scispace - formally typeset
Search or ask a question

Showing papers on "Interferon published in 1976"


Journal ArticleDOI
TL;DR: Parenteral interferon therapy was associated with a rapid and reproducible fall in all Dane-particle markers in four patients with chronic hepatitis B infection and chronic active hepatitis and may be useful in limiting carrier infectivity or eradicating chronic infection.
Abstract: Four patients with chronic hepatitis B infection and chronic active hepatitis were treated with human leukocyte interferon. Three of them had consistently elevated levels of circulating Dane-particle markers, including Dane-particle-associated DNA polymerase activity, hepatitis B core antigen and Dane-particle-associated DNA. Parenteral interferon administration at a dosage between 6.0 X 10(3) and 17 X 10(4) U per kilogram per day was associated with a rapid and reproducible fall in all Dane-particle markers in the three patients. The suppressive effect was transient when the interferon was given for 10 days or less but appeared to be more permanent when administration was prolonged for a month or more. In addition, long-term interferon therapy was associated with a marked fall in hepatitis B surface antigen in two of three patients and a disappearance of e antigen in two of two patients. Interferon may be useful in limiting carrier infectivity or eradicating chronic infection.

482 citations


Journal ArticleDOI
02 Dec 1976-Nature
TL;DR: The presence of a dsRNA-dependent protein kinase activity in interferon cell sap is reported, which does not correspond either to the major polypeptide product of theinterferon-dsRNA specific phosphorylation, or, presumably, to phosphorylated IF-E2.
Abstract: PROTEIN synthesis in cell-free systems from mouse L-cells pretreated with the antiviral agent interferon1 shows an enhanced sensitivity to inhibition by double-stranded RNA (dsRNA)2,3. The possible significance of this with respect to events in intact interferon-treated virus-infected cells has already been discussed2,4. We have already shown that the addition of small amounts of a post-ribosomal supernatant fraction from interferon-treated cells (interferon cell sap) renders protein synthesis in control cell-free systems sensitive to inhibition by dsRNA4. Our results are in accord with a two-step model involving an initial 100-fold activation of an inhibitor on incubation of the interferon cell sap with ATP and dsRNA (activation step), the activated inhibitor then interacting with the protein-synthetic system to inhibit translation (inhibitory step)5. In view of the dependence of the inhibition of protein synthesis upon incubation with ATP as well as dsRNA5 it was of interest to determine if a protein kinase(s) is involved, as seems to be the case in reticulocyte lysates in which phosphorylation of the initiator Met-tRNA binding factor (IF-E2) has been implicated following incubation of the lysates under a variety of inhibitory conditions including the presence of dsRNA (P. Farrell, K. Balkow, T. Hunt and R. J. Jackson, personal communication)6. In accord with this, we report here the presence of a dsRNA-dependent protein kinase activity in interferon cell sap. The inhibitor of protein synthesis which is activated on incubation of interferon cell sap with ATP and dsRNA, however, is heat stable and of relatively low molecular weight. It does not correspond either to the major polypeptide product of the interferon-dsRNA specific phosphorylation, or, presumably, to phosphorylated IF-E2.

409 citations


Journal ArticleDOI
B. Lebleu1, G. C. Sen1, S. Shaila1, B. Cabrer, Peter Lengyel 
TL;DR: The addition of double-stranded RNA to an extract from Ehrlich ascites tumor cells which have been treated with an interferon preparation promotes the phosphorylation by [gamma-32P]ATP of at least two proteins: P1 and P2.
Abstract: We reported earlier that the addition of double-stranded RNA and ATP increases the endonuclease activity more in an extract of Ehrlich ascites tumor cells which have been treated with an interferon preparation than in a comparable extract from control cells. We report here that the addition of double-stranded RNA to an extract from Ehrlich ascites tumor cells which have been treated with an interferon preparation [or with the interferon inducer poly(I)-poly(C)] promotes the phosphorylation by [gamma-32P]ATP of at least two proteins: P1 (molecular weight of 64,000) and P2 (molecular weight of 37,000). Double-stranded RNA also promotes the phosphorylation of at least one (i.e., P1) of these two proteins in an extract from cells which have not been treated with interferon, but the extent of phosphorylation is much smaller. Double-stranded RNA which has been degraded by RNase III, or DNA, does not promote the phosphorylation.

