Adenovirus multiplication: inhibition by methisazone.

Methisazone (5 to 40 microM) inhibited the multiplication of types 3, 7, 9, 11, 14, 16, 17, 21, and 28 adenovirus; SV15 (a simian adenovirus) was also inhibited. A study of adenovirus 11 under single-cycle conditions showed that multiplication of the virus, was completely inhibited by 30 microM methisazone when addition of the compound was delayed until 13 hours after infection. A survey showed that the structure-activity relations of the action of methisazone against adenoviruses and pox viruses are similar.

The effect of iodination on the haemolytic property and the fatty acids of Newcastle disease virus.

Treatment of Newcastle disease virus with iodine inhibits haemolysis and infectivity, but has no effect on haemagglutination. This is shown to be concurrent with the incorporation of iodine in the hydrocarbon chain of fatty acyl residues of the viral membrane lipid. It is concluded that iodine incorporation, by reducing membrane fluidity, is responsible for these biological phenomena.

Saturation index of blood cell membrane fatty acids before and after IFN treatment in hairy cell leukemia.

Cells from the peripheral blood of 32 patients with hairy cell leukemia (HCL) were analyzed for cell membrane fatty acid composition. A consistent and significant change was found in the relative amounts of stearic and oleic acid components, which is expressed as the saturation index (SI), the ratio of stearic to oleic acid content. In all patients, SI was reduced in the erythrocytes, leukocytes, and platelets. On extended treatment with interferon, the hematological improvement was accompanied by an increase in SI. In two patients, one deteriorating after cessation of treatment and the other on a low maintenance dose of interferon, concurrent influenza infection induced temporary improvements in the blood cell counts, as well as increase in SI values. These results indicate that endogenous interferon can also be effective in inducing hematological and SI improvement in this disease. The relevance of low SI values and concomitant increase in membrane fluidity to the malignant transformation is discussed. It is proposed that one effect of interferon is to reduce the production of growth factors by reducing the malignant cell mass.

Erythroid precursor fusion induced by Sendai virus.

The ultrastructural events of the interaction of Sendai virus (SV) with fetal mouse erythroid precursors, and SV-induced fusion of erythroid precursors at different maturation stages are described. SV was shown to affect the erythroid nuclei causing interruption of the nuclear membrane, enlargement of the nucleolus and nuclear fusion. SV induced fusion also between dividing and non-dividing cells.

SEM observations on Sendai virus-induced fusion of embryonic mouse erythroblasts.

The events of fusion of 11- and 16-day embryonic mouse liver erythroblasts induced by Sendai virus (SV) were followed with the scanning electron microscope (SEM). Erythroid precursors incubated with the virus showed numerous 'pores' on the cell membrane. The cell fusion began with the appearance of a fine 'meshwork' structure between the adjacent cells, followed by a gradual formation of a common cell membrane and terminated with the appearance of polykaryons, in which the nuclei were easily recognized when located in the vicinity of the polykaryon membrane. There was no difference in the process of fusion between erythroblasts at identical and those at different stages of maturation.

Syncytia formation in HIV-1 infected cells is associated with an increase in cellular oleic acid.

Infection of cells with the human immunodeficiency virus type-1 (HIV-1) usually results in the formation of giant multinuclear cells (syncytia) [(1986) Nature 322, 470-474; (1986) Nature 322, 725-728; (1985) Hum. Pathol. 18, 760-765; (1987) Ann. Neurol. 21, 490-496]. The appearance of syncytia is associated with an increase in the monounsaturated oleic acid content. This report describes experiments which compare the activity of known antiviral agents with that of saturated fatty acid derivatives in inhibiting oleic acid and syncytia formation. A concept is introduced which proposes that infection of cells with the human immunodeficiency virus causes a rise in cellular oleic acid which leads to increased membrane fluidity.

Fatty acid composition of normal and malignant cells and cytotoxicity of stearic, oleic and sterculic acids in vitro.

