Potent Interferon Inducer Research Articles

Tumor necrosis factor-alpha-induced lung injury and its modulation by synthetic polynucleotide: a physiologic-morphometric analysis.

PolyI:C, a potent interferon (IFN) inducer, protects the isolated perfused lung (IPL) against platelet-activating factor (PAF)-induced injury. Because the release of PAF is stimulated by tumor necrosis factor (TNF), this study was designed to measure the effects of polyI:C on TNF-induced lung inflammation and injury. TNF (2.5 micrograms/kg) was administered to rabbits intravenously as continuous infusion over 2 h. PolyI:C was given intraperitoneally 16 h before TNF infusion. The rabbits were then anesthetized and sacrificed, and the lungs were ventilated with 20% O2 + 5% CO2 and perfused with buffer for 60 min. Lung weight gain was recorded continuously. After perfusion, lungs were inflation fixed for light and electron microscopy with morphometric analysis. Four groups of rabbit lungs were studied: (1) control; (2) polyI:C; (3) TNF, and (4) polyI:C + TNF. Lungs in the TNF group showed increased weight gain (15.4 +/- 2.4 g/h vs. 7.1 +/- 0.5 g/h in controls, p = .02) and increased volume of inflammatory cells (261% of control). These were mostly mononuclear cells (96%), primarily located in the interstitial and alveolar compartments (80%). In the polyI:C + TNF group, the weight gain of the IPL tended to be smaller (8.3 +/- 1.8 g/h, p = .08). Total inflammatory cell volume in the IPL remained elevated (330% of control), but mononuclear cells accounted for only 60% of the cell population. Most of these cells were found in the intravascular compartment (65%) implicating mononuclear cells in the early pathogenesis of TNF-induced pulmonary capillary injury in rabbits. PolyI:C, which attenuates TNF-induced injury, also modulates effects of TNF on mononuclear cell and granulocyte infiltration in the lung.

Interferon treatments: how to use an endogenous system as a therapeutic agent.

Journal of Interferon ResearchVol. 1992, No. special_issue Interferon Treatments: How to Use an Endogenous System as a Therapeutic AgentF. DIANZANIF. DIANZANISearch for more papers by this authorPublished Online:24 Apr 2009https://doi.org/10.1089/jir.1992.1992.109AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail FiguresReferencesRelatedDetailsCited byPlatelet factor 4 promotes rapid replication and propagation of Dengue and Japanese encephalitis virusesEBioMedicine, Vol. 39Complete remission of multiple myeloma after autoimmune hemolytic anemia: Possible association with interferon-α1 January 2007 | American Journal of Hematology, Vol. 82, No. 6DNA Damage Signaling and p53-dependent Senescence after Prolonged β-Interferon StimulationMolecular Biology of the Cell, Vol. 17, No. 4Synthesis and evaluation of 2-substituted 8-hydroxyadenines as potent interferon inducers with improved oral bioavailabilitiesBioorganic & Medicinal Chemistry, Vol. 12, No. 5Prodrugs of 9-Benzyl-8-hydroxy-2-(2-hydroxyethylthio)adenine: Potent Interferon Inducing Agents in MonkeysChemical and Pharmaceutical Bulletin, Vol. 52, No. 4Synthesis and structure–Activity relationships of 2-Amino-8-hydroxyadenines as orally active interferon inducing agentsBioorganic & Medicinal Chemistry, Vol. 11, No. 24Synthesis and structure–activity relationships of 2-substituted-8-hydroxyadenine derivatives as orally available interferon inducers without emetic side effectsBioorganic & Medicinal Chemistry, Vol. 11, No. 17Interferons19 April 2001Russian Experience in Screening, Analysis, and Clinical Application of Novel Interferon Inducers Elina B. Tazulakhova, Olga V. Parshina, Tatiana S. Guseva, and Felix I. Ershov7 July 2004 | Journal of Interferon & Cytokine Research, Vol. 21, No. 2Expression of Interferon-β is Associated with Growth Arrest of Murine and Human Epidermal CellsJournal of Investigative Dermatology, Vol. 112, No. 5Involvement of natural killer cells in endogenous biological retranslationBulletin of Experimental Biology and Medicine, Vol. 126, No. 2Mechanisms of Interferon ActionEffect of Interleukin-12 and Interleukin-10 on the Virus Replication and Apoptosis in T-Cells Infected with Feline Immunodeficiency Virus.Journal of Veterinary Medical Science, Vol. 60, No. 11Interferon antibodies in patients with infectious diseasesBiotherapy, Vol. 10, No. 1A highly sensitive electrochemiluminescence immunoassay for interferon alfa-2b in human serumJournal of Immunological Methods, Vol. 206, No. 1-2Viral Infections: Human Papillomavirus Infections Treated with Immunostimulatory Drugs and Vaccination TherapiesInterferon-betaInterferon antibodies in patients with infectious diseasesLong-acting delivery system of interferon: IFN minipelletJournal of Controlled Release, Vol. 33, No. 2Novel delivery system for proteins using collagen as a carrier material: the minipelletJournal of Controlled Release, Vol. 33, No. 2Immuntherapie der PapillomvirusinfektionenLong-term follow-up of patients with myocarditis and idiopathic dilated cardiomyopathy after immunomodulatory therapyFEMS Immunology & Medical Microbiology, Vol. 10, No. 1Interferon treatment of cutaneous T-cell lymphoma24 April 2009 | European Journal of Haematology, Vol. 51, No. 2 Volume 1992Issue special_issueMay 1992 To cite this article:F. DIANZANI.Interferon Treatments: How to Use an Endogenous System as a Therapeutic Agent.Journal of Interferon Research.May 1992.109-118.http://doi.org/10.1089/jir.1992.1992.109Published in Volume: 1992 Issue special_issue: April 24, 2009PDF download

