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Now showing items 33 - 48 of 1593

  • THY-1 Cell Surface Antigen (CD90) Has an Important Role in the Initial Stage of Human Cytomegalovirus Infection

    Li, Qingxue   Wilkie, Adrian R.   Weller, Melodie   Liu, Xueqiao   Cohen, Jeffrey I.  

    Human cytomegalovirus (HCMV) infects about 50% of the US population, is the leading infectious cause of birth defects, and is considered the most important infectious agent in transplant recipients. The virus infects many cell types in vivo and in vitro. While previous studies have identified several cellular proteins that may function at early steps of infection in a cell type dependent manner, the mechanism of virus entry is still poorly understood. Using a computational biology approach, correlating gene expression with virus infectivity in 54 cell lines, we identified THY-1 as a putative host determinant for HCMV infection in these cells. With a series of loss-of-function, gain-of-function and protein-protein interaction analyses, we found that THY-1 mediates HCMV infection at the entry step and is important for infection that occurs at a low m.o.i. THY-1 antibody that bound to the cell surface blocked HCMV during the initial 60 minutes of infection in a dose-dependent manner. Down-regulation of THY-1 with siRNA impaired infectivity occurred during the initial 60 minutes of inoculation. Both THY-1 antibody and siRNA inhibited HCMV-induced activation of the PI3-K/Akt pathway required for entry. Soluble THY-1 protein blocked HCMV infection during, but not after, virus internalization. Expression of exogenous THY-1 enhanced entry in cells expressing low levels of the protein. THY-1 interacted with HCMV gB and gH and may form a complex important for entry. However, since gB and gH have previously been shown to interact, it is uncertain if THY-1 directly binds to both of these proteins. Prior observations that THY-1 (a) interacts with alpha V beta 3 integrin and recruits paxillin (implicated in HCMV entry), (b) regulates leukocyte extravasation (critical for HCMV viremia), and (c) is expressed on many cells targeted for HCMV infection including epithelial and endothelial cells, fibroblast, and CD34+/CD38- stem cells, all support a role for THY-1 as an HCMV entry mediator in a cell type dependent manner. THY-1 may function through a complex setting, that would include viral gB and gH, and other cellular factors, thus links virus entry with signaling in host cells that ultimately leads to virus infection.
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  • Identification of Viral MicroRNAs Expressed in Human Sacral Ganglia Latently Infected with Herpes Simplex Virus 2

    Umbach, Jennifer L.   Wang, Kening   Tang, Shuang   Krause, Philip R.   Mont, Erik K.   Cohen, Jeffrey I.   Cullen, Bryan R.  

    Deep sequencing of small RNAs isolated from human sacral ganglia latently infected with herpes simplex virus 2 (HSV-2) was used to identify HSV-2 microRNAs (miRNAs) expressed during latent infection. This effort resulted in the identification of five distinct HSV-2 miRNA species, two of which, miR-H3/miR-I and miR-H4/miR-II, have been previously reported. Three novel HSV-2 miRNAs were also identified, and two of these, miR-H7 and miR-H9, are derived from the latency-associated transcript (LAT) and are located antisense to the viral transcript encoding transactivator ICP0. A third novel HSV-2 miRNA, miR-H10, is encoded within the unique long (U(L)) region of the genome, 3' to the U(L)15 open reading frame, and is presumably excised from a novel, latent HSV-2 transcript distinct from LAT.
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  • ISOLATED EPSTEIN-BARR VIRUS BZLF2 PROTEINS THAT BIND MHC CLASS II BETA CHAINS

    Isolated viral proteins, and pharmaceutical compositions made therefrom, are disclosed which are capable of binding to a 'beta' chain of a Class II Major Histocompatibility Complex antigen, thereby functioning to inhibit an antigen-specific response. The viral proteins also have superantigen-like activity, and inhibit EBV infection.
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  • The Capacity of UL49.5 Proteins To Inhibit TAP Is Widely Distributed among Members of the Genus Varicellovirus

    Verweij, Marieke C.   Lipinska, Andrea D.   Koppers-Lalic, Danijela   Van Leeuwen, Wouter F.   Cohen, Jeffrey I.   Kinchington, Paul R.   Messaoudi, Ilhem   Bienkowska-Szewczyk, Krystyna   Ressing, Maaike E.   Rijsewijk, Frans A. M.   Wiertz, Emmanuel J. H. J.  