288 citations


Journal ArticleDOI
TL;DR: The role of interferon in the pathogenesis of encephalomyocarditis (EMC) virus infection was determined by treating mice with potent, partially purified sheep anti-mouse Interferon globulin this paper.
Abstract: The role of interferon in the pathogenesis of encephalomyocarditis (EMC) virus infection was determined by treating mice with potent, partially purified sheep anti-mouse interferon globulin. In control mice, EMC virus was present in low titers in various visceral organs but attained high titers in the brain towards the 4th to 5th day, at which time mice died with signs of central nervous system disease. In mice treated with anti-mouse interferon globulin, virus was present in high titer in visceral organs 24--36 h after viral inoculation and virtually all mice were dead by 45 h. This rapid evolution of EMC virus infection was not observed in mice treated with the globulin fraction prepared from a normal sheep, from a sheep exhibiting a low anti-mouse interferon-neutralizing titer, nor from a sheep having a high titer of antibody to human leukocyte interferon. The experimental results indicated that anti-interferon globulin neutralized the interferon liberated by virus-infected cells, thus permitting extensive virus multiplication in several visceral organs. We conclude that interferon is an important early component of host resistance to this virus infection.

254 citations


Journal ArticleDOI
TL;DR: It is concluded that the early production of interferon is an importane element in the response of the mouse to several viruses exhibiting different pathogeneses.
Abstract: The effect of potent sheep anti-mouse interferon globulin was investigated in several different experimental virus diseases of mice In anti-interferon globulin-treated mice infected intraperitoneally with herpes simplex virus (HSV) type I, the latent period was shortened, and the overall LD50 was increased several hundredfold compared to virus-infected control mice When HSV was inoculated subcutaneously all anti-interferon globulin-treated mice died, whereas only 5% of virus-infected control mice died Subsequent treatment with anti-interferon globulin of previously HSV-infected mice did not result in reactivation of HSV Treatment of adult mice with anti-interferon globulin resulted in an earlier appearance of MSV-induced tumors, a greater number of mice bearing tumors, an increase in tumor size, and an increase in the duration of tumors All tumors eventually regressed despite reinjection of anti-interferon globulin Anti-interferon globulin treatment resulted in a rapid onset of disease and death in adult mice inoculated (intranasal) with VSV and in newborn mice infected with NDV Anti-interferon globulin exerted no effect on the course of influenza virus infection of mice We conclude that the early production of interferon is an importane element in the response of the mouse to several viruses exhibiting different pathogeneses

242 citations


Journal ArticleDOI
TL;DR: It is shown that in the subcellular fraction which contains the interferoninduced inhibitor(s) of translation, there is strong inhibition of polypeptide chains in the form of protein phosphorylation.

215 citations


Journal ArticleDOI
TL;DR: The results suggest that the depression of hepatic cytochrome P-450-dependent monooxygenase systems may be a general property of interferon inducing agents.

191 citations


Journal ArticleDOI
TL;DR: No patients experienced an objective tumor response to the administration of poly I - poly C, and most (76%) had progression of their disease while receiving the drug, and the correlation between drug dose and peak interferon titer was not linear.
Abstract: Polyriboinosinic-polyribocytidylic acid (poly I - poly C), an interferon inducer, was administered in multiple doses of 0.3-75 mg/m2 to 26 patients with a variety of solid tumors, 9 with acute leukemia, and 2 with chronic myelogenous leukemia in blast crisis. Forty-four separate drug trials were comprised of various schedules and routes of administration. Toxic reactions included fever (in 66% of the trials), transient elevation of serum glutamic-oxaloacetic transaminase and serum glutamic-pyruvic transaminase (25%), minimal laboratory evidence of coagulation abnormalities (59%), and hypersensitivity (5%). These toxic manifestations did not relate to dose level or magnitude of interferon induction. Poly I - poly C administered iv induced low serum concentrations of interferon in 24/38 trials (63%), but the correlation between drug dose and peak interferon titer was not linear. Poly I - poly C administered iv or im was not effective as an inducer of interferon in the cerebrospinal fluid. Similarly, poly I - poly C administered im or by inhalation did not produce detectable serum levels of interferon. No patients experienced an objective tumor response to the administration of poly I - poly C, and most (76%) had progression of their disease while receiving the drug.