Recombinant glycoprotein 120 of human immunodeficiency virus is a potent interferon inducer.

Cells infected with human immunodeficiency virus (HIV) induce antiviral activity in peripheral blood mononuclear cells (PBMC) from healthy donors. This activity is neutralized by anti-interferon-alpha antibody and partially destroyed at pH 2. Previous studies with enriched cell populations and monoclonal antibodies suggest that B lymphocytes are the main IFN-producing cells, and that both CD4 and HLA class II antigens are essential for IFN induction. Since the initial event of HIV infection of CD4+ cells is the interaction of the virus coat glycoprotein gp120 with CD4 molecule, we investigated whether gp120 is responsible for IFN induction. Using PBMC and recombinant gp120 obtained from a baculovirus expression system, dose-dependent induction of antiviral activity was observed with titers approaching 10(3) IU/ml. This induction was blocked in the presence of antibody to gp120. The antiviral activity was characterized as IFN-alpha by neutralization with IFN alpha-specific antibody. Preincubation of PBMC with anti-CD4 or the presence of soluble CD4 during incubation inhibited IFN induction, indicating that interaction of gp120 with cell-associated CD4 is responsible for this induction. Neither lymphoproliferation nor interleukin-2 (IL-2) production was observed during IFN induction. However, class G immunoglobulin secretion was enhanced by gp120, indicating that B cells are direct or indirect targets of gp120 stimulation in this experimental system. Since gp120 is shed from HIV-infected cells and occurs in the serum of acquired immunodeficiency syndrome (AIDS) patients, our data suggest that this glycoprotein is responsible for the induction of endogenous IFN and the polyclonal activation of B cells both of which are observed in AIDS patients.

