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  • 1
    Keywords: DIFFERENTIATION ; ACCUMULATION ; HPV ; E6 ; ONCOPROTEIN ; INDUCE
    Type of Publication: Journal article epub ahead of print
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  • 2
  • 3
    Keywords: Germany ; human ; GENE-EXPRESSION ; RNA ; papillomavirus ; IMMUNE-RESPONSES ; PARTICLES ; transgenic ; CERVICAL-CANCER ; CAPSID PROTEIN ; CODON USAGE ; FUSION PROTEIN PROTECTS ; human papillomavirus ; L1 PROTEIN ; ORAL IMMUNIZATION ; TYPE-16 ; VACCINES ; VIRUS-LIKE PARTICLES
    Type of Publication: Journal article published
    PubMed ID: 12915537
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  • 4
    Keywords: CELLS ; IN-VITRO ; tumor ; CELL ; Germany ; IN-VIVO ; KINASE ; VIVO ; PROTEIN ; MICE ; DNA ; INFECTION ; FAMILY ; CYCLE ; MEMBER ; MEMBERS ; PHOSPHORYLATION ; protein kinase ; PROTEIN-KINASE ; treatment ; TARGET ; virus ; NUCLEUS ; POLYPEPTIDE ; INVOLVEMENT ; DNA-REPLICATION ; KINASE-C ; MINUTE VIRUS ; PROTEIN-KINASE-C ; REPLICATION ; RECOMBINANT VACCINIA VIRUS ; REGULATORS ; AUTONOMOUS PARVOVIRUSES ; NONSTRUCTURAL PROTEINS ; BINDING MOTIF ; CELL POLARITY ; NS-1 PROTEIN ; VIRAL-INFECTION
    Abstract: Minute virus of mice NS1 protein is a multifunctional phosphoprotein endowed with a variety of enzymatic and regulatory activities necessary for progeny virus particle production. To regulate all of its different functions in the course of a viral infection, NS1 has been proposed to be modulated by posttranslational modifications, in particular, phosphorylation. Indeed, it was shown that the NS1 phosphorylation pattern is altered during the infectious cycle and that the biochemical profile of the protein is dependent on the phosphorylation state of the polypeptide.. Moreover, in vitro approaches have identified members of the protein kinase C (PKC) family, in particular, atypical PKC, as regulators of viral DNA replication through the phosphorylation of NS1 residues T435 and S473, thereby activating the protein for DNA unwinding activities. In order to substantiate these findings in vivo, we produced NS1 in the presence of a dominant-negative PKClambda mutant and characterized the purified protein in vitro. The NS1 protein produced under these conditions was found to be only partially phosphorylated and as a consequence to be deficient for viral DNA replication. However, it could be rescued for this viral function by treatment with recombinant activated PKClambda. Our data clearly demonstrate that NS1 is a target for PKClambda phosphorylation in vivo and that this modification is essential for the helicase activity of the viral polypeptide. In addition, the phosphorylation of NS1 at residues T435 and S473 appeared to occur mainly in the nucleus, providing further evidence for the involvement of PKClambda which, unlike PKCzeta, accumulates in the nuclear compartment of infected cells
    Type of Publication: Journal article published
    PubMed ID: 12477848
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  • 5
    Keywords: COMBINATION ; Germany ; INHIBITION ; SITE ; PROTEIN ; RELEASE ; MECHANISM ; DOMAIN ; BIOLOGY ; MEMBER ; MEMBERS ; MOLECULAR-BIOLOGY ; SEQUENCE ; SEQUENCES ; SIGNAL ; MATURATION ; ACID ; CLEAVAGE ; GLYCOPROTEIN ; virus ; RETROVIRUSES ; COMPONENT ; PEPTIDES ; REPLICATION ; INTERACTS ; CLEAVAGE SITE ; foamy virus ; GAG ; INFECTIVITY ; protease ; MALDI-MS ; molecular biology ; FEATURES ; RESIDUES ; VIRIONS ; 2-DIMENSIONAL ELECTROPHORESIS ; ENVELOPE GLYCOPROTEINS ; RESCUE ; TERMINAL GAG DOMAIN
    Abstract: The molecular biology of spuma or foamy retroviruses is different from that of the other members of the Retroviridae. Among the distinguishing features, the N-terminal domain of the foamy virus Env glycoprotein, the 16-kDa Env leader protein Elp, is a component of released, infectious virions and is required for particle budding. The transmembrane protein Elp specifically interacts with N-terminal Gag sequences during morphogenesis. In this study, we investigate the mechanism of Elp release from the Env precursor protein. By a combination of genetic, biochemical, and biophysical methods, we show that the feline foamy virus (FFV) Elp is released by a cellular furin-like protease, most likely furin itself, generating an Elp protein consisting of 127 amino acid residues. The cleavage site fully conforms to the rules for an optimal furin site. Proteolytic processing at the furin cleavage site is required for full infectivity of FFV. However, utilization of other furin proteases and/or cleavage at a suboptimal signal peptidase cleavage site can partially rescue virus viability. In addition, we show that FFV Elp carries an N-linked oligosaccharide that is not conserved among the known foamy viruses