    The lifelong infection by varicelloviruses is characterized by a fine balance between the host immune response and immune evasion strategies used by these viruses. Virus-derived peptides are presented to cytotoxic T lymphocytes by major histocompatibility complex (MHC) class I molecules. The transporter associated with antigen processing (TAP) transports the peptides from the cytosol into the endoplasmic reticulum, where the loading of MHC-I molecules occurs. The varicelloviruses bovine herpesvirus 1 (BoHV-1), pseudorabies virus, and equid herpesviruses 1 and 4 have been found to encode a UL49.5 protein that inhibits TAP-mediated peptide transport. To investigate to what extent UL49.5-mediated TAP inhibition is conserved within the family of Alphaherpesvirinae, the homologs of another five varicelloviruses, one mardivirus, and one iltovirus were studied. The UL49.5 proteins of BoHV-5, bubaline herpesvirus 1, cervid herpesvirus 1, and felid herpesvirus 1 were identified as potent TAP inhibitors. The varicella-zoster virus and simian varicellovirus UL49.5 proteins fail to block TAP; this is not due to the absence of viral cofactors that might assist in this process, since cells infected with these viruses did not show reduced TAP function either. The UL49.5 homologs of the mardivirus Marek's disease virus 1 and the iltovirus infectious laryngotracheitis virus did not block TAP, suggesting that the capacity to inhibit TAP via UL49.5 has been acquired by varicelloviruses only. A phylogenetic analysis of viruses that inhibit TAP through their UL49.5 proteins reveals an interesting hereditary pattern, pointing toward the presence of this capacity in defined clades within the genus Varicellovirus.
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  • Autophagy Quantification and STAT3 Expression in a Human Skin Organ Culture Model for Innate Immunity to Herpes Zoster

    Buckingham, Erin M.   Girsch, James   Jackson, Wallen   Cohen, Jeffrey I.   Grose, Charles  

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  • Evaluation of Total and IgA-Specific Antibody Targeting Epstein-Barr Virus Glycoprotein 350 and Nasopharyngeal Carcinoma Risk

    Coghill, Anna E.   Bu, Wei   Hsu, Wan-Lun   Nguyen, Hanh   Yu, Kelly J.   Chien, Yin-Chu   Chen, Chien-Jen   Cohen, Jeffrey I.   Hildesheim, Allan  

    Background. We previously reported that higher levels of antibody targeting Epstein-Barr virus (EBV) glycoprotein350 (gp350), an EBV vaccine candidate, were protective against nasopharyngeal carcinoma (NPC) in genetically high-risk families from Taiwan. The current study attempted to extend this association to a general population cohort. Methods. We compared total and IgA-specific gp350 antibody levels in 35 incident NPC cases and 81 disease-free controls from the Cancer Screening Program in Taiwan (23 943 individuals recruited 1991-1992). Luciferase immunoprecipitation assays quantified gp350 antibody. Results. Total EBVgp350 antibody levels were not higher in individuals who remained disease free compared to those who developed NPC (P =3D .11). This lack of a protective gp350 association persisted for cases diagnosed =3D 5 years (odds ratio [ OR] =3D 1.05; P =3D .91) and <5 years (OR =3D 1.85; P =3D .40) after blood draw. IgA-specific gp350 antibody levels were higher in cases than controls (OR =3D 7.03; P =3D .001). This increased risk was most pronounced for cases diagnosed <5 years after blood draw (OR =3D 11.7; P =3D .004). Conclusion. Unlike our prior findings in those with a strong family history of NPC, total gp350 antibody levels were not protective against NPC development in this general population setting.
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  • Serological Diagnosis of Human Herpes Simplex Virus Type 1 and 2 Infections by Luciferase Immunoprecipitation System Assay

    Burbelo, Peter D.   Hoshino, Yo   Leahy, Hannah   Krogmann, Tammy   Hornung, Ronald L.   Iadarola, Michael J.   Cohen, Jeffrey I.  

    Highly quantitative and high-throughput serological tests for evaluation of humoral responses to herpes simplex virus 1 (HSV-1) and HSV-2 are not available. The efficacy of luciferase immunoprecipitation system (LIPS) assays for antibody profiling and serologic diagnosis of HSV-1 and HSV-2 infection was investigated using a panel of five recombinant HSV antigens. Plasma samples from subjects seropositive for HSV-1 and/or HSV-2 or seronegative for HSV-1 and HSV-2 that had previously been analyzed by Western blotting and the Focus Plexus immunoassay were evaluated. The LIPS test measuring anti-gG1 antibody titers was 96% sensitive and 96% specific for detecting HSV-1 infection, compared with the Focus immunoassay, and was 92% sensitive and 96% specific, compared with Western blotting. The results for the anti-gG2 LIPS test for HSV-2 precisely matched those for Western blotting, with 100% sensitivity and 100% specificity, and showed robust antibody titers in all the HSV-2-infected samples that were over 1,000 times higher than those in HSV-2-negative or HSV-1-positive samples. Antibodies to three additional HSV-2 proteins, gB, gD, and ICP8, were detected in many of the HSV-1- and/or HSV-2-infected plasma samples and showed preferentially higher immunoreactivity in HSV-2-infected plasma. The titers of antibodies to these three HSV-2 antigens also significantly correlated with each other (R = 0.75 to 0.81; P < 0.0001). These studies indicate that the robust anti-gG1 and anti-gG2 antibody responses detected by LIPS assays are useful for HSV-1 and HSV-2 detection and suggest that profiling of antibody responses to a panel of HSV proteins may be useful for characterizing individual humoral responses to infection and for monitoring responses to vaccines.
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  • Insulin degrading enzyme is a cellular receptor mediating varicella-zoster virus infection and cell-to-cell spread

    Li, Qingxue   Ali, Mir A.   Cohen, Jeffrey I.  

