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PubMed1993

Interferon-alpha antibodies in patients with renal cell carcinoma treated with recombinant interferon-alpha-2A in an adjuvant multicenter trial. The Delta-P Study Group.

BACKGROUND: Prolonged therapy with interferon (IFN) may lead to the formation of IFN antibodies. METHODS: Patients with renal cell carcinoma (n = 270) with advanced localized disease were randomized after complete tumor resection to receive treatment with adjuvant recombinant IFN-alpha-2a (rIFN-alpha 2a) (9 x 10(6) IU subcutaneously, three times per week for a maximum of 12 months) versus no treatment. Patients (IFN-treated group, 106 patients; control group, 97 patients) were monitored for the presence of rIFN-alpha 2a antibodies. RESULTS: Of 86 IFN-treated patients observed for more than 2 months, 40 (47%) had IFN-alpha 2a-binding and 25 (29%) had IFN-alpha 2a-neutralizing antibodies developed within a median of 3 and 6 months, respectively. A distinct peak in binding antibody titers occurred at 6-9 months. Therapy-induced neutralizing antibodies were equally reactive with two other recombinant IFN-alpha-2 subtypes but poorly recognized natural IFN-alpha (IFN-alpha), recombinant IFN-alpha-1/alpha-8, and recombinant IFN-omega-1. The duration of remission and rate of relapse were independent of the antibody status, although neutralizing and most non-neutralizing antibodies correlated with a reduction in the IFN-induced increase in beta-2-microglobulin levels. CONCLUSIONS: Patients treated with IFN-alpha 2a should be monitored for the presence and clinical relevance of IFN-alpha antibodies to determine those who could respond to alternative treatment.

Adult↗
PubMed1985

Relationship between circulating interferon and anti-interferon antibodies and impaired natural killer cell activity in systemic lupus erythematosus.

Interferon (IFN) production and response are impaired in a high percentage of systemic lupus erythematosus (SLE) patients. In addition, elevated serum levels of alpha-IFN or anti-alpha-IFN antibodies are present in some SLE patients. This study examined the relationship of circulating IFN and anti-IFN antibodies to the impairment of natural killer (NK) cell function in SLE. All 15 SLE patients studied had measurable circulating alpha-IFN, while the normal controls had minimal serum IFN. Neither patient nor control sera contained any detectable anti-alpha-IFN activity. However, most of the SLE patients demonstrated defects in NK cell function. Because these defects in NK cell function appeared to be associated with circulating IFN, but not anti-IFN, antibodies, the effect of prolonged in vitro IFN exposure on NK cell function of peripheral blood mononuclear cells was determined. It was found that prolonged exposure to IFN induced both an apparent defect in IFN response and a definite impairment of baseline NK cell function. These results suggest that prolonged elevation of circulating alpha-IFN levels could be responsible, in part, for the defects in natural cytotoxicity present in SLE.

Autoantibodies↗
PubMed2006

Improved tolerability and quality of life with maintained efficacy using twice-daily low-dose interferon-alpha-2b: results of a randomized phase II trial of low-dose versus intermediate-dose interferon-alpha-2b in patients with metastatic renal cell carcinoma.

BACKGROUND: In vivo data have shown a more potent antiangiogenic effect and a higher antitumor activity of low-dose interferon (IFN) given twice daily. In a randomized Phase II trial, the authors tested the hypothesis that twice-daily low-dose IFN is more effective than daily intermediate-dose IFN in patients with metastatic renal cell cancer (MRCC). METHODS: A total of 118 patients (59 per arm) were randomly assigned to receive IFN at a dose of 0.5 million units (MU) given subcutaneously twice daily (IFN1) or IFN at a dose of 5 MU given subcutaneously daily (IFN5). The primary endpoint was progression-free survival (PFS). Secondary endpoints included response rate (RR), overall survival (OS), toxicity, and quality of life (QOL). RESULTS: There were no significant differences in either PFS or OS between IFN1 and IFN5 (median of 3.7 months and median of 3.4 months PFS, respectively; median of 25.5 months and median of 17.5 months OS, respectively). The RRs were identical in the 2 arms (6.7%; 95% confidence interval [95% CI], 1.8-16.5%). Two patients, 1 in each arm, remained in complete remission at the time of last follow-up, at 45+ and 38+ months from treatment. Thirty-two patients receiving IFN5 and 19 patients receiving IFN1 experienced Grade 3 or higher adverse events (graded using the National Cancer Institute Common Toxicity Criteria [version 2.0]) (P = .025). Eighteen patients receiving IFN5 and 4 patients receiving IFN1 had dose reductions (P = .002). There was a significant deterioration in QOL and an increase in depression associated with IFN5 but no change was noted with IFN1. CONCLUSIONS: Compared with IFN5, IFN1 is neither more nor less effective but is less toxic, with a better reported QOL. These results may have implications for the design of combination regimens incorporating IFN with targeted agents.