    Type of Publication: Journal article published
    PubMed ID: 15564468
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  • 6
    Keywords: CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; CELL ; Germany ; human ; PROTEIN ; MOLECULES ; RESPONSES ; INFECTION ; MECHANISM ; renal ; INDUCTION ; ANTIGEN ; CONTRAST ; mechanisms ; MOLECULE ; antibodies ; antibody ; PARTICLES ; virus ; NO ; PATHOGENESIS ; BETA ; E6 ; CLASS-I ; Jun ; REPLICATION ; INTERFERON ; KINETICS ; CYTOKINE ; pathogen ; VIRUS-INFECTION ; PATHOGENS ; HEMORRHAGIC-FEVER ; HIGH-TITER ; HUMAN MXA PROTEIN ; NUCLEOCAPSID PROTEIN ; PULMONARY SYNDROME ; PUUMALA-HANTAVIRUS ; RENAL SYNDROME ; RESPIRATORY EPITHELIAL-CELLS ; TULA VIRUS
    Abstract: Hantaviruses represent important human pathogens and can induce hemorrhagic fever with renal syndrome (HFRS), which is characterized by endothelial dysfunction. Both pathogenic and nonpathogenic hantaviruses replicate without causing any apparent cytopathic effect, suggesting that immunopathological mechanisms play an important role in pathogenesis. We compared the antiviral responses triggered by Hantaan virus (HTNV), a pathogenic hantavirus associated with HFRS, and Tula virus (TULV), a rather nonpathogenic hantavirus, in human umbilical vein endothelial cells (HUVECs). Both HTNV- and TULV-infected cells showed increased levels of molecules involved in antigen presentation. However, TULV-infected HUVECs upregulated HLA class I molecules more rapidly. Interestingly, HTNV clearly induced the production of beta interferon (IFN-beta), whereas expression of this cytokine was barely detectable in the supernatant or in extracts from TULV-infected HUVECs. Nevertheless, the upregulation of HLA class I on both TULV- and HTNV-infected cells could be blocked by neutralizing anti-IFN-beta antibodies. Most strikingly, the antiviral MxA protein, which interferes with hantavirus replication, was already induced 16 h after infection with TULV. In contrast, HTNV-infected HUVECs showed no expression of MxA until 48 h postinfection. In accordance with the kinetics of MxA expression, TULV replicated only inefficiently in HUVECs, whereas HTNV-infected cells produced high titers of virus particles that decreased after 48 h postinfection. Both hantavirus species, however, could replicate equally well in Vero E6 cells, which lack an IFN-induced MxA response. Thus, delayed induction of antiviral MxA in endothelial cells after infection with HTNV could allow viral dissemination and contribute to the pathogenesis leading to HFRS
    Type of Publication: Journal article published
    PubMed ID: 15163707
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  • 7
    Keywords: CANCER ; Germany ; human ; IN-VIVO ; POPULATION ; PROTEIN ; PROTEINS ; MICE ; RESPONSES ; DNA ; INFECTION ; INDUCTION ; ANTIGEN ; ANTIGENS ; T-CELL ; E7 ; papillomavirus ; IMMUNE-RESPONSES ; antibodies ; antibody ; PARTICLES ; virus ; PROGRESSION ; VECTOR ; cervical intraepithelial neoplasia ; CERVICAL-CANCER ; FUSION ; human papillomavirus ; TYPE-16 ; VACCINES ; VIRUS-LIKE PARTICLES ; SURFACE ; MAMMALIAN-CELLS ; VACCINE ; STRATEGIES ; EPITOPES ; IMMUNE-RESPONSE ; IMMUNITY ; hepatitis B virus ; IMMUNOGENICITY ; TARGETS ; ADENOVIRUS ; FUSION PROTEIN ; T-cell response ; YOUNG-WOMEN ; IMMUNIZATION ; RECOMBINANT ; secretion ; ENHANCEMENT ; CARRIER ; CANCER PROGRESSION ; INDUCE ; HEPATITIS-B ; E7 PROTEINS
