Página 3 dos resultados de 149 itens digitais encontrados em 0.001 segundos

Interferon Action against Human Parainfluenza Virus Type 3: Involvement of a Novel Antiviral Pathway in the Inhibition of Transcription

Choudhary, Suresh; Gao, Jing; Leaman, Douglas W.; De, Bishnu P.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /05/2001 EN
Relevância na Pesquisa
17.85%
Interferon (IFN)-induced 2′-5′ oligoadenylate synthetase (2-5A synthetase)/RNase L, PKR, and Mx proteins are considered to be the principal antiviral protein pathways through which IFN induces an antiviral state. It was previously reported that human parainfluenza virus type 3 (HPIV3) multiplication was inhibited by IFN-α in human lung epithelial cells A549 and that MxA was found to contribute to the inhibition process (Zhao et al., Virology 220:330–338, 1996). Viral primary transcription was dramatically inhibited in A549 cells after IFN-α treatment, but a step following primary transcription was inhibited in U87-MxA cells constitutively expressing MxA. Here we have investigated the role of MxA, believed to be cell type specific, and other antiviral pathways in the inhibition of viral primary transcription. Our data indicate that a novel IFN-induced pathway(s) is involved in the inhibition of primary transcription. This is based on the following findings: (i) IFN-α inhibited viral primary transcription in U87-MxA and other cell types including cells lacking MxA; (ii) cells constitutively expressing 2-5A synthetase had no antiviral effect against HPIV3; and (iii) primary transcription occurred in the absence of protein synthesis...

Serum Interferon (IFN)-Neutralizing Antibodies and Bioactivities of IFNs in Patients with Severe Type II Essential Mixed Cryoglobulinemia

Scagnolari, Carolina; Casato, Milvia; Bellomi, Francesca; De Pisa, Francesca; Turriziani, Ombretta; Coviello, Rossella; Pirro, Maria Rosaria; Dianzani, Ferdinando; Antonelli, Guido
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /01/2003 EN
Relevância na Pesquisa
17.63%
The efficacy of alpha interferon (IFN-α) in the treatment of severe type II essential mixed cryoglobulinemia (EMC) has been reported previously. In some patients, the development of neutralizing antibodies to recombinant IFN-α (rIFN-α) can affect the clinical response achieved with rIFN-α; a second treatment with natural IFN-α preparations may reinduce the clinical response. In the present study the ability of leukocyte IFN (LeIFN) to restore the response was investigated from a pharmacodynamic viewpoint. Specifically, the pharmacodynamic profiles of different IFN-α preparations were studied by measuring the serum neopterin levels and the levels of expression of protein MxA mRNA in in vivo peripheral blood mononuclear cells in two patients with EMC whose resistance to rIFN-α2a treatment increased concomitantly with the development of neutralizing antibodies. These markers were measured before injection and at 24 and 48 h after a single injection of rIFN-α2a, consensus IFN [(C)IFN], or LeIFN. No increase or only a slight increase in MxA mRNA levels was detectable after administration of rIFN-α2a or (C)IFN, whereas a significant increase (≥10-fold) in MxA mRNA expression was recorded following administration of LeIFN. The neutralizing antibodies to rIFN-α2a cross-react with (C)IFN. Sera from these patients neutralized most but not all of the subtypes present in the natural IFN-α (LeIFN) mixture...

Antiviral Effects of Geranylgeranylacetone: Enhancement of MxA Expression and Phosphorylation of PKR during Influenza Virus Infection

Unoshima, Masako; Iwasaka, Hideo; Eto, Junko; Takita-Sonoda, Yoshiko; Noguchi, Takayuki; Nishizono, Akira
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /09/2003 EN
Relevância na Pesquisa
27.14%
A cyclic polyisoprenoid compound, geranylgeranylacetone (GGA), has been used as antiulcer drug. GGA is also a potent inducer of heat shock proteins (HSPs). HSPs are considered to induce an antiviral effect; however, the detailed mechanism is unknown. To determine whether GGA might show antiviral activity and what the mechanism is, the effect of GGA against influenza virus (strain PR8) infection in vivo and in vitro was investigated. The results demonstrated that GGA treatment strongly suppressed the deleterious consequences of PR8 replication and was accompanied by an increase in HSP70 gene expression in mice. Results from in vitro analyses demonstrated that GGA significantly inhibited the synthesis of PR8-associated proteins and prominently enhanced expression of human myxovirus resistance 1 (MxA) followed by increased HSP70 transcription. Moreover, GGA augmented the expression of an interferon-inducible double-strand RNA-activated protein kinase (PKR) gene and promoted PKR autophosphorylation and concomitantly α subunit of eukaryotic initiation factor 2 phosphorylation during PR8 infection. It is proposed that GGA-induced HSP70 has potent antiviral activity by enhancement of antiviral factors and can clinically achieve protection from influenza virus infection.