Adult↗
PubMed1990

Specific high-affinity receptors for interferon-gamma on mouse bone marrow-derived mast cells: inhibitory effect of interferon-gamma on mast cell precursors.

Cultured mast cells derived from murine bone marrow were investigated for the presence of specific interferon-gamma (IFN-gamma) receptors, and for the effects of IFN-gamma on mast cell proliferation. 125I-labeled recombinant IFN-gamma (125I-Mu-rIFN-gamma) was shown to bind to high-affinity receptors on these cells. Scatchard analysis of binding data indicated the presence of about 500 homogeneous binding sites per cell, with an apparent equilibrium dissociation constant of 3 X 10(-10) M. The binding of 125I-Mu-rIFN-gamma to mast cells was inhibited by unlabeled Mu-rIFN-gamma but not by unlabeled Mu-IFN-alpha/beta. Cross-linking of 125I-Mu-rIFN-gamma to mast cell membrane proteins using a cross-linking agent yielded a predominant complex of 100 +/- 10 kDa on sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography which most likely represents the IFN-gamma-receptor complex. To assess the biological significance of these receptors, we studied the effects of Mu-rIFN-gamma on mast cell proliferation, which was markedly inhibited in mast cell precursors but not in mature mast cells. These in vitro results are in agreement with the antiproliferative effect of IFN-gamma previously reported for other hematopoietic progenitors, and suggest that IFN-gamma could find its application in the treatment of human systemic mastocytosis.

Animals↗
PubMed1990

Cell and type specificity of interferon action. Unusual characteristics of the transcriptional control of gene expression by interferon-gamma in T cells.

We have examined the mechanisms by which interferon (IFN)-gamma and IFN-alpha regulate the expression of 2'-5'-oligoadenylate synthetase (2-5A synthetase) and class I major histocompatibility complex antigens in murine T cells and in cell types of other histological origin. When treated with IFN-alpha both fibroblasts and T cell lines displayed a marked increase of the 2-5A synthetase activity and of the corresponding mRNA. The augmentation of the enzyme activity in T cells was induced by IFN-alpha at the transcriptional level, as determined by nuclear run-on analysis. In contrast IFN-gamma was capable of increasing 2-5A synthetase activity only in fibroblasts, but not in T cells. Nuclear run-on assays revealed that the 2-5A synthetase gene in T cells is not transcriptionally activated by IFN-gamma. After IFN-alpha and -gamma treatment we also observed a significant increase in class I gene expression in fibroblasts and T cell lines as measured both on the cell surface and by cytoplasmic RNA accumulation. In the case of the T cell line, DO1110, the observed increase in the steady-state levels of class I transcripts was a consequence of a high rate of H-2 gene transcription as demonstrated by run-on analysis. However, the molecular mechanisms involved in this IFN-dependent H-2 gene transcriptional activation are different between IFN-alpha and IFN-gamma. When the T cell lines DO1110, L12-R4 and EL4 were transfected with a plasmid containing a reporter gene (chloramphenicol acetyltransferase) under the control of a regulatory IFN-responsive DNA element of 237 bp or 1.4 kb, IFN-alpha was able to activate the transcription of these constructs. In contrast, IFN-gamma did not recognize the IFN-responsive element which, by itself, activated transcription of the reporter gene in response to IFN-gamma in other cellular types of non-T cell origin. Therefore, in the T cell lines examined, IFN-gamma increases the H-2 gene expression by acting on DNA elements located upstream of the regulatory segment used in this study or downstream of the cap site. This suggests a possible cell specificity in the activation of an IFN-responsive element, that in turn may regulate the IFN-inducible gene expression in a cell-specific fashion. Thus, the differential biological activities of IFN-gamma on T cells could be generated by a differential gene activation at the transcriptional level.