Enhanced wound healing in animal models by interferon and an interferon inducer

Healing of wounds is a significant biological process that involves the interactions of different cell types, growth factors, cytokines, and extracellular matrix molecules. Mice and rats were treated in vivo with interferon (IFN) alpha/beta or polyinosinic-polycytidylic acid (Poly I:C), a ds-RNA, a potent inducer of IFN. We observed faster and enhanced closure of wounds as compared to untreated controls on day 7 (wound area measured on Macintosh II CX using NIH image 1.30u program), increased migration of dermal fibroblasts in the wound bed, complete re-epithelialization evidenced by routine histology and scanning electron microscopic procedures, and increased collagen synthesis, which correlates to greater tensile strength. In addition, classical immunofluorescence procedures using frozen sections showed that dermal fibroblasts synthesized much more laminin following Poly I:C treatment, whereas no effect was observed on fibronectin synthesis. These results suggest that Poly I:C and IFN treatment result in a faster restoration of tissue integrity in both full skin punch biopsy and skin incision models.

Single amino acid changes in the viral glycoprotein M affect induction of alpha interferon by the coronavirus transmissible gastroenteritis virus

Transmissible gastroenteritis virus, an enteropathogenic coronavirus of swine, is a potent inducer of alpha interferon (IFN-alpha) both in vitro and in vivo. Previous studies have shown that virus-infected fixed cells or viral suspensions were able to induce an early and strong IFN-alpha synthesis by naive lymphocytes. Two monoclonal antibodies directed against the viral membrane glycoprotein M (29,000; formerly E1) were found to markedly inhibit virus-induced IFN production, thus assigning to M protein a potential effector role in this phenomenon (B. Charley and H. Laude, J. Virol. 62:8-11, 1988). The present report describes the selection and characterization of a collection of 125 mutant viruses which escaped complement-mediated neutralization by two IFN induction-blocking anti-M protein monoclonal antibodies. Two of these mutants, designated H92 and dm49-4, were found to exhibit a markedly reduced interferogenic activity. IFN synthesis by lymphocytes incubated with purified suspensions of these mutants was 30- to 300-fold lower than that of the parental virus. The transcription of IFN-alpha genes following induction by each mutant was decreased proportionally, as evidenced by Northern (RNA) blot analysis. The sequence of the M gene of 20 complement-mediated neutralization-resistant mutants, including the 2 defective mutants, was determined by direct sequencing of genome RNA. Thirteen distinct amino acid changes were predicted, all located at positions 6 to 22 from the N terminus of the mature M protein and within the putative ectodomain of the molecule. Two substitutions, Thr-17 to Ile and Ser-19 to Pro, were assumed to generate the defective phenotypes of mutants dm49-4 and H92, respectively. The alteration of an Asn-Ser-Thr sequence in dm49-4 virus led to the synthesis of an M protein devoid of a glycan side chain, which suggests a possible involvement of this structure in IFN induction. Overall, these data supported the view that an interferogenic determinant resides in the N-terminal, exposed part of the molecule and provided further evidence for the direct role of M protein in the induction of IFN-alpha by transmissible gastroenteritis virus. The acronym VIP (viral interferogenic protein) is proposed as a designation for this particular class of proteins.

Relationship of the chemical structure and immunobiological activities of lipoteichoic acid fromStreptococcus faecalis(Enterococcus hirae) ATCC 9790

Two molecular species of lipoteichoic acid (LTA 1 and LTA 2) were isolated from whole cells of Streptococcus faecalis (Enterococcus hirae) ATCC 9790 by hydrophobic chromatography on Octyl Sepharose CL-4B. Chemical analysis revealed that LTA 1 and LTA 2 contained two and four acyl lipid anchors respectively. LTA 1 was less active than LTA 2 in inducing cytokines, except interleukin-1 (IL-1), but their in vivo antitumour effects were similar. LTA 2 was a potent inducer of tumour necrosis factor (TNF) and interferon (IFN) production and had excellent antitumour activity against Meth A fibrosarcoma established in mice. Deacylation of LTA 2 by alkaline hydrolysis abolished these biological activities. The phosphatidylglycolipid fraction derived from LTA 2 after acid hydrolysis could also induce TNF, IFN, and IL-1 production, as well as having antitumour activity against Meth A fibrosarcoma. Therefore, the lipid anchor portion of S. faecalis LTA may play an important role in the manifestation of these various biological activities.