Nuclear localization of mouse Mx1 protein is necessary for inhibition of influenza virus.

Zürcher, T; Pavlovic, J; Staeheli, P
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /08/1992 EN
Relevância na Pesquisa
17.76%
The interferon-induced Mx1 protein of mice confers selective resistance to influenza virus. It inhibits viral mRNA synthesis in the nucleus of influenza virus-infected cells. The related human MxA protein is localized in the cytoplasm and can inhibit influenza virus and vesicular stomatitis virus but not other viruses. MxA blocks a poorly defined cytoplasmic multiplication step of influenza virus that follows primary transcription of the viral genome. We previously showed that nuclear variants of MxA that carry an artificial nuclear translocation signal were also active against influenza virus. However, these variants blocked primary transcription of influenza virus. In the present study, we addressed the question of whether cytoplasmic forms of Mx1 were capable of mimicking the antiviral action of MxA by determining the antiviral activities of mutant mouse Mx1 protein. Cytoplasmic Mx1(E614), which differs from wild-type Mx1 by a single amino acid substitution in its nuclear transport signal, failed to inhibit the multiplication of influenza virus and vesicular stomatitis virus. Relocation of Mx1(E614) to the nucleus with the help of the simian virus 40 large T nuclear translocation signal attached to its amino terminus restored the influenza virus-inhibiting activity. Other changes in the carboxy-terminal region of Mx1 also abolished transport to the nucleus and simultaneously abolished antiviral activity. One of these variants...

Human and mouse Mx proteins inhibit different steps of the influenza virus multiplication cycle.

Pavlovic, J; Haller, O; Staeheli, P
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /04/1992 EN
Relevância na Pesquisa
17.85%
Human MxA and mouse Mx1 are interferon-induced proteins capable of inhibiting the multiplication of influenza virus. MxA protein is localized in the cytoplasm, whereas Mx1 protein accumulates in the nucleus. Taking advantage of stably transfected cell lines that constitutively express either MxA or Mx1 protein, we examined the steps at which these proteins block influenza A viruses. In infected cells expressing MxA protein, all viral mRNAs synthesized as a result of primary transcription in the nucleus by the virion-associated RNA polymerase accumulated to normal levels. These primary viral transcripts were polyadenylated, were active in directing viral protein synthesis in vitro, and appeared to be efficiently transported to the cell cytoplasm. Yet viral protein synthesis and genome amplification were strongly inhibited, suggesting that MxA protein interfered with either intracytoplasmic transport of viral mRNAs, viral protein synthesis, or translocation of newly synthesized viral proteins to the cell nucleus. However, in infected cells expressing Mx1 protein, the concentrations of the longest primary transcripts encoding the three influenza virus polymerase proteins PB1, PB2, and PA were at least 50-fold reduced. Accumulation of the shorter primary transcripts encoding the other viral proteins was also inhibited but to a lesser extent. These results demonstrate that the mouse Mx1 protein interferes with primary transcription of influenza virus in the nucleus...

cDNA structures and regulation of two interferon-induced human Mx proteins.

