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PubMed1995

Vaccinia virus B18R gene encodes a type I interferon-binding protein that blocks interferon alpha transmembrane signaling.

Poxviruses encode a large number of proteins that attenuate the inflammatory and immune responses to infection. In this report we demonstrate that a number of orthopoxviruses express a type I interferon (IFN)-binding protein, which is encoded by the B18R open reading frame in the WR strain of vaccinia virus. The B18R protein has significant regions of homology with the alpha subunits of the mouse, human, and bovine type I IFN receptors, bound human IFN alpha 2 with high affinity, and inhibited transmembrane signaling as demonstrated by inhibition of Fc receptor factor gamma 1/gamma 2 and interferon-stimulated gene factor-3 formation as well as inhibition of the IFN alpha antiviral response. Among viral host response modifiers, the B18R protein is unique inasmuch as it exists as a soluble extracellular as well as a cell surface protein and thus should effectively block both autocrine and paracrine functions of IFN.

Amino Acid Sequence↗

PubMed1996

The locus-specific enhancer activity of the class I major histocompatibility complex interferon-responsive element is associated with a gamma-interferon (IFN)-inducible factor distinct from STAT1alpha, p48, and IFN regulatory factor-1.

Recent analyses of the upstream regulatory regions of the class I major histocompatibility complex genes in higher primates provided a generalized structural basis for the differential expression of A- and B-locus gene products in response to specific physiological stimulus. Among the regulatory sequences that differ between the loci is the interferon-responsive element (IRE). While the B-IRE is conserved, the A-IREs have species-specific sequence variation. We previously demonstrated that the B-IRE was an interferon (IFN)-inducible enhancer, whereas none of the A-IREs were functional. In the present study, we examined the biochemical basis for the enhancer activity of the conserved B-IRE and found that this may be attributed to a novel gamma-IFN-inducible factor. This factor accumulated in nuclei of cells within minutes of exposure to gamma-IFN. Its appearance was independent of de novo protein synthesis. However, it was not detected in nuclei of cells treated with herbimycin A, suggesting that its appearance depends on a protein kinase activation pathway. Supershift assays indicated that it was distinct from STAT1alpha, IFN regulatory factor-1, and p48, transcription factors known to bind IRE-like sequences found in regulatory regions of many non-major histocompatibility complex gamma-IFN-responsive genes. Competition assays show that this novel factor bound B-IRE with relatively high affinity, about 100-fold more than that for the A-IRE sequence. This factor was also present in STAT1alpha and p48 somatic mutants that also exhibited B-IRE enhancer activity in reporter gene bioassays in a manner similar to those seen with wild type cells. These observations indicate the existence of a novel gamma-IFN-dependent transcriptional activation pathway that correlates with the differential enhancer activity of the HLA-B IRE.

Benzoquinones↗

PubMed2000

Interaction between interferon consensus sequence-binding protein and COP9/signalosome subunit CSN2 (Trip15). A possible link between interferon regulatory factor signaling and the COP9/signalosome.

Interferon consensus sequence-binding protein (ICSBP) is a member of the interferon regulatory factors (IRF) that has a pivotal role in mediating resistance to pathogenic infections in mice and in promoting the differentiation of myeloid cells. ICSBP exerts some of its transcriptional activities via association with other factors that enable its binding to a variety of promoters containing DNA composite elements. These interactions are mediated through a specific COOH-terminal domain termed IAD (IRF association domain). To gain a broader insight of the capacity of ICSBP to interact with other factors, yeast two-hybrid screens were performed using ICSBP-IAD as a bait against a B-cell cDNA library. Trip15 was identified as a specific interacting factor with ICSBP in yeast cells, which was also confirmed by in vitro glutathione S-transferase pull-down assays and by coimmunoprecipitation studies in COS7 cells. Trip15 was recently identified as a component of the COP9/signalosome (CSN) complex composed of eight evolutionary conserved subunits and thus termed CSN2. This complex has a role in cell-signaling processes, which is manifested by its associated novel kinase activity and by the involvement of its subunits in regulating multiple cell-signaling pathways and cell-cycle progression. We show that in vitro association of ICSBP with the CSN leads to phosphorylation of ICSBP at a unique serine residue within its IAD. The phosphorylated residue is essential for efficient association with IRF-1 and thus for the repressor activity of ICSBP exerted on IRF-1. This suggests that the CSN has a role in integrating incoming signals that affect the transcriptional activity of ICSBP.