2',5'-Oligoadenylate Synthetase↗
PubMed1999

Interferon alfa subtypes and levels of type I interferons in the liver and peripheral mononuclear cells in patients with chronic hepatitis C and controls.

Viral infections stimulate the transcription of interferon type I, which includes IFN-alfa (IFN-alpha) (13 subtypes) and IFN-beta (a single substance). Hepatitis C virus (HCV) infection is remarkable by its ability to evade host antiviral defenses; however, there is little information as to whether endogenous IFN is activated or not in this disease. Additionally, despite the fact that the various IFN-alpha subtypes may differ in biological activity, there are no data concerning the IFN-alpha subtypes specifically expressed in normal and diseased liver tissue. Thus, we have analyzed the IFN-alpha subtypes and the mRNA levels of type I IFNs in samples of normal liver tissue and in liver from patients with chronic hepatitis C. Similar studies were performed in peripheral blood mononuclear cells (PBMC) from patients and controls. After amplification and cloning of IFN-alpha cDNA, we observed that 98 of the 100 clones from normal liver tissue corresponded to the IFN-alpha5 subtype. However, in livers with chronic hepatitis C and in PBMC from controls and patients, a variety of subtypes, in addition to IFN-alpha5, were detected, suggesting a participation of infiltrating leukocytes in the production of IFN-alpha in livers with chronic hepatitis C. As compared with controls, patients with chronic hepatitis C showed a significant increase in IFN-beta mRNA in both the liver and PBMC, while IFN-alpha mRNA was significantly increased in PBMC but markedly reduced in liver tissue. In conclusion, IFN-alpha5 is the sole IFN-alpha subtype expressed in normal liver tissue. The hepatic levels of IFN-alpha are reduced in chronic hepatitis C, an event that may favor viral persistence.

Adult↗
PubMed1985

Down-regulation of peripheral blood cell interferon receptors in chronic myelogenous leukemia patients undergoing human interferon (HuIFN alpha) therapy.

Our interest in studying interferon (IFN) receptor activity in peripheral blood cells (PBCs) from patients with chronic myelogenous leukemia (CML) receiving therapeutic doses of partially purified leukocyte IFN (IFN alpha) stems from a need for more adequate monitoring of IFN therapy. The binding of 35S-labelled recombinant DNA-derived leukocyte clone A IFN (35S-rIFN alpha A) to PBCs from 8 patients with CML was determined before and during IFN alpha treatment. The patients' mean pretherapy binding level (0.049 femtomoles of bound 35S-rIFN alpha A) was in the range of values obtained from 4 normal donors (mean of 0.054 femtomoles bound). Within 24 hr of the first IFN alpha dose, the mean femtomoles bound decreased 10-fold and remained low during the course of IFN alpha treatment. In I/I patient, we demonstrated that this decreased binding was due to a loss in number of IFN receptors. The apparent number of receptors after 5 doses of IFN alpha decreased from approximately 600 receptors per cell at pretherapy to approximately 75 receptors per cell, with no difference in the dissociation constants (1.13 X 10(-10)M, 0.968 X 10(-10)M, before and during treatment, respectively). In 4/4 patients, we demonstrated indirectly that the decreased binding was not due to receptor saturation as a result of residual circulating IFN alpha. In 3/3 patients, we demonstrated a gradual recovery of binding capacity after incubating the patients' PBCs at 37 degrees C. Within 2-7 days in vivo recovery of binding, comparable to pretherapy levels, was observed in 3/3 patients whose IFN alpha therapy was discontinued. Combining all these data, we conclude that in both responding and nonresponding patients with CML, IFN alpha exposure induces decreased binding of labelled IFN when a single recombinant DNA-derived IFN species is used. We feel the supporting data indicate that the decreased binding capacity may be due to receptor down-regulation. In the limited number of patients studied thus far, there was no correlation between clinical hematologic response and occurrence of down-regulation, however, down-regulation of cell surface receptors may be required to sustain a biological effect. Further studies of both the kinetics of down-regulation and activation of key enzyme systems are required to fully evaluate the relevance of these findings.