Aebi, M; Fäh, J; Hurt, N; Samuel, C E; Thomis, D; Bazzigher, L; Pavlovic, J; Haller, O; Staeheli, P
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /11/1989 EN
Relevância na Pesquisa
17.63%
Human cells treated with interferon synthesize two proteins that exhibit high homology to murine Mx1 protein, which has previously been identified as the mediator of interferon-induced cellular resistance of mouse cells against influenza viruses. Using murine Mx1 cDNA as a hybridization probe, we have isolated cDNA clones originating from two distinct human Mx genes, designated MxA and MxB. In human fibroblasts, expression of MxA and MxB is strongly induced by alpha interferon (IFN-alpha), IFN-beta, Newcastle disease virus, and, to a much lesser extent, IFN-gamma, MxA and MxB proteins have molecular masses of 76 and 73 kilodaltons, respectively, and their sequences are 63% identical. A comparison of human and mouse Mx proteins revealed that human MxA and mouse Mx2 are the most closely related proteins, showing 77% sequence identity. Near their amino termini, human and mouse Mx proteins contain a block of 53 identical amino acids and additional regions of very high sequence similarity. These conserved sequences are also present in a double-stranded RNA-inducible fish gene, which suggests that they may constitute a functionally important domain of Mx proteins. In contrast to mouse Mx1 protein, which accumulates in the nuclei of IFN-treated mouse cells...

Differential Antiviral Response of Endothelial Cells after Infection with Pathogenic and Nonpathogenic Hantaviruses

Kraus, Annette A.; Raftery, Martin J.; Giese, Thomas; Ulrich, Rainer; Zawatzky, Rainer; Hippenstiel, Stefan; Suttorp, Norbert; Krüger, Detlev H.; Schönrich, Günther
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /06/2004 EN
Relevância na Pesquisa
17.76%
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-β), 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-β antibodies. Most strikingly, the antiviral MxA protein, which interferes with hantavirus replication, was already induced 16 h after infection with TULV. In contrast...

Influenza A Virus Strains Differ in Sensitivity to the Antiviral Action of Mx-GTPase▿

Dittmann, Jan; Stertz, Silke; Grimm, Daniel; Steel, John; García-Sastre, Adolfo; Haller, Otto; Kochs, Georg
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
17.63%
Interferon-mediated host responses are of great importance for controlling influenza A virus infections. It is well established that the interferon-induced Mx proteins possess powerful antiviral activities toward most influenza viruses. Here we analyzed a range of influenza A virus strains for their sensitivities to murine Mx1 and human MxA proteins and found remarkable differences. Virus strains of avian origin were highly sensitive to Mx1, whereas strains of human origin showed much weaker responses. Artificial reassortments of the viral components in a minireplicon system identified the viral nucleoprotein as the main target structure of Mx1. Interestingly, the recently reconstructed 1918 H1N1 “Spanish flu” virus was much less sensitive than the highly pathogenic avian H5N1 strain A/Vietnam/1203/04 when tested in a minireplicon system. Importantly, the human 1918 virus-based minireplicon system was almost insensitive to inhibition by human MxA, whereas the avian influenza A virus H5N1-derived system was well controlled by MxA. These findings suggest that Mx proteins provide a formidable hurdle that hinders influenza A viruses of avian origin from crossing the species barrier to humans. They further imply that the observed insensitivity of the 1918 virus-based replicon to the antiviral activity of human MxA is a hitherto unrecognized characteristic of the “Spanish flu” virus that may contribute to the high virulence of this unusual pandemic strain.

Alpha/Beta Interferon (IFN-α/β)-Independent Induction of IFN-λ1 (Interleukin-29) in Response to Hantaan Virus Infection▿

Stoltz, Malin; Klingström, Jonas
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
17.63%
Type III interferons ([IFNs]IFN-λ and interleukin-28 and -29 [IL-28/29]) are recently recognized cytokines with innate antiviral effects similar to those of type I IFNs (IFN-α/β). Like IFN-α/β, IFN-λ-expression can be induced by viruses, and it is believed that type I and III IFNs are regulated in the same manner. Hantaviruses are weak IFN-α/β inducers and have surprisingly been shown to activate IFN-α/β-independent IFN-stimulated gene (ISG) expression. Here, we show that in Hantaan virus (HTNV)-infected human epithelial A549 cells, induction of IFN-λ1 preceded induction of MxA and IFN-β by 12 and 24 h, respectively, and IFN-α was not induced at all. Furthermore, induction of IFN-λ1 and MxA was observed in HTNV-infected African green monkey epithelial Vero E6 cells, a cell line that cannot produce type I IFNs, clearly showing that HTNV can induce IFN-λ1 and ISGs in the complete absence of IFN-α/β. In HTNV-infected human fibroblast MRC-5 cells, which lack the IFN-λ receptor, induction of MxA coincided in time with IFN-β-induction. UV-inactivated HTNV did not induce any IFNs or MxA in any cell line, showing that activation of IFN-λ1 is dependent on replicating virus. Induction of both IFN-β and IFN-λ1 in A549 cells after poly(I:C)-stimulation was strongly inhibited in HTNV-infected cells...

