSC proliferation during Herpes Simplex Virus-1 brain infection. Total numbers of nestin(+) NSCs increased significantly in infected brains at 6days post infection (p.i.). However, by 15days p.i. the nestin(+) population decreased significantly below levels observed in uninfected brains and remained depressed through 30days p.i. This initial increase in NSC population occurred concurrently with increased brain cell proliferation, which peaked at 3days p.i. On closer examination, we found that while actively proliferating Sox2(+) NSCs increased in number at 6days p.i., proliferating DCX(+) neuroblasts contributed to the increased response at 3days p.i. However, overall proliferation decreased steadily from 15days p.i. to below control levels. To determine the mechanisms involved in altering NSC proliferation, neurotrophin and growth factor expression profiles were assessed. FGF-2 gene expression increased at 5days p.i. and was robustly down-regulated at 15days p.i. (>1000-fold), which was further confirmed by increased FGF-2 immunostaining around the lateral ventricles. Furthermore, supplementing infected animals with recombinant FGF-2, at 15days p.i., significantly increased the number of proliferating brain cells. These findings demonstrate that the temporal changes in NSC proliferation are mediated through the regulation of FGF-2 and that the NSC niche may benefit from supplementation with FGF-2 during HSV-1 brain infection.
- Association of Pathogen Burden and Hypertension: The Persian Gulf Healthy Heart Study. [JOURNAL ARTICLE]
- Am J Hypertens 2013 Jun 6.
BACKGROUND:Chronic infection with cytomegalovirus (CMV), Chlamydia pneumoniae, herpes simplex virus 1 (HSV-1), and Helicobacter pylori may contribute to essential hypertension. However, the evidence now available does not clarify whether the aggregate number of pathogens (pathogen burden) may be associated with hypertension.
METHODS: Sera from 1,754 men and women aged ≥25 years were analyzed for immunoglobulin G antibodies to C. pneumoniae, HSV-1, H. pylori, and CMV using enzyme-linked immunosorbent assay. The aggregate number of seropositives to the studied viral and bacterial agents was defined as pathogen burden. Hypertension was defined according to World Health Organization criteria.
RESULTS :A total of 459 (26.3%) of the subjects had hypertension. In the hypertensive group, 4.2% had 0 or 1 pathogens present, 20.6% had 2, 43.2% had 3, and 32.1% had 4; in the normotensive group, 7.9% had 0 or 1, 28.4% had 2, 42.7% had 3, and 21.0% had 4. Of the 4 studied pathogens, H. pylori seropositivity showed a significant independent association with hypertension (odds ratio (OR) =1.37; 95% confidence interval (CI) =1.05-1.79; P = 0.02). In multiple logistic regression analyses, the pathogen burden did not show a significant independent association with hypertension. Coinfection with H. pylori and C. pneumoniae was significantly associated with hypertension compared with double seronegativity after adjustment for age, sex, chronic low-grade inflammation, and cardiovascular risk factors (OR = 1.68; 95% CI = 1.14-2.47; P = 0.008].
CONCLUSIONS :The pathogen burden was not associated with hypertension. However, coinfection with C. pneumoniae and H. pylori showed a significant association with essential hypertension, independent of cardiovascular risk factors and chronic low-grade inflammation.
- Pyrrolidine dithiocarbamate inhibits herpes simplex virus type 1 and 2 replication and its activity may be mediated through dysregulation of ubiquitin-proteasome system. [JOURNAL ARTICLE]
- J Virol 2013 Jun 5.
Pyrrolidine dithiocarbamate (PDTC) is widely used as an antioxidant or an NF-κB inhibitor. It has been reported to inhibit the replication of human rhinoviruses, poliovirus, coxsackievirus and influenza virus. In this paper, we reported that PDTC could inhibit the replication of herpes simplex virus types 1 and 2 (HSV-1 and HSV-2). PDTC suppressed the expression of HSV-1 and HSV-2 viral immediately-early (IE) and the late genes (gD) and the production of viral progeny. This antiviral property was mediated by the dithiocarbamate moiety of PDTC and required the presence of Zn(2+). Although PDTC could potently block reactive oxygen (ROS) generation, it was found that this property did not contribute to its anti-HSV activity. PDTC showed no activity in disrupting MAPK pathway activation induced by viral infection that was vital for the virus propagation. We found that PDTC modulated cellular ubiquitination, and further influenced HSV-2-induced IκB-α degradation to inhibit NF-κB activation and enhanced PML stability in nucleus, resulting in the inhibition of viral gene expression. These results suggested that the antiviral activity of PDTC might be mediated by its dysregulation of cellular ubiquitin-proteasome system (UPS).