Blood Cells↗
PubMed1988

Correlation of immunomodulatory and therapeutic activities of interferon and interferon inducers in metastatic disease.

The mechanism of therapeutic activity of recombinant murine interferon-gamma (rMu IFN-gamma) and the IFN inducer polyinosinic-polycytidylic acid solubilized with poly-L-lysine in carboxy methyl cellulose (pICLC) in treating metastatic disease was investigated by comparing effector cell augmentation with therapeutic activity in mice bearing experimental lung metastases (B16-BL6 melanoma). Effector cell functions in spleen, peripheral blood, and lung (the organ with tumor) were tested after 1 and 3 weeks of rMu IFN-gamma or pICLC administration (intravenous, three times a week). In these studies, natural killer (NK), lymphokine-activated killer (LAK), cytolytic T lymphocytes (CTL) (against specific and nonspecific targets), and macrophage tumoricidal and tumoristatic activities were measured. rM IFN-gamma and pICLC had therapeutic activity and immunomodulatory activity in most assays of immune function examined. Specific CTL activity of pulmonary parenchymal mononuclear cells (PPMC), but not in splenocytes or peripheral blood lymphocytes (PBL), during week 3 and not during week 1, correlated with the therapeutic activity of rMu IFN-gamma and of pICLC. Macrophage tumoricidal activity in PPMC, but not in alveolar macrophages, also correlated with the therapeutic activity of rMu IFN-gamma, but the opposite was true for the therapeutic activity of pICLC. NK activity of PPMC, but not of splenocytes or PBL, during week 1 correlated with the therapeutic activity of pICLC; in contrast, NK activity at any site did not correlate with the therapeutic activity of rMu IFN-gamma. LAK activity at any site did not correlate with the therapeutic activity of either agent.

Animals↗
PubMed1986

Pretreatment of human lymphocytes with interferon enhances the synthesis of interferon in cocultures with allogeneic cells.

Human lymphocytes pretreated with interferon (IFN) alpha, beta, or gamma produced 17 times more IFN alpha (600-10,000 units/ml) than nontreated lymphocytes when cocultivated with allogeneic cells. Significant increases in IFN production (500-3,000 units/ml) were observed when lymphocytes were treated with IFN for just 2 h, and peak levels (10,000 units/ml) were produced after a 4-h treatment. The amount of IFN required to show the maximum priming effect was between 100 and 1,000 units; higher levels of IFN were inhibitory. The levels of IFN increased as the lymphocyte-to-target-cell ratio increased from 2:1 to 10:1 and decreased at higher ratios. The decrease in IFN production at higher ratios of lymphocytes to target cells could not be attributed to the presence of a soluble suppressor substance. The additional IFN found in supernates was attributed to enhanced production of IFN by the same cells, rather than recruitment of more cells to produce IFN. This conclusion is based on the fact that no increase in the number of cells staining positive for IFN production was observed in primed lymphocytes. The increased amount of IFN due to priming enhanced both nonsensitized cytotoxic activity and the transfer of antiviral activity, which could be prevented by antibody to IFN. The data suggest that priming may be an important biological mechanism for obtaining significant levels of IFN more rapidly in the vicinity of transformed cells or virus-infected tissues.

Cells, Cultured↗
PubMed1989

Induction of proteins in interferon-alpha- and interferon-gamma-treated polymorphonuclear leukocytes.

Interferon-gamma (IFN-gamma) treatment of polymorphonuclear leukocytes (PMNs) results in an activation of their functions. Studying the IFN responsiveness of PMNs and using antibodies to the IFN-induced proteins, we have observed the ability of IFN-alpha to stimulate the production of the IFN-induced 67,000 and 56,000 dalton proteins and the ability of IFN-gamma to induce the synthesis of the 67,000, 56,000, and 42,000 dalton proteins. The induction of these proteins is dependent on de novo RNA synthesis, as its induction is inhibited if the IFNs and actinomycin D are added to the cells simultaneously. The results of this study confirm the ability of PMNs to carry out gene activation and demonstrate the ability of PMNs to respond to both IFN-alpha and IFN-gamma.

Adaptor Proteins, Signal Transducing↗
PubMed1989

Gamma interferon induces monocyte killing of Listeria monocytogenes by an oxygen-dependent pathway; alpha- or beta-interferons by oxygen-independent pathways.

