Interferon

About: Interferon is a research topic. Over the lifetime, 28969 publications have been published within this topic receiving 1219645 citations. The topic is also known as: IFN & interferons.

Inhibition of interferon signaling by rabies virus phosphoprotein P: activation-dependent binding of STAT1 and STAT2.

Abstract: Rabies virus (RV) phosphoprotein P is an interferon (IFN) antagonist counteracting transcriptional activation of type I IFN (K. Brzozka, S. Finke, and K. K. Conzelmann, J. Virol 79:7673-7681, 2005). We here show that RV P in addition is responsible for preventing IFN-α/β- and IFN-γ-stimulated JAK-STAT signaling in RV-infected cells by the retention of activated STATs in the cytoplasm. Expression of IFN-stimulated response element- and gamma-activated sequence-controlled genes was severely impaired in cells infected with RV SAD L16 or in cells expressing RV P protein from transfected plasmids. In contrast, a recombinant RV expressing small amounts of P had lost the ability to interfere with JAK-STAT signaling. IFN-mediated tyrosine phosphorylation of STAT1 and STAT2 was not impaired in RV P-expressing cells; rather, a defect in STAT recycling was suggested by distinct accumulation of tyrosine-phosphorylated STATs in cell extracts. In the presence of P, activated STAT1 and STAT2 were unable to accumulate in the nucleus. Notably, STAT1 and STAT2 were coprecipitated with RV P only from extracts of cells previously stimulated with IFN-α or IFN-γ, whereas in nonstimulated cells no association of P with STATs was observed. This conditional, IFN activation-dependent binding of tyrosine-phosphorylated STATs by RV P is unique for a viral IFN antagonist. The 10 C-terminal residues of P are required for counteracting JAK-STAT signaling but not for inhibition of transcriptional activation of IFN-β, thus demonstrating two independent functions of RV P in counteracting the host's IFN response.

Activation of the human "beta 2-interferon/hepatocyte-stimulating factor/interleukin 6" promoter by cytokines, viruses, and second messenger agonists.

Abstract: The hallmark of "beta 2-interferon (IFN-beta 2)/hepatocyte-stimulating factor/interleukin 6" gene expression is its inducibility in different types of human cells (fibroblasts, monocytes, epithelial cells, and endothelial cells) by different stimuli, which include cytokines such as tumor necrosis factor, interleukin 1 (IL-1) and platelet-derived growth factor, different viruses, and bacterial products such as endotoxin. The activation by cytokines, viruses, and second messenger agonists of the IFN-beta 2 promoter linked to the bacterial chloramphenicol acetyltransferase (CAT) gene was studied after transfection into HeLa cells. A chimeric gene containing IFN-beta 2 DNA from -1180 to +13 linked to the CAT gene was inducible approximately 10-fold by phorbol 12-myristate 13-acetate (PMA), followed, in decreasing order, by pseudorabies and Sendai viruses (7- to 11-fold each); serum (6- to 9-fold); the cytokines tumor necrosis factor, IL-1, and epidermal growth factor (3- to 5-fold each); the cAMP agonists BrcAMP and forskolin and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (2- to 6-fold each); poly(I).poly(C) (2- to 4-fold); 1,2-diacylglycerol and the calcium ionophore A23187 (1.5- to 2-fold each). Bacterial endotoxin did not activate this IFN-beta 2/CAT fusion gene in HeLa cells. Deletion of the 5' boundary of the IFN-beta 2 DNA from -1180 to -596 in the fusion gene preserved its activation by IL-1, tumor necrosis factor, epidermal growth factor, serum, pseudorabies, and Sendai viruses and by PMA, Br-cAMP, and forskolin; deletion to -225 led to a small reduction (by a factor of 1.5-2) in the responsiveness to serum, PMA, and Sendai virus but not to the other inducers; a further deletion to -112 greatly reduced all responsiveness. Thus, the region between -225 and -113 in IFN-beta 2, which contains DNA motifs similar to the regulatory elements in the human c-fos gene, appears to contain the major cis-acting regulatory elements responsible for the activation of the IFN-beta 2 promoter by several different cytokines, viruses, and second messenger agonists.

Inhibition of the Type I Interferon Response by the Nucleoprotein of the Prototypic Arenavirus Lymphocytic Choriomeningitis Virus

Abstract: The prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) is a formidable battle horse for the study of viral immunology, as well as viral persistence and associated diseases. Investigations with LCMV have uncovered basic mechanisms by which viruses avoid elimination by the host adaptive immune response. In this study we show that LCMV also disables the host innate defense by interfering with beta interferon (IFN-beta) production in response to different stimuli, including infection with Sendai virus and liposome-mediated DNA transfection. Inhibition of IFN production in LCMV-infected cells was caused by an early block in the IFN regulatory factor 3 (IRF-3) activation pathway. This defect was restored in cells cured of LCMV, indicating that one or more LCMV products are responsible for the inhibition of IRF-3 activation. Using expression plasmids encoding individual LCMV proteins, we found that expression of the LCMV nucleoprotein (NP) was sufficient to inhibit both IFN production and nuclear translocation of IRF-3. To our knowledge, this is the first evidence of an IFN-counteracting viral protein in the Arenaviridae family. Inhibition of IFN production by the arenavirus NP is likely to be a determinant of virulence in vivo.

A recombinant vaccinia virus based ELISPOT assay detects high frequencies of Pol-specific CD8 T cells in HIV-1-positive individuals

Abstract: OBJECTIVES HIV-1-specific CD8 T cells are considered to be critical in anti-HIV responses. It is important to quantify these cells and to determine their antigenic targets. Here quantification of interferon (IFN)-gamma secreting, virus-specific cells was achieved with an enzyme linked immuno spot (ELISPOT) assay. METHODS Peripheral blood mononuclear cells (PBMC) were infected with recombinant vaccinia vectors expressing HIV-1 genes (gag, pol, env or nef) and added to wells precoated with anti-IFN-gamma monoclonal antibodies. Spot forming cells (SFC), i.e. antigen-specific T cells were detected 24 h later by the addition of biotinylated anti-IFN-gamma monoclonal antibodies, followed by avidin-bound biotinylated horseradish peroxidase. RESULTS In a cohort of 19 patients, of whom 15 were on highly active antiretroviral therapy, 18 had primed T cells directed against one or more HIV-1 antigens (P 90% loss of antigen-specific SFC when vaccinia virus was used as a vector. The number of CD8 SFC exceeded the number of memory cells detected in limiting dilution assays by > 1 log10, whereas a correlation was found between the frequency of effector cells detected by both ELISPOT and MHC class I peptide tetramer assays. CONCLUSIONS Vaccinia virus vectors used in ELISPOT assays are useful for determining the frequency and specificity of CD8 T cells for individual HIV-1 gene products. The dominance of cytolytic T lymphocytes (CTL) recognizing pol proteins suggests that this antigen should be considered in vaccine strategies.