3T3 Cells↗

PubMed2002

Interferons inhibit tumor necrosis factor-alpha-mediated matrix metalloproteinase-9 activation via interferon regulatory factor-1 binding competition with NF-kappa B.

Enhanced expression of matrix metalloproteinase-9 (MMP-9) correlates with invasion during tumor progression. Interferons (IFNs) inhibit MMP-9 activation in response to tumor necrosis factor-alpha (TNF-alpha), and the latter activates the MMP-9 gene through NF-kappaB. Understanding the molecular basis for MMP-9 inhibition may provide tools to control cell invasion. The data reported here show the critical role of interferon regulatory factor-1 (IRF1) in the inhibition of MMP-9. (i) IFN treatment suppresses TNF-alpha-induced MMP-9 reporter activity in STAT1(+/+) cells but not in STAT1(-/-) cells. (ii) IRF1 transfection blocks TNF-alpha-mediated MMP-9 activation. (iii) IFNs phosphorylate STAT1 and induce IRF1 but do not affect Ikappa-B degradation nor NF-kappaB nuclear translocation. (iv) Nuclear NF-kappaB (p50/p65) and IRF1, but not STAT1, bind to the MMP-9 promoter region containing an IFN-responsive-like element overlapping the NF-kappaB-binding site. (v) Recombinant IRF1, although unable to bind to an NF-kappaB consensus sequence, competes with NF-kappaB proteins for binding to the MMP-9 promoter. (vi) Conversely recombinant p50/p65 proteins reduce IRF1-DNA binding. (vii) In cells cotransfected with IRF1 and/or p65 expression vectors, an excess of IRF1 reduces MMP-9 reporter activity, whereas an excess of p65 blocks the inhibitory effect of IFN-gamma. Thus, in contrast to the known synergism between IRF1 and NF-kappaB, our data identify a novel role for IRF1 as a competitive inhibitor of NF-kappaB binding to the particular MMP-9 promoter context.

Base Sequence↗

PubMed2003

Interferon-gamma augments CARD4/NOD1 gene and protein expression through interferon regulatory factor-1 in intestinal epithelial cells.

Although intestinal epithelial cells appear to be functionally hyporesponsive to normal intestinal flora, human intestinal epithelial cells can respond to enteroinvasive bacteria and induce an inflammatory response. This initial inflammatory response leads to the recruitment of polymorphonuclear leukocytes to the affected site in vitro and in vivo. CARD4/NOD1 is a potential cytosolic receptor for peptidoglycan in mammalian cells that resembles pathogen-resistant proteins of plants. In this context, CARD4/NOD1 is a candidate for a recognition protein of intracellular bacteria or peptidoglycan in intestinal epithelial cells. In this study, we demonstrate that CARD4/NOD1 is constitutively expressed in intestinal epithelial cell lines and isolated primary intestinal epithelial cells. Interferon-gamma (IFN gamma), which is a potent pro-inflammatory cytokine in intestinal mucosal inflammation, activates CARD4/NOD1 mRNA transcription in a time- and dose-dependent manner and results in augmentation of CARD4/NOD1 protein in SW480 cells. Promoter analysis of CARD4/NOD1 indicates that interferon regulatory factor-1 (IRF-1) binding motif (-791 to -782) is essential for the effect of IFN gamma. Nuclear extracts from SW480 cells treated with IFN gamma show specific binding of oligonucleotides corresponding to this IRF-1-binding motif, which was supershifted by anti-IRF-1 antibody in electrophoretic mobility shift assay. Overexpression of IRF-1 protein activates the CARD4/NOD1 promoter but not the deletion mutant of the IRF-1-binding site in a co-transfection assay of IRF-1 expression plasmid with CARD4/NOD1 promoter. These studies suggest that the Th1 cytokine, IFN gamma, activates CARD4/NOD1 transcription and regulate innate immune mechanisms in the condition of intestinal mucosal inflammation.

Adaptor Proteins, Signal Transducing↗

PubMed2004

The up-regulation of human caspase-8 by interferon-gamma in breast tumor cells requires the induction and action of the transcription factor interferon regulatory factor-1.