188 citations


Journal ArticleDOI
TL;DR: Oxidation of this polypeptide with periodic acid and subsequent staining with Fuchsin base indicates that it contains carbohydrate ans suggests that the human fibroblast interferon is a glycoprotein.
Abstract: Interferon produced by human diploid fibroblast cells in culture has been purified approximately 5000-fold. The purified interferon, when analyzed by electrophoresis on polyacrylamide gel containing sodium dodecyl sulfate, contains only one polypeptide component of 20,000 molecular weight. The interferon activity comigrates with this polypeptide, indicating identity of the activity and the polypeptide. Oxidation of this polypeptide with periodic acid and subsequent staining with Fuchsin base indicates that it contains carbohydrate ans suggests that the human fibroblast interferon is a glycoprotein.

163 citations


Journal Article
TL;DR: It is suggested that lymphokines, apart from their normal mediator function, may play a role as regulators of the generating immune response.
Abstract: Purified human lymphocyte interferon (PIF) was added to mixed lymphocyte cultures; DNA synthesis was measured and killer-cell generation was determined. At certain concentrations, PIF ingibited proliferation, but at the same time increased the killer efficiency of the resultant culture cells. It is suggested that lymphokines, apart from their normal mediator function, may play a role as regulators of the generating immune response.

152 citations


Journal ArticleDOI
TL;DR: Treatment of young and mature mice with potent mouse interferon preparations results in a marked enhancement of the expression of histocompatibility antigens on the surface of thymocytes and splenic lymphocytes as measured by an enhanced absorption of alloantiserum, postulate that such modifications of the cell surface may reflect an effect of interferons on lymphocyte maturation.
Abstract: Treatment of young and mature mice with potent mouse interferon preparations results in a marked enhancement of the expression of histocompatibility antigens on the surface of thymocytes and splenic lymphocytes as measured by an enhanced absorption of alloantiserum. We postulate that such modifications of the cell surface may reflect an effect of interferon on lymphocyte maturation and may be relevant to the effect of interferon on lymphocyte function.

Journal ArticleDOI
15 Jul 1976-Virology
TL;DR: The results indicate an interaction between gangliosides and several types of interferon and suggest a role for membrane ganglioides in the antiviral action of Interferon.

Journal ArticleDOI
01 Apr 1976-Virology
TL;DR: Results indicate that unlike its effect on the majority of viruses, interferon does not inhibit MLV by a general inhibition of viral protein synthesis; rather, it appears to inhibit one or more of the later steps in MLV replication which occur after the expression of viral gs antigen.

Journal ArticleDOI
TL;DR: The main differnce observed after treatment was a depression of the nucleocapsid hepatitis-0 core antigen in the liver, indicating that hepatitis-B virus infection is sensitive to interferon.

Journal ArticleDOI
22 Jul 1976-Nature
TL;DR: It is provided strong evidence that the antiviral and CMI activities of interferon preparations are indeed intrinsic properties of the covalent structure ofinterferons.
Abstract: Identification of the cell multiplication inhibitory factors in interferon preparations as interferons

Journal ArticleDOI
11 Mar 1976-Nature
TL;DR: The experiments indicate that chromosome 21 codes for a cell-surface component required as a specific receptor for human interferon, and these inhibit the response of live human cells to interferons.
Abstract: ANTICELLULAR sera able to block specific cell responses are important in the study of surface receptors. Particularly useful are antibodies against the human cellular antigens coded for by a specific chromosome, which can be prepared by immunising mice with mouse–human somatic cell hybrids containing defined human chromosomes1. We have applied this method to the study of the mechanism by which the presence of human chromosome 21 renders such hybrids sensitive to human interferon2. Interaction of an interferon with sensitive cells induces intracellular biochemical changes, including the formation of an inhibitor of protein synthesis, making the cell unable to support virus replication3,4. We have obtained antibodies to hybrid cells containing human chromosome 21, and these inhibit the response of live human cells to interferon. Our experiments indicate that chromosome 21 codes for a cell-surface component required as a specific receptor for human interferon.