A Murine Model of NK Cell Mediated Resorption

There is increasing evidence that some models of immunologically mediated murine embryo demise involve nonspecific lytic effector cells. In this paper, we use two double stranded synthetic RNAs, known as potent interferon inducers and NK cell activators, the Poly (I). Poly (C) and the less toxic Poly (I). Poly (C12U). These polynucleotides enhance fetal resorption rates in both resorption prone and none-resorption prone strains of mice. We have studied the kinetics of the phenomenon, and observed an anti-implantation-like effect of early injection during early pregnancy. The abortifacient effects can be adoptively transferred to naive recipients by spleen cells from Ds RNA injected donors. Such effects are abrogated if the cells are pretreated with anti-NK cell antiserum. The relevance of these findings to the survival of the conceptus is suggested.

Interferon Induction by Viruses. XVIII. Vesicular Stomatitis Virus–New Jersey: A Single Infectious Particle Can Both Induce and Suppress Interferon Production

In contrast to wild-type vesicular stomatitis virus (VSV) of Indiana (Ind.) origin which express interferon (IFN) inducing- and IFN induction-suppressing activities as mutually exclusive properties, individual particles of wild-type VSV of the New Jersey (N.J.) serotype (Hazelhurst [H] isolate) paradoxically can both induce IFN and suppress its induction in cells coinfected with a potent inducer of IFN. The properties of IFN induction, and its suppression, appear to reside in the particle that manifests infectivity. Analyses of IFN induction dose-response curves to measure IFN-inducing particles (IFP), and IFN yield-reduction curves to measure IFN induction-suppressing particles (ISP) generated by VSV-N.J.(H) in aged chick embryo cells revealed that (i) a single particle per cell sufficed to induce a quantum (full) yield of IFN, or to suppress fully IFN production by a coinfecting inducing virus, and (ii) the addition of one or more IFP per cell did not suppress the yield of IFN beyond the plateau level. The time-course of IFN production in chick cells infected with VSV-N.J. (H) revealed about a 4-h lag, even when the cells were coinfected with a potent inducer that normally induced IFN 1 or 2 h sooner. Thus, VSV-N.J.(H) appears to regulate the production of IFN in cells--even that initiated by other inducers. Expression of IFP and ISP activities both required primary transcription, with respective genomic targets similar to those reported for VSV-Ind. N.J.(H) is the first wild-type VSV observed to express IFP and ISP activities concomitantly. A model is presented to suggest how these two antagonistic properties might be expressed by a single infectious particle.

Mill Hill Strain of Parainfluenza 1 Virus Is a Potent Human Interferon Inducer

The interferon (IFN)-inducing capacities of the widely used Cantell strain of Sendai and the Mill Hill strain of parainfluenza 1 were compared. The Mill Hill strain proved to be a more potent inducer of IFN than the Cantell strain when tested in human peripheral blood leukocytes and amniotic membrane cultures. The Mill Hill strain did not produce defective particles readily, nor did these particles appear necessary for IFN induction. The Mill Hill strain of parainfluenza 1 virus appears superior to the Cantell strain of Sendai virus for the production of natural human IFN.

Stimulation of T Cells and Induction of Interferon by Toxic Shock Syndrome Toxin 1

Toxic shock syndrome toxin 1 (TSST-1) is a potent immunomodulating substance isolated from Staphylococcus aureus strains associated with toxic shock syndrome (TSS). Flow cytometric analysis was used to compare scatter changes in several cell-surface phenotype markers on human mononuclear cells exposed in vitro to TSST-1 or to phytohemagglutinin, a lectin with similar effects on the immune response. The results showed differences between PHA and TSST-1 in the appearance of the tested T cell subset markers and of interleukin 2 receptors. In general, the stimulation of mononuclear cells by TSST-1 was slower than that by phytohemagglutinin. TSST-1 induced the production of interferon in cultures of murine spleen cells. By means of inhibition studies with specific antibodies to interferon, the interferon produced was characterized as the gamma type. Human mononuclear cells exposed to the toxin also produced gamma interferon, with levels similar to those induced by staphylococcal enterotoxin A, a known potent interferon inducer. The induction of gamma interferon by TSST-1 may play a role in the immunosuppression caused by TSST-1.