    Abstract: Induction of effective immune responses may help prevent cancer progression. Tumor-specific antigens, such as those of human papillomaviruses involved in cervical cancer, are targets with limited intrinsic immunogenicity. Here we show that immunization with low doses (10(6) infectious units/dose) of a recombinant human adenovirus type 5 encoding a fusion of the E7 oncoprotein of human papillomavirus type 16 to the carboxyl terminus of the surface antigen of hepatitis B virus (HBsAg) induces remarkable E7-specific humoral and cellular immune responses. The HBsAg/E7 fusion protein assembled efficiently into virus-like particles, which stimulated antibody responses against both carrier and foreign antigens, and evoked antigen- specific kill of an indicator cell population in vivo. Antibody and T-cell responses were significantly higher than those induced by a control adenovirus vector expressing wild-type E7. Such responses were not affected by preexisting immunity against either HBsAg or adenovirus. These data demonstrate that the presence of E7 on HBsAg particles does not interfere with particle secretion, as it occurs with bigger proteins fused to the C terminus of HBsAg, and results in enhancement of CD8(+)-mediated T-cell responses to E7. Thus, fusion to HBsAg is a convenient strategy for developing cervical cancer therapeutic vaccines, since it enhances the immunogenicity of E7 while turning it into an innocuous secreted fusion protein
    Type of Publication: Journal article published
    PubMed ID: 16188983
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  • 8
    Keywords: CELLS ; EXPRESSION ; INHIBITOR ; KINASE ; MICROSCOPY ; GENE ; GENES ; PROTEIN ; PROTEINS ; LINES ; ACTIVATION ; COMPLEX ; COMPLEXES ; FAMILY ; CELL-LINES ; CYCLE ; ASSOCIATION ; MATURATION ; virus ; MEMBRANE ; LINE ; LOCALIZATION ; EPITHELIAL-CELLS ; REPLICATION ; cell lines ; EPSTEIN-BARR-VIRUS ; lamin ; electron microscopy ; Epstein-Barr virus ; ELECTRON-MICROSCOPY ; TRANSFECTION ; interaction ; PHOSPHORYLATION SITES ; MATURE ; transcript ; LYTIC CYCLE ; PSEUDORABIES VIRUS ; UL34 GENE-PRODUCT ; EA-D ; HUMAN-HERPESVIRUS 6 ; PRIMARY ENVELOPMENT ; U(L)34 PROTEIN
    Abstract: We have reported in the accompanying paper that the BFRF1 protein of Epstein-Barr virus (EBV) is important for efficient primary viral envelopment and egress (A. Farina, R. Feederle, S. Raffa, R. Gonnella, R. Santarelli, L. Frati, A. Angeloni, M. R. Torrisi, A. Faggioni, and H.-J. Delecluse, J. Virol. 79:3703-3712). Here we describe the characterization of the product of the EBV BFLF2 gene, which belongs to a family of conserved herpesviral genes which include the UL31 genes of herpes simplex virus and of pseudorabies virus and whose products are known to interact with UL34, the positional homolog of BFRF1. BFLF2 is an early transcript and is expressed in a variety of cell lines upon EBV lytic cycle activation. Western blotting of purified virion preparations showed that BFLF2 is a component of intracellular virions but is absent from mature extracellular virions. Coimmunoprecipitation experiments indicated that BFLF2 interacts with BFRF1, which was confirmed by immunofluorescence confocal microscopy showing that the two proteins colocalize on the nuclear membrane not only upon cotransfection in epithelial cells but also during viral replication. In cells carrying an EBV mutant with the BFRF1 gene deleted (293-BFRF1-KO cells) BFLF2 expression was low, and it was restored to wild-type levels upon treatment of the cells with the proteasome inhibitor MG132. Furthermore, recomplementing the 293-BFRF1-KO cells by BFRF1 transfection restored BFLF2 expression to the wild-type level. In addition, when expressed alone BFLF2 was localized diffusely inside the nucleus, whereas in the presence of BFRF1 the two proteins colocalized at the nuclear rim. Finally, 293 epithelial cells transfected with either protein or cotransfected were analyzed by electron microscopy to investigate potential alterations in the morphology of the nuclear membrane. The ultrastructural analysis revealed that (i) BFRF1 caused duplications of the nuclear membrane, similar to those reported to occur during the course of herpesviral replication, and (ii) while BFLF2 alone did not cause any apparent alteration, coexpression of the two proteins dramatically induced profound convolutions of the duplicated nuclear membrane. Both biochemical and morphological analysis showed association of the BFRF1-BFLF2 complex with a component of the nuclear lamina, lamin B. Taken together, these results and those of the accompanying paper (Farina et al., J. Virol. 79:3703-3712) indicate an important role of BFRF1 and BFLF2 in the early steps of EBV maturation at the nuclear membrane