Journal ArticleDOI
G. E. Brown1, B. Lebleu1, M. Kawakita1, S. Shaila1, G. C. Sen1, Peter Lengyel1 
TL;DR: Reovirus messenger RNAs are degraded faster in crude extracts from mouse Ehrlich ascites tumor cells which have been treated with either a partially purified interferon preparation or the interferons inducer poly(I)·poly(C) than in corresponding extracts from untreated cells.

Journal ArticleDOI
TL;DR: It is concluded that despite their physical and antigenic differences, the antiviral expressions of both classical and immune interferons are ultimately mediated by the same genetic locus, AVG.
Abstract: The responses of normal fibroblasts and of fibroblasts trisomic and monosomic for chromosome 21 to exogenously administered virus-induced (classical) and phytohemagglutinin-induced (immune) human interferon were determined. The virus-induced interferon was obtained from leukocytes treated with Sendai virus and from neonatal foreskin fibroblasts treated with Newcastle disease virus. With both classical and immune interferons, the mean response of the trisomic cell lines was three times that of the normal cells, whereas that of the monosomic lines was half or less that of the normal cells, Furthermore, a line trisomic for only the distal half of the long arm of chromosome 21 (q21 leads to qter) also demonstrated increased sensitivity to virus- and phytohemagglutinin-induced interferons, a fact that indicated that the gene responsible for the antiviral effect of interferon, AVG, is located on this part of chromosome 21. Responses to the two categories of interferon (virus-induced and phytohemagglutinin-induced) of individual cell lines of different degrees of sensitivity were strongly correlated (r=0.79). It is concluded, therefore, that despite their physical and antigenic differences, the antiviral expressions of both classical and immune interferons are ultimately mediated by the same genetic locus, AVG.

Journal ArticleDOI
19 Feb 1976-Nature
TL;DR: This work has shown that cells stimulated to produce interferon fail to become antiviral in the presence of ouabain, and this conclusion has been drawn from experiments with ouABain which inhibits the action, but not the production of primateinterferon.
Abstract: RECENT studies have indicated that antiviral action of interferon is triggered by interaction with the cell membrane: Sepharose-bound mouse interferon (IF–Sepharose) retains its antiviral activity, and direct contact with the target cells is necessary to produce the antiviral effect1,2. Cells stimulated by double-stranded polyriboinosinic-polyribocytidylic acid to produce interferon are not protected from viral infection in the presence of interferon antiserum, indicating that interferon acts only after it has left the cells in which it is produced3. The same conclusion has been drawn from experiments with ouabain which inhibits the action, but not the production of primate interferon: cells stimulated to produce interferon fail to become antiviral in the presence of ouabain4.

Journal ArticleDOI
30 Sep 1976-Nature
TL;DR: While investigating the effect of interferon on the growth and development of newborn mice, it was found that daily injection of potent mouse interferons resulted in extensive liver cell degeneration and death between days 8 and 14.
Abstract: IN addition to the well known antiviral action1 interferon preparations exert various biological effects on cells (for references see refs 2 and 3). While investigating the effect of interferon on the growth and development of newborn mice, we found that daily injection of potent mouse interferon preparations resulted in extensive liver cell degeneration and death between days 8 and 14 (ref. 4). When interferon treatment, begun at birth, was stopped between days 6 and 8 of life, liver cell damage appeared to be reversible and most mice recovered. In the ensuing months, several of these mice died and although the liver and other organs appeared normal, the kidneys were pale and the surface was granular. Histological examination revealed a severe glomerulonephritis. We report here an investigation of this phenomenon.