Treatment of human breast tumor cells with interferon-gamma (IFN-gamma) elevates caspase-8 expression and sensitizes these cells to death receptor-mediated apoptosis through the increased processing and activation of apical procaspase-8. We have characterized the human caspase-8 gene promoter and studied the transcriptional regulation of caspase-8 gene expression in MCF-7 breast tumor cells treated with IFN-gamma. Our findings show that IFN-gamma induces the up-regulation of caspase-8 mRNA expression through a protein synthesis-dependent mechanism involving the action of the IFN-gamma-inducible transcription factor interferon regulatory factor-1 (IRF-1) and without altering mRNA stability. The human caspase-8 gene promoter lacks recognizable TATA and CAAT boxes but contains a consensus Sp1 binding site. We have identified two major IFN-gamma-inducible transcriptional start sites in these cells by S1 nuclease mapping, confirmed by primer extension analysis. Deletion analysis of the promoter defined an 82-bp minimal region responsible for IFN-gamma-inducible promoter activity. In this region, we have identified an IFN-stimulated response element that is important for both the basal and IFN-gamma-enhanced transcriptional activities. Electrophoretic mobility shift assay analysis demonstrated that IFN-gamma induces a complex between an oligonucleotide probe containing the ISRE motif and IRF-1 over a similar time scale to the induction of caspase-8 mRNA. Exogenously expressed IRF-1 in MCF-7 cells up-regulated the activity of a luciferase reporter plasmid containing an 82-bp region of the caspase-8 promoter. These data define a new pathway through which IFN-gamma might control the sensitivity of tumor cell to death receptor-mediated apoptosis.

Amino Acid Motifs↗

PubMed2005

Interferon regulatory factor 1 is an essential and direct transcriptional activator for interferon {gamma}-induced RANTES/CCl5 expression in macrophages.

Interferon regulatory factor 1 (IRF-1) is an important transcription factor in interferon gamma (IFNgamma)-mediated signaling in the development and function of NK cells and cytotoxic T lymphocytes. RANTES (regulated on activation normal T cell expressed and secreted; CCL5) is a member of the CC chemokine family of proteins, which is strongly chemoattractant for several important immune cell types in host defense against infectious agents and cancer. However, the role of IFNgamma and IRF-1 in the regulation of RANTES gene expression and their operative mechanisms in macrophages have not been established. We report here that RANTES expression in IRF-1-null mice, primarily in macrophages, in response to carcinogenic stimulation in vivo and in vitro and to IFNgamma but not to lipopolysaccharide in vitro, was markedly decreased. As a result, RANTES-mediated chemoattraction of CCR5(+) target cells was also severely impaired. Adenovirus-mediated gene transduction of IRF-1 in primary macrophages resulted in enhanced RANTES expression. The IFNgamma and IRF1 response element was localized to a TTTTC motif at -147 to -143 of the mouse RANTES promoter, to which endogenous or recombinant IRF-1 can physically bind in vitro and in vivo. This study uncovers a novel IFNgamma-induced pathway in RANTES expression mediated by IRF-1 in macrophages and elucidates an important host defense mechanism against neoplastic transformation.

Adenoviridae↗

PubMed1998

Interferon enhances tumor necrosis factor-induced vascular cell adhesion molecule 1 (CD106) expression in human endothelial cells by an interferon-related factor 1-dependent pathway.

Tumor necrosis factor (TNF) and interleukin 1 are known to initiate endothelial vascular cell adhesion molecule (VCAM)-1 transcription primarily by activating nuclear factor (NF)-kappaB, which translocates to the nucleus. In addition to two NF-kappaB elements found within the minimal cytokine-inducible VCAM-1 promoter, an interferon-related factor (IRF) element (IRF-1) has been identified close to the transcription initiation site, suggesting that cytokines that induce IRF-1 might affect VCAM-1 expression levels. We therefore investigated the effects of interferons (IFNs), which strongly induce IRF-1, on VCAM-1 transcription and expression. We show that IFN-alpha and -gamma enhance TNF-induced VCAM-1 mRNA transcription and protein expression in human endothelial cells. IFN enhancement of TNF-induced expression is also seen using chloramphenicol acetyl transferase reporter genes linked to the minimal cytokine inducible VCAM-1 promoter. Nuclear IRF-1 is the molecular basis of IFN enhancement, because (a) IFN plus TNF-treated cells displayed increased nuclear IRF-1 levels and increased IRF-1 binding to the VCAM-1 promoter, compared with cells treated with TNF alone; (b) kinetics of nuclear IRF-1 levels correlated with VCAM-1 mRNA levels; (c) transfection with an IRF-1 construct substituted for IFN treatment; and (d) transfection with an expression construct encoding IRF-2, a competitive inhibitor of IRF-1, reduced TNF-induced VCAM-1 expression. Our experiments show that IFN amplifies TNF-induced VCAM-1 expression at the transcriptional level by an IRF-1-dependent pathway.