    Type of Publication: Journal article published
    PubMed ID: 15731265
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  • 9
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; tumor ; Germany ; SYSTEM ; RNA ; LINES ; CELL-LINES ; SUPPRESSION ; CERVICAL-CANCER ; LINE ; p53 ; HPV ; MAMMALIAN-CELLS ; DEGRADATION ; cell lines ; PROTEASOME ; E6 ONCOPROTEIN ; TUMOR-SUPPRESSOR ; INTERFERENCE ; DESTRUCTION ; SUPPRESSOR ; ABILITY ; RNAS ; UBIQUITIN-PROTEIN LIGASE
    Abstract: The ubiquitin-protein ligase E6-AP is utilized by the E6 oncoprotein of human papillomaviruses (HPVs) associated with cervical cancer to target the tumor suppressor p53 for degradation. Here, we report that downregulation of E6-AP expression by RNA interference results in both the accumulation of p53 and growth suppression of the HPV-positive cervical cancer cell lines HeLa and SiHa. In addition, HeLa cells, in which p53 expression was suppressed by RNA interference, are significantly less sensitive to the downregulation of E6-AP expression with respect to growth suppression than parental HeLa cells. These data indicate that the antigrowth-suppressive properties of E6-AP in HPV-positive cells depend on its ability to induce p53 degradation
    Type of Publication: Journal article published
    PubMed ID: 15994823
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  • 10
    Keywords: ANGIOGENESIS ; CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; IN-VITRO ; tumor ; TUMOR-CELLS ; human ; VITRO ; GENE ; GENE-EXPRESSION ; TUMORS ; LINES ; MICE ; INFECTION ; TRANSCRIPTION FACTOR ; CELL-LINES ; virus ; MALIGNANCIES ; gene expression ; CELL-LINE ; LINE ; PATHOGENESIS ; VASCULATURE ; cell lines ; EPSTEIN-BARR-VIRUS ; FACTOR MESSENGER-RNA ; VEGF ; NASOPHARYNGEAL CARCINOMA ; GENE-PRODUCT ; Epstein-Barr virus ; MALIGNANCY ; SUBSET ; CAPACITY ; TUMOR-GROWTH ; secretion ; TRANSLATION ; LEVEL ; SARCOMA-ASSOCIATED HERPESVIRUS ; EBV ; FACTOR/VASCULAR PERMEABILITY FACTOR ; INTERNAL RIBOSOME ENTRY ; LATENT MEMBRANE PROTEIN-1 ; LYMPHOPROLIFERATIVE DISEASE ; PRIMARY EFFUSION LYMPHOMAS
    Abstract: Although Epstein-Barr virus (EBV)-associated malignancies are primarily composed of cells with one of the latent forms of EBV infection, a small subset of tumor cells containing the lytic form of infection is often observed. Whether the rare lytically infected tumor cells contribute to the growth of the latently infected tumor cells is unclear. Here we have investigated whether the lytically infected subset of early-passage lymphoblastoid cell lines (LCLs) could potentially contribute to tumor growth through the production of angiogenesis factors. We demonstrate that supernatants from early-passage LCLs infected with BZLF1-deleted virus (Z-KO LCLs) are highly impaired in promoting endothelial cell tube formation in vitro compared to wild-type (WT) LCL supernatants. Furthermore, expression of the BZLF1 gene product in trans in Z-KO LCLs restored angiogenic capacity. The supernatants of Z-KO LCLs, as well as supernatants from LCLs derived with a BRLFI-deleted virus (R-KO LCLs), contained much less vascular endothelial growth factor (VEGF) in comparison to WT LCLs. BZLF1 gene expression in Z-KO LCLs restored the VEGF level in the supernatant. However, the cellular level of VEGF mRNA was similar in Z-KO, R-KO, and WT LCLs, suggesting that lytic infection may enhance VEGF translation or secretion. Interestingly, a portion of the vasculature in LCL tumors in SCID mice was derived from the human LCLs. These results suggest that lytically infected cells may contribute to the growth of EBV-associated malignancies by enhancing angiogenesis. In addition, as VEGF is a pleiotropic factor with effects other than angiogenesis, lytically induced VEGF secretion may potentially contribute to viral pathogenesis
    Type of Publication: Journal article published
    PubMed ID: 16254334
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