Human peripheral blood monocytes purified by counterflow centrifugal elutriation were treated with recombinant interferons-gamma (IFN-gamma), alpha (IFN-alpha), or beta (IFN-beta)--and tested for their capacity to kill Listeria monocytogenes. All three IFNs increased the monocyte bactericidal activity in a dose-dependent fashion. Exogeneous catalase, an inhibitor of monocyte-generated hydrogen peroxide, did not affect bactericidal activity. However, exogenous superoxide dismutase inhibited killing by IFN-gamma-activated monocytes, but not by IFN-alpha- or IFN-beta-activated monocytes. By contrast, exogenous soybean trypsin inhibitor inhibited killing by IFN-alpha or IFN-beta-activated monocytes, but not by IFN-gamma-activated monocytes. Combinations of IFN-gamma and IFN-alpha resulted in no increase in bactericidal activity. Finally, treatment with IFN-gamma resulted in different receptiveness of the cell to subsequent oxidative burst-stimulating signals than did treatment with either IFN-alpha or IFN-beta. These results suggest that monocytes treated with IFN-gamma kill L. monocytogenes by an oxygen-dependent mechanism, but treatment with IFN-alpha or IFN-beta elicits principally oxygen-independent mechanisms.

Blood Bactericidal Activity↗
PubMed2003

Synergistic antiviral effect of a combination of mouse interferon-alpha and interferon-gamma on mouse hepatitis virus.

Although interferon (IFN)-alpha and IFN-gamma have been reported to exhibit a synergistic antiviral effect through the different signaling pathways in vitro, their therapeutic efficacy is not well defined in vivo. The current study was carried out to investigate the combined antiviral effect in a model of mouse hepatitis virus Type 2 (MHV-2) infection, in which fulminant hepatitis is developed. MHV-2 was injected intraperitoneally into 4-week-old ICR mice, IFN or the vehicle was administered intramuscularly for 5 days, and the antiviral effect was evaluated based on survival periods, liver histology, serum alanine transaminase (ALT) levels, and MHV-2 virus titers in the liver tissues. The animals in the group treated with a combination of IFN-alpha and IFN-gamma survived for longer periods than the groups treated with IFN-alpha alone and IFN-gamma alone (IFN-alpha 10(3) (IU/mouse)/-gamma 10(3) vs. IFN-alpha 10(3), P < 0.005; IFN-alpha 10(3)/-gamma 10(3) vs. IFN-gamma 10(3), P < 0.001). This is consistent with the lower levels of hepatocellular necrosis and serum ALT and the decreased titers of MHV-2 virus in the liver tissues (48 hr, P < 0.001; 72 hr, P < 0.001). These findings indicate that a combination of IFN-alpha and IFN-gamma exhibits a synergistic antiviral effect on MHV-2 infection. The biology of MHV-2 is quite different from that of human hepatitis viruses; however, these results suggest the beneficial combined therapy of IFN-alpha and IFN-gamma for the treatment of human viral hepatitis.

Animals↗
PubMed1985

Production of interferon alpha and interferon gamma by peripheral blood leukocytes from patients with chronic hepatitis B virus infection.

Peripheral blood leukocytes from patients with chronic hepatitis B virus (HBV) infection were studied for their capacity to produce interferon (IFN) alpha or IFN gamma. Yields of IFN alpha in leukocyte cultures stimulated with influenza A virus or human leukemic cells were significantly lower than those obtained from healthy controls. Production of IFN gamma in response to induction with protein A of Staphylococcus aureus was also significantly diminished. Defects of IFN production in leukocyte cultures showed no correlation with active viral replication or the degree of severity of HBV-associated liver disease. The demonstration of partial defects of endogenous IFN production provides a rationale for using IFN replacement therapy in patients with chronic HBV infection.

Adolescent↗
PubMed2005

Early viral kinetics and treatment outcome in combination of high-dose interferon induction vs. pegylated interferon plus ribavirin for naive patients infected with hepatitis C virus of genotype 1b and high viral load.