Cell Compartmentation↗

PubMed1992

Influence of human recombinant interferon-alpha and interferon-gamma on bone marrow progenitor cells of HIV-positive individuals.

As a result of a pathophysiologically unexplainable bone marrow failure, most patients with progressive stages of human immunodeficiency virus (HIV) infection develop anemia, leukopenia, and thrombocytopenia. Besides the possibility of immune-mediated cytolysis or of direct viral infection of hemopoietic progenitor cells, the inhibitory influence of cytokines, for example interferon-alpha (IFN-alpha) and IFN-gamma, on hemopoiesis of HIV-infected patients might be considered as one parameter that contributes to myelosuppression. Therefore, progenitor cells from the bone marrow of HIV+ and HIV- persons were exposed to increasing concentrations of recombinant human IFN-alpha and IFN-gamma in methylcellulose assays. The colony formation of pluripotent (CFU-GEMM), erythroid (BFU-E), and granulocyte-macrophage (CFU-GM) progenitor cells was inhibited by both interferons. The 50% inhibitory doses (ID50) of IFN-alpha were 125.6 U/mL and 131.5 U/mL for BFU-E from HIV-infected persons and normal controls, respectively; the corresponding ID50 of IFN-alpha for CFU-GM growth was 1095.8 U/ml and above 3000 U/ml. When IFN-gamma was studied the ID50 was 341.7 and 2794.6 U/ml for BFU-E from HIV-infected and healthy individuals, respectively, while the ID50 for CFU-GM was above the highest dose levels in both groups (greater than 3000 U/ml). The ID50 for CFU-GEMM was below the lowest dose levels of IFN alpha and IFN gamma tested in both groups (less than 10 U/ml). The inhibitory effects could be specifically neutralized by monoclonal antibodies against IFN-alpha and IFN-gamma, thus confirming that the suppressive effects were due to the cytokines used.

Adult↗

PubMed1981

Heterogeneity of human gamma interferon preparations: evidence for presence of alpha interferon.

Human gamma interferon (HulFN-gamma) preparations induced with several mitogens (Staphylococcal enterotoxin A, Phytohemagglutinin, or Pokeweed mitogen) had low levels of cross-species antiviral activity on bovine cells (approximately 1-5%) and were not neutralized by antisera to either human interferon alpha (HulFN-alpha) or beta (HulFN-beta). After purification on controlled pore glass beads (CPG) these preparations could be fractionated into a minor component which was highly active on bovine cells and a major component that was virtually inactive on bovine cells. The highly cross-active component was pH2 stable and was neutralized by an anti-HulFN-alpha antiserum, while the major, lowly cross-active component was pH2 labile and was not neutralized by either anti-HulFN-alpha or HulFN-beta antisera. Chromatography of a CPG-purified mitogen-induced IFN preparation on anti-HulFN-alpha Sepharose showed that, while the large majority of HulFN-gamma preparations passed through the column, a minor component was retained and eluted at pH2. Thus, human leukocyte suspensions stimulated by mitogens produced predominantly HulFN-gamma, but also produce some HulFN-alpha.

Animals↗

PubMed1988

Pharmacokinetics of recombinant murine interferon-gamma and human interferon-alpha A/D(Bgl) administered in concert and their influence on natural killer cell function in mice.

The pharmacokinetics of recombinant murine interferon-gamma (rMuIFN-gamma) administered alone and in combination with recombinant hybrid human interferon-alpha (rHuIFN-alpha A/D-[Bgl]) were studied following intravenous (i.v.) and intramuscular (i.m.) injections into mice. The concomitant influence of these IFNs on splenic natural killer (NK) cell function was also examined. The coinjection of both IFNs did not affect the pharmacokinetics of either after i.v. administration. However, simultaneous injection of both IFNs i.m. does result in statistically significant changes in the serum concentrations of rHuIFN-alpha A/D(Bgl). The clinical benefits of the increased bioavailability of rHuIFN-alpha A/D(Bgl) are not apparent since NK cell enhancement after both IFNs were injected together was the same as that obtained after injection of rHuIFN-alpha A/D(Bgl) alone. NK cell enhancement after both IFNs were injected together was the same as that obtained after injection of rHuIFN-alpha A/D(Bgl) alone. Correspondingly, the coinjection of both IFNs did not affect the pharmacokinetics of either.

Animals↗

PubMed1994

Construction and activity of phosphorylatable human interferon-alpha B2 and interferon-alpha A/D.