The aim of this study was to investigate the hypothesis that saturated fatty acids are differentially cytotoxic to cancer cells. Three studies were undertaken to: (1) measure the toxicities of stearic and oleic acids to normal and malignant cells in vitro, (2) assess if there is any relationship between toxicity and relative fatty acid composition and (3) determine whether the relative fatty acid composition of a cancer cell line could be modified by sterculic acid, an inhibitor of delta-9-desaturase. Stearic (18:0) and oleic (18:1) acids inhibited the colony-forming abilities of five human cancer cell lines and two non-neoplastic cell lines in a dose-dependent fashion. The concentration of oleic acid required to reduce colony formation ability by 50% was 2.5-6.0-fold greater than that of stearic acid. Addition of sterculic acid to a cancer cell line resulted in steady-state levels of stearic acid and increasing percentage of oleic acid.

Alpha 2 interferon in the prevention of N-nitroso-methyl urea induced breast cancer in rats.

Human interferons have been shown to be effective treatment for hairy cell leukaemia and are now commercially available. Their role in treatment of solid tumours has yet to be established. This study assessed the value of alpha 2 interferon (IFN) in an experimental breast cancer model. Four groups of female Sprague-Dawley rats were studied. The first received three intravenous injections (7 mg/kg) of N-nitroso-methyl urea (NMU) at weeks 0, 3 and 7. The second received the same NMU dosage regime plus IFN (100,000 IU, twice weekly for 3 weeks). A third received IFN alone and the fourth was a control group receiving three intravenous injections of normal saline. At week 16, 19 of 20 rats in the NMU alone group had developed tumours significantly more than four of 15 rats with tumour in the NMU plus IFN group (P less than 0.001). Both the mean tumour number/rat and the mean tumour weight/rat was significantly more in the NMU group than the NMU plus IFN group P less than 0.05). No rats in the IFN alone or control group developed tumour. These data suggest that IFN prevents carcinogen induced breast cancer in rats. It may have a role in the prevention and treatment of human breast cancer.

Reduction in the stearic to oleic acid ratio in human malignant liver neoplasms.

Total lipid extracts of liver tissue from 14 patients with primary and secondary liver tumours were analysed for relative values of saturation of 18 carbon chain length fatty acids (C18FA). The saturation indices (ratio C18S:C18u) of the tumour areas were significantly and consistently lower than the corresponding values in the non-tumour areas (P less than 0.001). It is proposed that the relative increase in unsaturated C18FA (oleic acid) could prove to be a chemical marker reflecting deficient cellular control of the desaturation of stearic acid.

Reduction in the stearic to oleic acid ratio in the circulating red blood cells: a possible tumour marker in solid human neoplasms.

Gas liquid chromatography study of the 18 carbon chain length fatty acids (C18FA) of the human red blood cells (RBCs) was performed on 65 patients with various clinical disorders. It was found that the stearic to oleic acid ratio (SI) of the RBCs was significantly lower (P less than 0.001) in patients with malignant conditions (n = 20, SI = 0.62 +/- 0.16) compared with pathological non-malignant diseases (n = 10, SI = 1.19 +/- 0.2) and the normal control group (n = 35, SI = 1.57 +/- 0.5). Our early results suggest that the increased unsaturation (oleic acid) in the circulating RBCs could be used as a chemical marker in various solid neoplasms.

The effects of iodine on the biological activities of myxoviruses.

Lugol's solution destroys the biological activities of Newcastle disease virus (NDV) after 15 s incubation at 37 degrees C. The rates of inactivation are slower at lower temperatures and at acid pH. At 4 degrees C and pH 5.8, the functions associated with the virus membrane, (haemolysis (HL), cell fusion and infectivity) are inactivated within 32 min, while haemagglutination (HA) and neuraminidase (N) are resistant to inactivation for several hours. Adjustment of NDV, Sendai and influenza A virus allantoic harvests to pH 5.8 and subsequent treatment with undiluted Lugol's solution (pH 5.8) for 15 min has a minimal effect on HA but results in complete loss of infectivity. It is suggested that iodination could be a useful method for vaccine production with membrane-bound viruses. It is postulated that the separation and dissociation of the membrane-associated properties of paramyxoviruses from the glycoprotein functions is due to the higher affinity of iodine for the lipids. Iodine could react with the carbon-carbon double bond (C=C) of the unsaturated fatty acids. This could lead to a change in the physical properties of the lipids and membrane immobilization.