An investigation was carried out to determine whether early viral monitoring could predict efficiently the virological response to combination therapy of two different regimens in treatment-naive chronic hepatitis C patients infected with genotype 1b with high baseline viral load. Patients were randomly assigned to receive interferon (IFN) alpha-2b induction (6 MU daily for 2 weeks) followed by 6 MU thrice weekly for 46 weeks (IFN/R group; n = 20), or pegylated IFN alpha-2b (1.5 microg/kg) weekly for 48 weeks (PEG/R group; n = 28), in combination with ribavirin (600-1,000 mg daily). Serum HCV RNA was quantitated at 0, 6, 12, 24, and 48 hr post-dose, weekly during the first 4 weeks, and thereafter viral kinetics were assessed every 4 weeks. The sustained virological response rates in the IFN/R and PEG/R groups were 40% (8/20) and 43% (12/28), respectively. The non-virological response rates were 40% (8/20) and 39% (11/28), respectively. The cumulative virological response rates were similar in both groups. Multivariate analyses identified no independent baseline variables linked to sustained virological or non-virological response. Early log viral load changes from baseline in both groups were significantly greater at all time-points after 24 hr in virological response patients than in non-virological response patients (P < 0.001 for all). On the receiver operating characteristics curves for prediction of non-virological response, the area under the curves (0.951-1.000), sensitivity (90%-100%), and negative predictive value (96%- 100%) were similar at any time-points after 24 hr. For prediction of sustained virological response, sensitivity of 80% with 86% negative predictive value was observed for negative HCV RNA at week 12, with the highest area under the curves value of 0.919. The results suggest that early monitoring of viral kinetics is a useful measure to predict virological response, and might facilitate development of rational and effective therapeutic strategies.

Adult↗
PubMed1993

Interleukin-2 production by T cells: a study of the immunoregulatory actions of interferon-alpha, interferon-gamma, and tumor necrosis factor-alpha in phenotypically different T cell clones.

The production of interleukin 2 (IL-2) by phytohemagglutinin (PHA)-stimulated human leukemia T cell lines MOLT-13 and MOLT-14, the T cell receptor (TcR) gamma delta-bearing clones, was significantly increased by adding human natural interferon-gamma (IFN-gamma) to the cell cultures. In addition, the IL-2 production by PHA-stimulated MOLT-13 and MOLT-14 cells was also augmented by human natural tumor necrosis factor-alpha (TNF-alpha) in a dose-dependent manner but was inhibited by IFN-alpha even at low concentrations (10 IU/ml). This pattern of reactivity is different from the responsiveness of the MOLT-16 cells, a TcR alpha beta-bearing cell line, which respond to IFN-alpha and TNF-alpha, but not to IFN-gamma, by augmentation of IL-2 production. These results suggest that (1) the addition of IFN-gamma has a direct effect on PHA-stimulated MOLT-13 and MOLT-14, resulting in an augmentation of IL-2 production; (2) phenotypically different T cell lines vary in their susceptibility to IFN-alpha and IFN-gamma regulation; and (3) the augmentation of IL-2 production by TNF-alpha appears to have no correlation with phenotypically different T cell clones.

Clone Cells↗
PubMed1997

Evidence for induction of interferon-alpha and interferon-beta in retinal glial cells of Müller.

Studies were performed to determine if retinal glial cells of Müller transcribe the genes for interferon-alpha (IFNalpha) or IFNbeta upon exposure to virus. Responses to herpes simplex virus type 1 (HSV-1) were tested with cultured murine Müller cells and, in vivo, with retinas obtained after bilateral injection of either HSV-1 or buffer into the anterior chamber of the eyes of BALB/c mice. Induction of IFN transcription and relative temporal changes in transcript levels occurred over time after either in vitro or in vivo exposure to HSV-1. Transcription of both IFN genes was induced in cultured glia within 1 hr after exposure to virus. IFN transcripts were detected in retinas by 24 hr postinfection and these were maximal at 3 days. By in situ hybridization (ISH), IFNalpha2 mRNA localized to focal areas in the intact retinas of virus-injected eyes and was consistent with our previous report of a transient, focal appearance of viral antigens in those retinas. Uninfected cells and ocular tissues were negative for IFN transcripts. Combined ISH and immunohistochemistry on retinal impression smears confirmed that glial fibrillary acidic protein-positive Müller cells are an intraretinal source of IFNalpha and IFNbeta transcripts after ocular exposure to HSV-1. Our results support a role for Muller cells as participants in intraretinal antiviral or immunomodulatory responses via type 1 IFN production and may have implications for future therapeutic interventions.