Journal ArticleDOI
Knight E1
22 Jul 1976-Nature
TL;DR: It is shown that both the antiviral and the cell growth inhibitory activity of human fibroblast interferon reside in the same glycoprotein.
Abstract: IT has been shown repeatedly that preparations of mouse interferon inhibit the growth of mouse cells in vitro1–4 In addition to inducing the antiviral state and inhibiting cell growth, preparations of mouse interferon stimulate interferon production by priming5, enhance phagocytic activity6, and potentiate in cells the toxic effect of double-strand ed RNA7. All attempts with preparations of mouse interferon to separate the antiviral activity from the non-antiviral activities have been unsuccessful3,5,8. With human interferon few experiments have been reported, although the data available indicate inhibition of growth by preparations of human leukocyte interferon9–11. It has been claimed that the antiviral and cell growth inhibitory activities of human leukocyte interferon reside in different molecules and can be separated from each other by certain methods of fractionation12. In a more recent report13, however, separation of the two activities could not be demonstrated even in drastic denaturing conditions. I have shown that both the antiviral and the cell growth inhibitory activity of human fibroblast interferon reside in the same glycoprotein.

Journal ArticleDOI
G. C. Sen1, B. Lebleu1, G. E. Brown1, M. Kawakita1, E Slattery1, Peter Lengyel1 
25 Nov 1976-Nature
TL;DR: Characteristics of the faster degradation of reovirus mRNA in S30INT supplemented with dsRNA are described and it is shown that ATP is required, in addition to ds RNA, for the acceleration of mRNA degradation in S 30INT, and this phenomenon can be divided into two phases.
Abstract: INTERFERONS are glycoproteins which are synthesised in various animal cells following viral infection. They are excreted, interact with other cells and inhibit in them the replication of a broad range of viruses1. Extracts from interferon-treated Ehrlich ascites tumour cells (S30INT) differ in various biochemical characteristics from extracts from control cells (S30C) (refs 2–4 and see also refs 5–8). We have reported recently that reovirus messenger RNAs (mRNAs) are degraded faster in reaction mixtures containing S30INT than in those containing S30C, but only if the reaction mixtures are supplemented with double-stranded (ds) RNA9. We have also reported10 that dsRNA promotes the phosphorylation by ATP of at least two proteins in S30INT. Here we describe further characteristics of the faster degradation of reovirus mRNA in S30INT supplemented with dsRNA. ATP is required, in addition to dsRNA, for the acceleration of mRNA degradation in S30INT (ref. 11), and we show that this phenomenon can be divided into two phases. In the first phase (activation) both dsRNA and ATP, but not reovirus mRNA, are required; in the second phase (endonuclease action), in which added reovirus mRNA is degraded, it seems that neither dsRNA nor ATP has to be present.

Journal ArticleDOI
TL;DR: The species specificity of interferons does not appear to reside solely at the point of the initial interaction with their binding sites, and the interferon interaction with cell membranes was temperature-sensitive.
Abstract: Thyrotropin (10 muM) inhibited the antiviral activity of interferon. When added after interferon, thyrotropin (TSH) had no effect on antiviral activity. There was also no inhibition of interferon action in cells washed with medium between incubations with TSH and interferon. 125I-Labeled TSH and 125I-labeled cholera toxin could bind to preparations of mouse L-cell plasma membranes. The binding was specific in that it was prevented by unlabeled thyrotropin or cholera toxin, but not by insulin, glucagon, prolactin, growth hormone, human chorionic gonadotropin, or luteinizing hormone. Mouse interferon inhibited 125I-labeled TSH binding to L-cell plasma membranes. The effect of mouse interferon on 125I-labeled cholera toxon binding was more complex, inhibition occurring only after an initial enhancement at low interferon concentrations. A 10-fold higher concentration of interferon was required to inhibit 125I-labeled TSH binding. Mouse interferon was also able to displace bound 125I-labeled TSH, but not bound 125I-labeled cholera toxin. The interferon interaction with cell membranes was temperature-sensitive. Human interferon could induce changes in binding of 125I-labeled TSH and 125I-labeled cholera toxin to mouse L-cell plasma membranes similar to those induced by mouse interferon. Mouse interferon induced similar changes in plasma membranes of human KB-3 cells, which are insensitive to both human and mouse interferons. In view of these results, the species specificity of interferons does not appear to reside solely at the point of the initial interaction with their binding sites.