The Viral Nucleoprotein Determines Mx Sensitivity of Influenza A Viruses▿

Zimmermann, Petra; Mänz, Benjamin; Haller, Otto; Schwemmle, Martin; Kochs, Georg
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /08/2011 EN
Relevância na Pesquisa
17.63%
Host restriction factors play a crucial role in preventing trans-species transmission of viral pathogens. In mammals, the interferon-induced Mx GTPases are powerful antiviral proteins restricting orthomyxoviruses. Hence, the human MxA GTPase may function as an efficient barrier against zoonotic introduction of influenza A viruses into the human population. Successful viruses are likely to acquire adaptive mutations allowing them to evade MxA restriction. We compared the 2009 pandemic influenza A virus [strain A/Hamburg/4/09 (pH1N1)] with a highly pathogenic avian H5N1 isolate [strain A/Thailand/1(KAN-1)/04] for their relative sensitivities to human MxA and murine Mx1. The H5N1 virus was highly sensitive to both Mx GTPases, whereas the pandemic H1N1 virus was almost insensitive. Substitutions of the viral polymerase subunits or the nucleoprotein (NP) in a polymerase reconstitution assay demonstrated that NP was the main determinant of Mx sensitivity. The NP of H5N1 conferred Mx sensitivity to the pandemic H1N1 polymerase, whereas the NP of pandemic H1N1 rendered the H5N1 polymerase insensitive. Reassortant viruses which expressed the NP of H5N1 in a pH1N1 genetic background and vice versa were generated. Congenic Mx1-positive mice survived intranasal infection with these reassortants if the challenge virus contained the avian NP. In contrast...

Search for Specific Biomarkers of IFNβ Bioactivity in Patients with Multiple Sclerosis

Malhotra, Sunny; Bustamante, Marta F.; Pérez-Miralles, Francisco; Rio, Jordi; Ruiz de Villa, Mari Carmen; Vegas, Esteban; Nonell, Lara; Deisenhammer, Florian; Fissolo, Nicolás; Nurtdinov, Ramil N.; Montalban, Xavier; Comabella, Manuel
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 23/08/2011 EN
Relevância na Pesquisa
17.63%
Myxovirus A (MxA), a protein encoded by the MX1 gene with antiviral activity, has proven to be a sensitive measure of IFNβ bioactivity in multiple sclerosis (MS). However, the use of MxA as a biomarker of IFNβ bioactivity has been criticized for the lack of evidence of its role on disease pathogenesis and the clinical response to IFNβ. Here, we aimed to identify specific biomarkers of IFNβ bioactivity in order to compare their gene expression induction by type I IFNs with the MxA, and to investigate their potential role in MS pathogenesis. Gene expression microarrays were performed in PBMC from MS patients who developed neutralizing antibodies (NAB) to IFNβ at 12 and/or 24 months of treatment and patients who remained NAB negative. Nine genes followed patterns in gene expression over time similar to the MX1, which was considered the gold standard gene, and were selected for further experiments: IFI6, IFI27, IFI44L, IFIT1, HERC5, LY6E, RSAD2, SIGLEC1, and USP18. In vitro experiments in PBMC from healthy controls revealed specific induction of selected biomarkers by IFNβ but not IFNγ, and several markers, in particular USP18 and HERC5, were shown to be significantly induced at lower IFNβ concentrations and more selective than the MX1 as biomarkers of IFNβ bioactivity. In addition...