Animals↗
PubMed2002

Recovery of paramyxovirus simian virus 5 with a V protein lacking the conserved cysteine-rich domain: the multifunctional V protein blocks both interferon-beta induction and interferon signaling.

The V protein of the Paramyxovirus simian virus 5 (SV5) is a multifunctional protein containing an N-terminal 164 residue domain that is shared with the P protein and a distinct C-terminal domain that is cysteine-rich and which is highly conserved among Paramyxoviruses. We report the recovery from Vero cells [interferon (IFN) nonproducing cells] of a recombinant SV5 (rSV5) that lacks the V protein C-terminal specific domain (rSV5VDeltaC). In Vero cells rSV5VDeltaC forms large plaques and grows at a rate and titer similar to those of rSV5. In BHK or CV-1 cells rSV5VDeltaC forms small plaques and grows poorly. However, even when grown in Vero cells rSV5VDeltaC reverts to pseudo-wild-type virus in four to five passages, indicating the importance of the V protein for successful replication of SV5. Whereas rSV5 grows in many cell types with minimal cytopathic effect (CPE), rSV5VDeltaC causes extensive CPE in the same cell types. To overcome the antiviral state induced by IFN, many viruses have evolved mechanisms to counteract the effects of IFN by blocking the production of IFN and abrogating IFN signaling. Whereas rSV5 blocks IFN signaling by mediating the degradation of STAT1, rSV5VDeltaC does not cause the degradation of STAT1 and IFN signaling occurs through formation of the ISGF3 transcription complex. Furthermore, we find that rSV5 infection of cells prevents production of IFN-beta. The transcription factor IRF-3 which is required for transcription of the IFN-beta gene is not translocated from the cytoplasm to the nucleus in rSV5-infected cells. In contrast, in rSV5VDeltaC-infected cells IRF-3 is localized predominantly in the nucleus and IFN-beta is produced. By using ectopic expression of IRF-3, it was shown that after dsRNA treatment and expression of the V protein IRF-3 remained in the cytoplasm, whereas after dsRNA treatment and expression of the P protein (which lacks the C-terminal cysteine-rich domain) IRF-3 was localized predominantly in the nucleus. Thus, SV5 blocks two distinct pathways of the innate immune response, both of which require the presence of the C-terminal specific cysteine-rich domain of the multifunctional SV5 V protein.

Amino Acid Sequence↗
PubMed1988

Serum interferon activity in inflammatory bowel disease. Arachidonic acid release and lipoxygenation activated by alpha-class interferon in human neutrophils.

Serum interferon (IFN) of alpha-class was studied in 64 consecutive patients, 26 with Crohn's disease, 38 with ulcerative colitis, and in 34 healthy volunteers. Detectable IFN-alpha in 10 patients was associated with a moderate to severe activity of chronic inflammatory bowel disease (CIBD). However, 19 of 28 patients (68%) with activity in their disease did not have elevated IFN-alpha levels. The three groups, ulcerative colitis, Crohn's disease, and healthy volunteers did not reveal any statistically significant difference in serum IFN-alpha, as four of 34 healthy controls without intercurrent infections had elevated levels as well. Possible effects of alpha, beta, and gamma classes of IFN on endogenous arachidonic acid (AA) release and metabolism in human neutrophils was investigated in a substudy. IFN-alpha caused a dose-dependent release of AA from phospholipids and metabolism of a modest fraction of leukotriene B4 (LTB4) and 5-hydroxyeicosatetraenoic acid (5-HETE) at doses reaching a maximum of 100 IU/ml. IFN of the beta and gamma classes did not exert such effects. Addition of complement 5a to cells activated by IFN-alpha caused induction of increased 5-lipoxygenase activity with unchanged release of AA. As only 16% of all CIBD patients had elevated IFN-alpha levels as compared to 12% among the group of healthy volunteers, IFN-alpha does not seem to be of importance for the perpetuation of the inflammatory reaction in ulcerative colitis or Crohn's disease, and other factors may therefore be responsible for activation of the inflammatory cells to production of LTB4 and 5-HETE.

Adult↗