The polymerase chain reaction (PCR) was used to introduce a phosphorylation site into human interferon-alpha B2 (Hu-IFN-alpha B2) and the chimeric human interferon-alpha A/D (Hu-IFN-alpha A/D). The phosphorylation sites were created by adding an amino acid consensus sequence for phosphorylation by the cAMP-dependent protein kinase to the carboxyl termini of the IFNs. The resultant modified IFNs (Hu-IFN-alpha B2-P and Hu-IFN-alpha A/D-P) were expressed in Escherichia coli and purified. The purified proteins exhibited antiviral activities similar to that of unmodified Hu-IFN-alpha B2 and Hu-IFN-alpha A/D. The Hu-IFN-alpha B2-P and Hu-IFN-alpha A/D-P can be phosphorylated by the catalytic subunit of the cAMP-dependent protein kinase and [gamma-32P]ATP with retention of biological activities. The introduction of phosphorylation sites into Hu-IFN-alpha B2 and Hu-IFN-alpha A/D provides new reagents for studies of receptor binding, pharmacokinetics, and other studies where labeled IFNs are useful.

Amino Acid Sequence↗

PubMed1995

Exogenous interferon-gamma induces endogenous synthesis of interferon-alpha and -beta by murine macrophages for induction of nitric oxide synthase.

Murine macrophages (M phi) are activated either by interferon-gamma (IFN-gamma) or interferon-alpha/beta (IFN-alpha/beta) in combination with bacterial lipopolysaccharide (LPS) to induce synthesis of tumor necrosis factor alpha (TNF-alpha) and nitric oxide synthase (iNOS) mRNA synthesis for generation of tumor cytotoxic nitric oxide (NO). In the present study, the effect of exogenous IFN-gamma on the induction of endogenous mRNA synthesis and secretion of IFN-alpha/beta by murine M phi was investigated. Neutralizing antibodies to IFN-alpha/beta reversed TNF-alpha and NOS mRNA synthesis, as well as nitric oxide (NO)-mediated tumor cytotoxicity. Quantitative reverse transcription polymerase chain reaction (RT-PCR) revealed that treatment of M phi with IFN-gamma induced increases in both IFN-alpha and IFN-beta mRNA synthesis by approximately 2-fold and 10-fold, respectively, which corresponded to a 2-fold increase in secretion of IFN-alpha/beta by ELISA. These data indicate that exogenous IFN-gamma induces endogenous synthesis and secretion of IFN-alpha/beta by M phi, which appears to act in concert with endogenously synthesized TNF-alpha for the autocrine induction of NOS mRNA synthesis.

Animals↗

PubMed1998

Differential viral induction of distinct interferon-alpha genes by positive feedback through interferon regulatory factor-7.

Interferon (IFN) genes are among the earliest transcriptional responses to virus infection of mammalian cells. Although the regulation of the IFNbeta gene has been well characterized, the induction of the large family of IFNalpha genes has remained obscure. We report that the IFNalpha genes can be divided into two groups: an immediate-early response gene (IFNalpha4) which is induced rapidly and without the need for ongoing protein synthesis; and a set of genes that display delayed induction, consisting of at least IFNalpha2, 5, 6 and 8, which are induced more slowly and require cellular protein synthesis. One protein that must be synthesized for induction of the delayed gene set is IFN itself, presumably IFNalpha4 or IFNbeta, which stimulates the Jak-Stat pathway through the IFN receptor, resulting in activation of the transcription factor interferon-stimulated gene factor 3 (ISGF3). Among the IFN-stimulated genes induced through this positive feedback loop is the IFN regulatory factor (IRF) protein, IRF7. Induction of IRF7 protein in response to IFN and its subsequent activation by phosphorylation in response to virus-specific signals, involving two C-terminal serine residues, are required for induction of the delayed IFNalpha gene set.

Animals↗

PubMed1990

Prognostic values of tumor necrosis factor/cachectin, interleukin-1, interferon-alpha, and interferon-gamma in the serum of patients with septic shock. Swiss-Dutch J5 Immunoglobulin Study Group.