Modification of immunological responses and clinical disease during topical R-837 treatment of genital HSV-2 infection

R-837, a compound with no in vitro anti-HSV activity, was administered intravaginally to guinea pigs (5 mg/kg every 12 h) for five days beginning 12 h after genital HSV-2 inoculation. Drug treatment reduced vaginal viral replication ( P<0.0001), completely protected against primary disease and reduced recurrent genital HSV disease ( P<0.0001). Drug treatment also induced mild fever, weight loss, and decreased water intake. R-837 was a potent interferon inducer, which also induced variable enhancement of cell-mediated cytolytic activity against HSV-2 targets. Less than 36 h of vaginal HSV shedding was observed in animals with R-837 induced early enhancement of HSV-target cytolysis. Compared to placebo, R-837 decreased ELISA and ADCC antibody to HSV-2, but accelerated HSV-2 specific in vitro IL-2 production and peripheral blood mononuclear cell (PBMC) proliferation. R-837 exhibited potent anti-HSV activity in vivo apparently due to cytokine induction and enhancement of cell-mediated responses.

Inositol phospholipid turnover and protein kinase C translocation are stimulated by poly(I) · poly(C) in human amnion cells (UAC)

Polyinosinic-polycytidylic acid, a potent inducer of interferon (IFN) production and activator of some IFN-induced enzymes, inhibits [ 3H]uridine incorporation into the RNA of vesicular stomatitis virus even in the absence of IFN synthesis, transiently triggers the breakdown of inositol phospholipids and activates the translocation of protein kinase C. Since IFNs also have similar activities these results suggest that IFN induction and IFN function are realised through common biochemical pathways.

The inhibition of endotoxin-induced local inflammation by LDH virus or LDH virus-infected tumors is mediated by interferon.

The footpad swelling reaction induced by local injection of S. marcescens lipopolysaccharide was found to be inhibited in mice given a transplantable tumor (TA3) or cell-free ascitic fluid from tumor-bearing mice. The tumor was shown to contain LDH virus, which is known to cause inapparent persistent infections in mice. Monoclonal antibodies directed against protein VP3 of the LDH virus could partially abrogate the anti-inflammatory effect of the TA3-ascitic fluid, and, conversely, the anti-inflammatory effect could be obtained by LDH virus isolated from the tumor and reproduced by serial passage of cell-free fluids. Inhibition of the footpad reaction was seen in the acute but not in the chronic phase of LDH virus infection, suggesting that the anti-inflammatory effect might be due to endogenous interferon (IFN) which, similarly, was only detectable in the acute phase. Newcastle disease virus, another potent interferon inducer, had a similar inhibitory effect on the footpad reactivity. Moreover, the inhibitory effect of LDH virus infection could partially be abrogated by administration of a polyclonal antibody directed against murine IFN-alpha,beta. Finally, passively administered natural murine IFN-alpha,beta or recombinant murine IFN-alpha 1 (but not recombinant murine IFN-beta) was found to cause inhibition of the footpad reaction. Since Gram-negative bacteria and their lipopolysaccharides have the ability to induce a systemic interferon response, our findings suggest that this interferon may play a modulatory role in local inflammation caused by these bacteria. Our findings also open a new perspective for interferon therapy of certain inflammatory reactions to bacterial infections.

Mitogenic effect of double-stranded RNA in human fibroblasts: role of autogenous interferon.