Journal ArticleDOI
TL;DR: Human leukocyte and tritium-labeled fibroblast interferons, prepared by induction with Sendai virus and with double-stranded polyinosinic acid respectively, have been studied in relation to the carbohydrate moieties attached to them to reduce the heterogeneous character of interferon.

Journal ArticleDOI
TL;DR: Chimpanzees chronically infected with hepatitis-B virus showed transient changes in several markers of infection when treated with the interferon inducer polyriboinosinic-polyribocytidylic acid-poly-l-lysine carboxymethyl cellulose, and defective (D.N.A.A.-polymerase-negative) Dane particles increased in titre transiently during treatment; these may play a role in the modulation of hepatitis- B virus infection.

Journal Article
TL;DR: Modifications in cell membrane structure can change the response tointerferon; on the other hand, interferon might induce changes in the cell membrane which finally result in an altered response to toxins and, in some instances, in recovery of lost contact inhibition in transformed cells.
Abstract: The cell membrane, in addition to other functions, plays an important role in regulating cell metabolism governed by messenger proteins (or other substances) acting from the outside. The interferon receptor system located in the cell membrane (used as a model) might consist of two components: a binding site and an activator site. As shown by experiments based on competition between interferons for the same receptor, binding is not necessarily followed by activation of the antiviral state. It is possible that polysaccharid residues present in gangliosides play an important role in binding. A critical concentration of interferon molecules in contact with the receptors is needed to induce the antiviral state, which is thus a cooperative process. The activation and probably the amplification of the response require free membrane-bound energy and the integrity of the cytoskeletal components of the cell. Modifications in cell membrane structure can change the response to interferon; on the other hand, interferon might induce changes in the cell membrane which finally result in an altered response to toxins and, in some instances, in recovery of lost contact inhibition in transformed cells.

Journal ArticleDOI
TL;DR: Cholera toxin added together with interferon inhibited the establishment of antiviral activity in mouse L-cells and treatment of cells with the toxin before addition of interferons also inhibited theestablishment of antivirus activity.

Journal ArticleDOI
TL;DR: It was concluded that the complexity of the response of mice to an inducer makes analysis of the role of IF in the ensuing events difficult, but it is very likely that the in vivo effects observed here are to some degree mediated by IF.
Abstract: Previous studies have shown that interferon (IF) preparations enhance phagocytic activity in cultured mouse peritoneal macrophages. It is shown here that cell culture fluids containing large amounts of IF, which had been treated with acid and clarified of the inducer, Newcastle disease virus, enhanced phagocytic activity when injected into mice. Enhanced phagocytic activity also was observed after injection of Newcastle disease virus into mice, but the contribution of IF to this event was unclear. The kinetics of the phagocytic response to inducers in vivo were biphasic. Depression of phagocytosis occurred around 16 to 18 h after injection of Newcastle disease virus. The observed enhancement began about 12 h later and lasted for at least 60 h more. It was concluded that the complexity of the response of mice to an inducer makes analysis of the role of IF in the ensuing events difficult. However, because of documented phagocytosis-enhancing effects of IF in vitro, it is very likely that the in vivo effects observed here are to some degree mediated by IF. On this basis, the concept of the activity of IF as a lymphokine is potentially expanded.

Journal ArticleDOI
01 Sep 1976-Virology
TL;DR: Characterization studies, including the use of mock-interferons, interferons of different sources, and a highly purified preparation, permitted to assign the virus-trapping effect to the interferon molecule rather than to some form of impurity in the preparations.

Journal ArticleDOI
TL;DR: It was shown that at least two antigenically distinct interferons may be involved in suppressing the immune response, and interferon was effective in inhibiting the in vitro PFC response of antigen-primed spleen cells, indicating that it can block the response of memory lymphocytes.