Serum concentrations of immunoreactive tumor necrosis factor/cachectin (TNF), interleukin-1 beta (IL-1 beta), interferon-gamma (IFN gamma), and interferon-alpha (IFN alpha) were prospectively measured in 70 patients with septic shock to determine their evolution and prognostic values. In a univariate analysis, levels of TNF (P = .002) and IL-1 beta (P = .05) were associated with the patient's outcome, but not IFN alpha (P = .15) and IFN gamma (P = .26). In contrast, in a stepwise logistic regression analysis, the severity of the underlying disease (P = .01), the age of the patient (P = .02), the documentation of infection (nonbacteremic infections vs. bacteremias, P = .03), the urine output (P = .04), and the arterial pH (P = .05) contributed more significantly to prediction of patient outcome than the serum levels of TNF (P = .07). After 10 days, the median concentration of TNF was undetectable (less than 100 pg/ml) in the survivors, whereas it remained elevated (305 pg/ml, P = .002) in the nonsurvivors. Thus, in patients with septic shock due to various gram-negative bacteria, other parameters than the absolute serum concentration of immunoreactive TNF contributed significantly to the prediction of outcome.

Adolescent↗

PubMed1992

Synergistic interaction of interferon-beta and interferon-gamma in coxsackievirus B3-infected carrier cultures of human myocardial fibroblasts.

The antiviral effects of human interferon-beta (IFN-beta) and human recombinant interferon-gamma (rIFN-gamma) were studied in persistently coxsackievirus B3-infected carrier cultures of human myocardial fibroblasts over a period of 21 days. Synergism was observed with concentrations as low as 30 IU of IFN-beta plus 10 IU of rIFN-gamma/mL, reducing mean viral titers from 6.0 x 10(7) to 1.3 x 10(4) pfu/mL and number of infected cells from 14.4% to 0.1% as determined by quantitative in situ hybridization. Higher concentrations of IFNs (both > or = 30 IU/mL) were associated with transient antagonism followed by antiviral synergism. With 100 IU of IFN-beta plus 30 IU of rIFN-gamma/mL, elimination of infectious virus was consistently achieved and sustained for 6 weeks after cessation of IFN application, whereas at least threefold higher concentrations were required with single drugs. In summary, our data support a concept of low-dose IFN combination schedules that might become useful in the treatment of enteroviral heart disease.

Cells, Cultured↗

PubMed1985

Changes of chromatin conformation around mouse interferon-beta gene associated with induction of interferon synthesis.

Changes of chromatin structure around the mouse interferon-beta gene associated with induction were examined by the use of sensitivity to digestion with DNaseI. Upon induction, the DNaseI-sensitivity of mouse interferon-beta gene was increased and seven DNaseI-hypersensitive sites were mapped. One of them, which was located at approximately 100bp upstream and was insensitive in the uninduced state, showed a marked sensitivity upon induction. Four others, located at 580bp and 430bp upstream, and 1.9kb and 2.2kb downstream, whose levels of DNaseI-sensitivity were very low in the uninduced state, showed significant sensitivity in the induced state. Two remaining sites, located at 7.5kb upstream and 7.6kb downstream, had relatively high DNaseI-sensitivities even in the uninduced state and slightly increased their sensitivities upon induction.

Animals↗

PubMed2001

Treatment of patients with chronic hepatitis C not responding to interferon with high-dose interferon alpha with or without ribavirin: final results of a prospective randomized trial. Austrian Hepatitis Study Group.

OBJECTIVE: To investigate the efficacy of high-dose interferon alpha (IFN-alpha) with or without ribavirin in interferon (IFN) non-responders. STUDY DESIGN: 304 chronic hepatitis C patients received 5 MU IFN-alpha2b (IntronA, Schering-Plough, Kenilworth, NJ, USA) three times a week for 3 months. Non-responders were randomized either to continue with IFN (IFN 5 MU/TIW followed by 10 MU/TIW, each for 3 months) alone (group A: n = 76, m: f = 54: 22, age 45.7 +/- 12 years, 16% cirrhosis, alanine aminotransferase [ALT] 66 +/- 35 U/l) or in combination with ribavirin (approximately 14 mg/kg/day) (group B: n = 81, m: f = 57: 24, age 48.2 +/- 12 years, 17% cirrhosis, ALT 71 +/- 40 U/l). At the end of treatment, patients were followed for 6 months. MAIN OUTCOME MEASURES: Virological response at end of treatment and 6 months thereafter. SETTING: University hospitals and tertiary referral centres. RESULTS: At the end of treatment, eight (10.8%) and 25 (31.3%, P= 0.0066) patients were HCV-RNA negative, and 51 and 39 were HCV-RNA positive, in groups A and B, respectively. There were 17 drop-outs in each group. Six months after treatment, only one patient in group A (1.3%) and seven patients (8.6%, P= 0.06) in group B had normal ALT and undetectable serum HCV-RNA. CONCLUSIONS: A combination of high-dose IFN with ribavirin induces a short-lasting complete response in about one-third of IFN-non-responders.

Adult↗