The synthetic double-stranded RNA polyinosinate-polycytidylate [poly(I).poly(C)] was mitogenic in cultures of human foreskin fibroblasts, as demonstrated by a stimulation of 3H-thymidine incorporation and an increase in cell density. Poly(I).poly(C) is a potent inducer of interferon (IFN)-beta in human fibroblasts. Single-stranded poly(l) or poly(C) were not mitogenic in human fibroblasts and did not stimulate IFN production. Antiserum to interferon (IFN)-beta, added to poly(I).poly(C)-stimulated cultures in order to neutralize endogenously generated IFN, markedly amplified the mitogenic action. Under similar experimental conditions, antiserum to IFN-beta did not enhance the mitogenic action of epidermal growth factor (EGF). Dexamethasone enhanced the mitogenic action of poly(I).poly(C) in a manner similar to antiserum against IFN-beta. This effect of dexamethasone correlated with its marked inhibitory action on poly(I).poly(C)-stimulated IFN production. Together with the results of other related studies, these findings support the notion of an evolutionary link between the generation of a mitogenic signal and IFN induction. In addition, these results support the concept that autocrine secretion of IFN-beta can exert negative feedback control of cell proliferation.

Interferon production in inbred mice during herpetic eye disease

Low levels (less than 5 units/eye) of interferon (IFN) were detected in the eyes of BALB/c and C57BL/6 mice one to five days after instillation of 10(7) pfu/eye of herpes simplex virus type 1 (HSV) onto scarified corneas. This dose of virus produced herpetic keratitis characterized by dendritic epithelial lesions one day post infection in both strains of mice. The disease progressed to severe necrotizing stromal keratitis in the eyes of all BALB/c mice, but only three of 10 eyes of C57BL/6 mice by 21 days after infection. Footpad immunization 30 days prior to ocular infection protected both strains from stromal disease, but did not enhance IFN production in the eye. At lower inoculating doses of virus (less than or equal to 10(5) pfu/eye), C57BL/6 mice showed greater resistance to stromal disease and produced less virus over a shorter period of time than BALB/c mice. No IFN was detected at any time after infection with doses of virus less than 10(7) pfu/eye, nor was IFN detected in plasma of any infected mice. The failure to detect high levels of IFN in homogenates of eyes did not reflect an inability of ocular tissues to produce IFN since IFN-beta was detected as early as two hours after topical treatment with the potent IFN inducer, carboxymethylacridanone (CMA). The two mouse strains produced similar levels of IFN in the eye in response to CMA. These data indicated that the relative resistance of mice to HSV eye infection was not related to the rapid local production of IFN, nor was resistance related to systemic IFN production in plasma or spleen.

Toxicity of polyinosinic-polycytidylic acid admixed with poly-L-lysine and solubilized with carboxymethylcellulose in mice.

Polyinosinic-polycytidylic acid [poly(I,C)] is a double-stranded RNA that is a potent interferon (IFN) inducer in rodents and, when suitably complexed with poly-L-lysine and carboxymethylcellulose [poly(I,C)-LC], also in primates and humans. In addition, poly(I,C)-LC has shown significant therapeutic activity in a number of preclinical tumor models and significant toxicity in both the preclinical and clinical settings. To better understand the toxicity of this agent, particularly in light of the previously reported bell-shaped dose response curve for immunomodulation and therapeutic activity, we undertook a pharmacological/toxicological study of poly(I,C)-LC. These experiments revealed that the injection of toxic doses of poly(I,C)-LC significantly reduced the body weight of animals and induced serological and histological abnormalities. We found that poly(I,C) is the toxic moiety of poly(I,C)-LC and that both agents induced pulmonary thrombosis as well as hepatic necrosis. The hepatic necrosis was reflected in serum enzyme levels, with significant increases in ornithine carbonyl transferase, serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase levels. In addition, reduced platelet counts indicated a significant increase in platelet consumption in agreement with the thrombosis. There were, however, only minor changes in prothrombin and activated prothrombin times. It was of interest that coincubating poly(I,C)-LC and peritoneal macrophages in vitro resulted in the production of tumor necrosis factor, which has a similar pattern of toxicity; this finding suggests that poly(I,C)-LC's pattern of toxicity may be associated with the induction of TNF and/or IFN.