IFN-α Is Constitutively Expressed in the Human Thymus, but Not in Peripheral Lymphoid Organs

Colantonio, Arnaud D.; Epeldegui, Marta; Jesiak, Maria; Jachimowski, Loes; Blom, Bianca; Uittenbogaart, Christel H.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 31/08/2011 EN
Relevância na Pesquisa
17.44%
Type I interferons have been typically studied for their effects in the context of bacterial or viral infections. However in this report, we provide evidence that Interferon-alpha (IFN-α) expressing cells are present in the thymus in the absence of infection. We show that pDC express the highest level of IFN-α and that MxA, which is exclusively expressed after engagement of the type I IFN receptor by IFN-α/β, is expressed in normal fetal and post-natal thymus, but not in the periphery. The highest level of MxA is expressed in mature thymocytes and pDC located in the medulla and at the cortico-medullary junction. The anti-microbial peptide LL-37, which is expressed in the thymus, when complexed with eukaryotic nucleic acids, induces the secretion of IFN-α by thymic pDC. This results in the upregulation of MxA expression in responsive thymocytes. We propose that the secretion of IFN-α in the thymus may function to regulate the rate of T cell development and modulate the requirements for the selection of developing T cells.

RESISTANCE OF PANCREATIC CANCER CELLS TO ONCOLYTIC VESICULAR STOMATITIS VIRUS: ROLE OF TYPE I INTERFERON SIGNALING

Moerdyk-Schauwecker, Megan; Shah, Nirav R.; Murphy, Andrea M.; Hastie, Eric; Mukherjee, Pinku; Grdzelishvili, Valery Z.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
17.44%
Oncolytic virus (OV) therapy takes advantage of common cancer characteristics, such as defective type I interferon (IFN) signaling, to preferentially infect and kill cancer cells with viruses. Our recent study (Murphy et al., 2012, J. Virol., 86: 3073-87) found human pancreatic ductal adenocarcinoma (PDA) cells were highly heterogeneous in their permissiveness to vesicular stomatitis virus (VSV) and suggested at least some resistant cell lines retained functional type I IFN responses. Here we examine cellular responses to infection by the oncolytic VSV recombinant VSV-ΔM51-GFP by analyzing a panel of 11 human PDA cell lines for expression of 33 genes associated with type I IFN pathways. Although all cell lines sensed infection by VSV-ΔM51-GFP and most activated IFN-α and β expression, only resistant cell lines displayed constitutive high-level expression of the IFN-stimulated antiviral genes MxA and OAS. Inhibition of JAK/STAT signaling decreased levels of MxA and OAS and increased VSV infection, replication and oncolysis, further implicating IFN responses in resistance. Unlike VSV, vaccinia and herpes simplex virus infectivity and killing of PDA cells was independent of the type I IFN signaling profile, possibly because these two viruses are better equipped to evade type I IFN responses. Our study demonstrates heterogeneity in the type I IFN signaling status of PDA cells and suggests MxA and OAS as potential biomarkers for PDA resistance to VSV and other OVs sensitive to type I IFN responses.

Use of a Standardized MxA Protein Measurement-Based Assay for Validation of Assays for the Assessment of Neutralizing Antibodies Against Interferon-β

Wadhwa, Meenu; Subramanyam, Meena; Goelz, Susan; Goyal, Jaya; Jethwa, Vijay; Jones, Wendy; Files, James G.; Kramer, Daniel; Bird, Chris; Dilger, Paula; Tovey, Michael; Lallemand, Christophe; Thorpe, Robin
Fonte: Mary Ann Liebert, Inc. Publicador: Mary Ann Liebert, Inc.
Tipo: Artigo de Revista Científica
Publicado em /11/2013 EN
Relevância na Pesquisa
27.14%
Effective monitoring of the development of neutralizing antibodies (NAbs) against IFN-β in multiple sclerosis (MS) patients on IFN-β therapy is important for clinical decision making and disease management. To date, antiviral assays have been the favored approach for NAb determination, but variations in assay conditions between laboratories and the increasing use of novel assays have contributed to the reporting of inconsistent antibody data between laboratories and between products. This study, undertaken at the request of the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA), is a joint effort by manufacturers of IFN-β products (approved in Europe) towards harmonization of a NAb assay that facilitates generation of comparable NAb data, which, in conjunction with clinical outcomes, should prove useful for clinicians treating MS patients with IFN-β products. This article describes the standardized cellular myxovirus resistance protein A (MxA) protein measurement-based assay for detection of IFN-β NAbs and its use for the validation of assays used for the quantitative determination of such antibodies. Although titers varied between laboratories and the products used, utilization of IFN-β1a rather than IFN-β1b as the challenge antigen produced more consistent results in the NAb assay. Adoption of the standardized assay improves comparability between laboratories circumventing problems that arise when different...