    Varicella-zoster virus (VZV) causes chickenpox and shingles. While varicella is likely spread as cell-free virus to susceptible hosts, the virus is transmitted by cell-to-cell spread in the body and in vitro. Since VZV glycoprotein E (gE) is essential for virus infection, we postulated that gE binds to a cellular receptor. We found that insulin-degrading enzyme (IDE) interacts with gE through its extracellular domain. Downregulation of IDE by siRNA, or blocking of IDE with antibody, with soluble IDE protein extracted from liver, or with bacitracin inhibited VZV infection. Cell-to-cell spread of virus was also impaired by blocking IDE. Transfection of cell lines impaired for VZV infection with a plasmid expressing human IDE resulted in increased entry and enhanced infection with cell-free and cell-associated virus. These studies indicate that IDE is a cellular receptor for both cell-free and cell-associated VZV.
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  • Human cytomegalovirus evades antibody-mediated immunity through endoplasmic reticulum-associated degradation of the FcRn receptor

    Liu, Xiaoyang   Palaniyandi, Senthilkumar   Zhu, Iowis   Tang, Jin   Li, Weizhong   Wu, Xiaoling   Ochsner, Susan Park   Pauza, C. David   Cohen, Jeffrey I.   Zhu, Xiaoping  

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  • The Presidency in the Era of 24-Hour News by Jeffrey E. Cohen

    Vaughn, Justin S.  

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  • Varicella-Zoster Virus ORF12 Protein Activates the Phosphatidylinositol 3-Kinase/Akt Pathway To Regulate Cell Cycle Progression

    Liu, XueQiao   Cohen, Jeffrey I.  

    Varicella-zoster virus (VZV) activates the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and alters cell cycle progression, but the viral protein(s) responsible for these activities is unknown. We previously reported that the VZV open reading frame 12 (ORF12) protein triggers phosphorylation of ERK. Here, we demonstrate that the VZV ORF12 protein also activates the PI3K/Akt pathway to regulate cell cycle progression. Transfection of cells with a plasmid expressing the ORF12 protein induced phosphorylation of Akt, which was dependent on PI3K. Infection of cells with wild-type VZV triggered phosphorylation of Akt, while infection with an ORF12 deletion mutant induced less phosphorylated Akt. The activation of Akt by ORF12 protein was associated with its binding to the p85 subunit of PI3K. Infection of cells with wild-type VZV resulted in increased levels of cyclin B1, cyclin D3, and phosphorylated glycogen synthase kinase 3 beta (GSK-3 beta), while infection with the ORF12 deletion mutant induced lower levels of these proteins. Wild-type VZV infection reduced the G(1) phase cell population and increased the M phase cell population, while infection with the ORF12 deletion mutant had a reduced effect on the G(1) and M phase populations. Inhibition of Akt activity with LY294002 reduced the G(1) and M phase differences observed in cells infected with wild-type and ORF12 mutant viruses. In conclusion, we have found that the VZV ORF12 protein activates the PI3K/Akt pathway to regulate cell cycle progression. Since VZV replicates in both dividing (e.g., keratinocytes) and nondividing (neurons) cells, the ability of the VZV ORF12 protein to regulate the cell cycle is likely important for VZV replication in various cell types in the body.
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  • The Presidency in the Era of 24-Hour News\r by Jeffrey E. Cohen

    Vaughn   Justin S.  

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  • Extra-Intestinal Manifestations of Salmonella Infections

    COHEN, JEFFREY I.   BARTLETT, JOHN A.   COREY, G. RALPH  

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  • Magnesium Restores Activity to Peripheral Blood Cells in a Patient With Functionally Impaired Interleukin-2-Inducible T Cell Kinase

    Howe, Matthew K.   Dowdell, Kennichi   Roy, Amitava   Niemela, Julie E.   Wilson, Wyndham   McElwee, Joshua J.   Hughes, Jason D.   Cohen, Jeffrey I.  

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  • Going Local: Presidential Leadership in the Post-Broadcast Age , by Jeffrey E. Cohen

    Burkhalter, Stephanie  

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  • Stone: An Ecology of the Inhuman. By Jeffrey Jerome Cohen

    Grant   David M.  

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