Influence of H-2 haplotypes on poly IC induction of xanthine oxidase and poly IC induced decreases in P-450 mediated enzyme activities

Polyriboinosinic - polyribocytidylic acid (poly IC), a potent interferon inducer, induced xanthine oxidase 24 hours after treatment with 5 mg/kg ip to different degrees among four H-2 congenic mice (P < 0.05): B10 (H-2b: 236 ± 27% of the control value) > B10.RIII (H-2r: 171 ± 29%) = B10.F (H-2n: 161 ± 12%) > B10.BR (H-2K: 136 ± 15%). Aryl hydrocarbon hydroxylase (AHH) activity showed an inverse correlation with inducibility of xanthine oxidase (r = −0.71, P < 0.01). However, there were no significant changes in activities of heme pool associated enzymes, such as catalase, tryptophan pyrrolase and d-aminolevulinic acid synthase in these mice. H-2 haplotype seems to have an influence on poly IC induction of xanthine oxidase thereby causing a decrease in AHH.

Treatment with poly I.C. enhances lipid peroxidation and the activity of xanthine oxidase, and decreases hepatic P-450 content and activities in mice and rats

Treatment of mice and rats with polyriboinosinic acid-polyribocytidylic acid (poly I.C., 5 mg/kg i.p.), a potent interferon inducer, decreased hepatic cytochrome P-450 system content and activities without influencing P-450-independent xenobiotic metabolizing enzymes. Treatment with poly I.C. decreased the content of P-450 by 28% in mice (P less than 0.05) and 30% in rats (P less than 0.05) but did not alter the activity of cytochrome c reductase. With treatment of poly I.C., the activity of XO increased 87% in mice (P less than 0.01) and 30% in rats (P less than 0.01). Lipid peroxidation was enhanced by 82% in mice (P less than 0.01) and 95% in rats (P less than 0.05). These results raise the possibility that a part of the depression of P-450 system content and activities by poly I.C. might be caused by enhanced lipid peroxidation associated with increased activity of XO.

Pyrimidinones. 1. 2-Amino-5-halo-6-aryl-4(3H)-pyrimidinones. Interferon-inducing antiviral agents

Interferon induction and antiviral activity was discovered with 2-amino-5-bromo-6-phenyl-4(3H)-pyrimidinone. An analogue study incorporating a series of 2-amino-5-substituted-6-arylpyrimidinones revealed that the most potent interferon inducers were mono- and difluorophenyl analogues. These same analogues were also potent antiviral agents against Semliki Forest virus and herpes simplex type 1. In addition the monomethoxyphenyl analogues were potent antiviral agents but weak interferon inducers. Relatively modest structural changes led to dramatic changes in bioactivity. There was a relatively poor correlation between levels of circulating interferons induced and systemic antiviral activity.

Effect of pyrimidinone treatment on lethal and immunosuppressive murine cytomegalovirus infection.

The 2-amino-5-halo-pyrimidinones, which are potent interferon inducers and antiviral agents, were found to be protective against lethal cytomegalovirus (CMV) challenge in weanling or neonatal mice when administered before virus challenge. This protection was dependent upon the dosage of pyrimidinone administered. Weanling mice infected with a sublethal challenge of CMV exhibited moderate to severe immunosuppression as measured by reduced splenic cell blastogenic responses in vitro to the mitogen concanavalin A. Treatment of mice with pyrimidinones during the course of CMV immunosuppression resulted in substantial augmentation of splenic cell blastogenic responses. The degree of augmentation appeared to be dependent on the severity of CMV-induced immunosuppression.