Structural Requirements for the Antiviral Activity of the Human MxA Protein against Thogoto and Influenza A Virus*

Patzina, Corinna; Haller, Otto; Kochs, Georg
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
27.14%
Background: Interferon-induced human MxA GTPase is an innate immunity factor with broad antiviral activity.

Host genetic variations are associated with virological response to interferon therapy of chronic HCV in Han Chinese patients

Chen, Hongbo; Zhang, Yuanyuan; Huang, Peng; Xu, Yin; Wang, Jie; Su, Jing; Yu, Rongbin
Fonte: Editorial Department of Journal of Biomedical Research Publicador: Editorial Department of Journal of Biomedical Research
Tipo: Artigo de Revista Científica
Publicado em /11/2014 EN
Relevância na Pesquisa
17.85%
Previous studies have suggested that host genetic polymorphisms may affect virological response to pegylated-interferon and ribavirin (PEG-IFN/ ribavirin) therapy in chronic HCV infection. IL28B and MxA are the most intensively studied genes in Chinese Han population. The current research is to summarize published data and evaluate the overall association of meaningful SNPs in these two genes with virological response to interferon-based therapy. Literature search was performed in online database and a systematic review was conducted based on the search results. Meaningful single nucleotide polymorphisms (SNPs) were summarized and analyzed for odds ratio (OR) and 95% confidence intervals (95% CI). Data manipulation and statistical analyses were performed by using STATA 12.0 and Review Manager version 5.1. Eighteen papers were included for final data analysis. Three SNPs of IL28B and two SNPs of MxA were found to be associated with higher sustained virological response (SVR) to interferon therapy. The ORs and 95% CIs of each variant were: IL28B rs8099917 TT (OR: 4.35, 95% CI: 3.10∼6.12), IL28B rs12979860 CC (OR: 5.37, 95% CI: 3.95∼7.31), IL28B rs7248668 CC (OR: 3.50, 95% CI: 2.30∼5.35), MxA rs2071430 GT (OR: 2.03, 95% CI: 1.31∼3.13)...

Host and viral determinants for MxB restriction of HIV-1 infection

Matreyek, Kenneth A; Wang, Weifeng; Serrao, Erik; Singh, Parmit Kumar; Levin, Henry L; Engelman, Alan
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
EN_US
Relevância na Pesquisa
17.44%
Background: Interferon-induced cellular proteins play important roles in the host response against viral infection. The Mx family of dynamin-like GTPases, which include MxA and MxB, target a wide variety of viruses. Despite considerable evidence demonstrating the breadth of antiviral activity of MxA, human MxB was only recently discovered to specifically inhibit lentiviruses. Here we assess both host and viral determinants that underlie MxB restriction of HIV-1 infection. Results: Heterologous expression of MxB in human osteosarcoma cells potently inhibited HIV-1 infection (~12-fold), yet had little to no effect on divergent retroviruses. The anti-HIV effect manifested as a partial block in the formation of 2-long terminal repeat circle DNA and hence nuclear import, and we accordingly found evidence for an additional post-nuclear entry block. A large number of previously characterized capsid mutations, as well as mutations that abrogated integrase activity, counteracted MxB restriction. MxB expression suppressed integration into gene-enriched regions of chromosomes, similar to affects observed previously when cells were depleted for nuclear transport factors such as transportin 3. MxB activity did not require predicted GTPase active site residues or a series of unstructured loops within the stalk domain that confer functional oligomerization to related dynamin family proteins. In contrast...

Ribavirin Enhances IFN-α Signalling and MxA Expression: A Novel Immune Modulation Mechanism during Treatment of HCV

Stevenson, Nigel J.; Murphy, Alison G.; Bourke, Nollaig M.; Keogh, Catherine A.; Hegarty, John E.; O'Farrelly, Cliona
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 16/11/2011 EN
Relevância na Pesquisa
27.44%
The nucleoside analogue Ribavirin significantly increases patient response to IFN-α treatment of HCV, by directly inhibiting viral replication. Recent studies indicate that Ribavirin also regulates immunity and we propose that Ribavirin enhances specific interferon sensitive gene (ISG) expression by amplifying the IFN-α-JAK/STAT pathway. We found that IFN-α-induced STAT1 and STAT3 phosphorylation was increased in hepatocytes co-treated with Ribavirin and IFN-α, compared to IFN-α alone. Ribavirin specifically enhanced IFN-α induced mRNA and protein of the anti-viral mediator MxA, which co-localised with HCV core protein. These novel findings indicate for the first time that Ribavirin, in addition to its viral incorporation, also enhances IFN-α-JAK/STAT signalling, leading to a novel MxA-mediated immuno-modulatory mechanism that may enhance IFN-α anti-viral activity against HCV.