- HSV-1 exploits the innate immune scavenger receptor MARCO to enhance epithelial adsorption and infection. [Journal Article]
- Nat Commun 2013.:1963.
Herpes simplex virus type 1 is an important epithelial pathogen and has the potential for significant morbidity in humans. Here we demonstrate that a cell surface scavenger receptor, macrophage receptor with collagenous structure (MARCO), previously thought to enhance antiviral defense by enabling nucleic acid recognition, is usurped by herpes simplex virus type 1 and functions together with heparan sulphate proteoglycans to mediate adsorption to epithelial cells. Ligands of MARCO dramatically inhibit herpes simplex virus type 1 adsorption and infection of human keratinocytes and protect mice against infection. Herpes simplex virus type 1 glycoprotein C closely co-localizes with MARCO at the cell surface, and glycoprotein C binds directly to purified MARCO with high affinity. Increasing MARCO expression enhances herpes simplex virus type 1 infection while MARCO(-/-) mice have reduced susceptibility to infection by herpes simplex virus type 1. These findings demonstrate that herpes simplex virus type 1 binds to MARCO to enhance its capacity for disease, and suggests a new therapeutic target to alter pathogenicity of herpes simplex virus type 1 in skin infection.
- Detection of the inflammatory process in a Behçet's disease-like mouse model using 18F-fluorodeoxyglucose positron emission tomography. [JOURNAL ARTICLE]
- Clin Exp Rheumatol 2013 Jun 5.
OBJECTIVES:The major role of herpes simplex virus (HSV) type 1 infection in Behçet's disease (BD) immunopathogenesis has been demonstrated and inoculating the earlobes of ICR mice with HSV produced a BD-like mouse model. 18Ffluorodeoxyglucose positron emission tomography (FDG PET) is widely used for diagnosing numerous human diseases other than malignancies. The aim of our study was to evaluate the inflammatory activities of BD-like symptoms in a HSV type 1-induced BD-like mouse model by small-animal FDG PET.
METHODS:Five HSV-infected ICR mice with BD-like lesions, two asymptomatic HSV-infected mice, and two untreated mice were scanned with microPET, and autopsy specimens were histopathologically assessed to evaluate for infiltration by mixed inflammatory cells.
RESULTS:The histopathological evaluation of the inflammatory process in knee and elbow joints significantly correlated with the quantitative assessment of FDG accumulation in the same joints in BD-like ICR mice, HSV-infected asymptomatic mice, and untreated control mice. Small-animal FDG PET clearly detected asymptomatic joint inflammatory processes in both BD-like mice and HSV-infected asymptomatic mice. In addition, genital ulcers and skin ulcers with associated perilesional lymphadenopathies in BD-like models were detected by microPET. However, biodistributed PET-positive images from the stasis of secreted FDG into the bowel lumen could not be distinguished from the inflammatory bowel lesions of BD when compared to FDG uptake in control mice.
CONCLUSIONS:Our data indicate that FDG PET can non-invasively and quantitatively detect the inflammatory process in an HSV-induced BD-like mouse model.
- Salmonella engineered to express CD20-targeting antibodies and a drug-converting enzyme can eradicate human lymphomas. [JOURNAL ARTICLE]
- Blood 2013 Jun 4.
Escape from immune detection favors both tumor survival and progression, and new approaches to circumvent this are essential to combat cancers. Non-virulent, tumor-tropic bacteria, such as Salmonella typhimurium, can unmask a tumor by transforming it into a site of inflammation, however, Salmonella's non-specific invasiveness leads to off-target effects diluting its therapeutic efficacy and making its use in human patients inherently risky. Here, we demonstrate that Salmonella tumor-specificity can be significantly improved via a surface expressed single-domain antibody directed to a tumor-associated antigen (CD20). Antibody-dependent bacterial targeting specifies the infection of CD20+ lymphoma cells in vitro and in vivo, while significantly diminishing non-specific cell invasion. Indeed, CD20-targeted Salmonella were less generally invasive, even in organs that normally serve as physiological reservoirs. Furthermore, tumor-specific Salmonella engineered to carry the Herpes Simplex Virus Thymidine Kinase (HSV-TK) pro-drug converting enzyme effectively treat human lymphoma xenografts when co-administered intra-tumorally or intra-venously with ganciclovir in mice lacking a functional adaptive immune system. Therefore, tumor-targeted Salmonella could prove effective even in those patients displaying a debilitated immune system, which is often the case with late-stage cancers. Altogether, antibody-displaying Salmonella vectors can mediate a tumor-specific response and rejection with few detectable side effects while specifically delivering cytotoxic payloads.