Interferon-Stimulated Genes Response in Endothelial Cells Following Hantaan Virus Infection

Kim, In-Wook; Hwang, Ji-Young; Kim, Sung-Kwang; Kim, Jong-Kyu; Park, Ho-Sun
Fonte: The Korean Academy of Medical Sciences Publicador: The Korean Academy of Medical Sciences
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
17.63%
The regulation mechanism of interferon (IFN) and IFN-stimulated genes is a very complex procedure and is dependent on cell types and virus species. We observed molecular changes related to anti-viral responses in endothelial cells during Hantaan virus (HTNV) infection. We found that there are two patterns of gene expression, the first pattern of gene expression being characterized by early induction and short action, as in that of type I IFNs,' and the other being characterized by delayed induction and long duration, as those of IRF-7, MxA, and TAP-1/2. Even though there are significant differences in their induction folds, we found that all of IFN-α/β, IRF-3/7, MxA, and TAP-1/2 mRNA expressions reached the peak when the viral replication was most active, which took place 3 days of post infection (d.p.i.). In addition, an interesting phenomenon was observed; only one gene was highly expressed in paired genes such as IFN-α/β (3/277-folds), IRF-3/7 (2.2/29.4-folds), and TAP-1/2 (26.2/6.1-folds). Therefore, IFN-β, IRF-7, and TAP-1 seem to be more important for the anti-viral response in HTNV infection. MxA was increased to 296-folds at 3 d.p.i. and kept continuing 207-folds until 7 d.p.i.. The above results indicate that IFN-β works for an early anti-viral response...

Association of TRIM22 with the Type 1 Interferon Response and Viral Control during Primary HIV-1 Infection▿

Singh, Ravesh; Gaiha, Gaurav; Werner, Lise; McKim, Kevin; Mlisana, Koleka; Luban, Jeremy; Walker, Bruce D.; Karim, Salim S. Abdool; Brass, Abraham L.; Ndung'u, Thumbi;
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
17.76%
Type 1 interferons (IFNs) induce the expression of the tripartite interaction motif (TRIM) family of E3 ligases, but the contribution of these antiviral factors to HIV pathogenesis is not completely understood. We hypothesized that the increased expression of select type 1 IFN and TRIM isoforms is associated with a significantly lower likelihood of HIV-1 acquisition and viral control during primary HIV-1 infection. We measured IFN-α, IFN-β, myxovirus resistance protein A (MxA), human TRIM5α (huTRIM5α), and TRIM22 mRNA levels in peripheral blood mononuclear cells (PBMCs) of high-risk, HIV-1-uninfected participants and HIV-1-positive study participants. Samples were available for 32 uninfected subjects and 28 infected persons, all within 1 year of infection. HIV-1-positive participants had higher levels of IFN-β (P = 0.0005), MxA (P = 0.007), and TRIM22 (P = 0.01) and lower levels of huTRIM5α (P < 0.001) than did HIV-1-negative participants. TRIM22 but not huTRIM5α correlated positively with type 1 IFN (IFN-α, IFN-β, and MxA) (all P < 0.0001). In a multivariate model, increased MxA expression showed a significant positive association with viral load (P = 0.0418). Furthermore, TRIM22 but not huTRIM5α, IFN-α, IFN-β, or MxA showed a negative correlation with plasma viral load (P = 0.0307) and a positive correlation with CD4+ T-cell counts (P = 0.0281). In vitro studies revealed that HIV infection induced TRIM22 expression in PBMCs obtained from HIV-negative donors. Stable TRIM22 knockdown resulted in increased HIV-1 particle release and replication in Jurkat reporter cells. Collectively...