Evidence of a viral aetiology in endemic (Balkan) nephropathy.

Segemental and focal pathological changes were found in the glomeruli and tubules of postoperative renal-biopsy specimens from seven cases of clinically confirmed endemic (Balkan) nephropathy. In the glomeruli, there was mesangial reaction and segmental thickening of the basement membrane with subendothelial and membranous depositions. In the tubules there was spongiform degeneration and fusion of cells. In all the cells of the nephron numerous cytoplasmic vesicles containing free and budding particles (80-200 nm) were found. These particles had the characteristics of a coronarivus. Balkan nephropathy occurs almost exclusively in people who have been in close contact with pigs. Coronaviruses have been isolated from pigs, and it is suggested that a slow coronavirus infection causes endemic nephropathy in man.

Reversible increase in the saturation of C18 fatty acids induced by diphtheria toxin in tissue culture cells.

Diptheria toxin (DT) reversibly increases the saturation of the long-chain C18 fatty acids (C18FA) in concentrations which are at least 100-fold smaller than the concentrations which completely inhibit host cell protein synthesis. The concentrations required for induction of the increase in the saturation of the C18FA in fibroblasts are 100-fold smaller than the concentrations for the epithelial cells. The increase in saturation of the C18FA was proportional to the concentration of DT. A cytopathic effect appeared with DT concentrations which induced a near-maximal increase in the saturation of the C18FA, but the cells remained viable. However, at very high concentrations of DT and depending on the type of cell, there was no change in the fatty acids, and the treated cells disintegrated. Interferon, which also induces a reversible increase in the saturation of the C18FA (K. Apostolov and W. Barker, FEBS Lett. 126:261-264, 1981), produces a cumulative effect when used in conjunction with DT. This additive effect of DT and interferon is discussed in the light of other similar biological activities of these agents.

Enhancement of haemolysis by Newcastle disease virus (NDV) after pre-treatment with heterophile antibody and complement.

Pre-treatment of Newcastle disease virus (NDV) with fresh human plasma enhances its haemolytic (HL) capacity by several factors. The effect is due to complement activation by the heterophile anti-chick antibody present in human plasma. All the adult human plasmas tested were effective, also 91/100 human cord blood sera. The antibody was mainly of the IgM class. The enhanced HL was due to integration and transference of the complement 'holed' virus envelope membrane and subsequent leakage of haemoglobin. High concentration of activated complement destroys the integrity of the virus enevelope. Treatment of chick erythrocytes and fibroblasts with human plasma also produced lysis of the cells.

Association of the cytopathic effect of sindbis virus with increased fatty acid saturation.

The effect of Sindbis virus on cell leakiness, as measured by chromium release, and on the fatty acids in chick embryo fibroblasts and Vero cells was studied. The appearance of the cytopathic effect in both cell types coincided with virus replication, increased cell leakiness and relative increase in saturated eighteen carbon fatty acid (C18:0, stearic acid) compared to the eighteen carbon unsaturated fatty acids (C18UFA). It is postulated that the increase in cell leakiness and the appearance of cytopathic effect could be the result of a physical change in the lipids of the cell membrane brought about by the increase in the saturation of the eighteen carbon fatty acids.

The correlation of fatty acid content of infected cells and virions with Newcastle disease virus (NDV) virulence.

Chick embryo fibroblasts (CEF) infected with virulent strains of Newcastle disease virus (NDV) showed a dramatic increase in total unsaturated fatty acids (UFA). This increase was not seen in cells infected with the avirulent strains of NDV, Sendai virus or influenza A (PR8). The virions of the virulent strains of NDV harvested from the chorioallantoic cavity also had a higher UFA content compared to the avirulent ones. The kinetics of UFA increase in the virulent strains could be correlated with published data on the kinetics of RNA and protein synthesis inhibition, polykaryon formation and membrane permeability changes.

Reversible inhibition of Newcastle disease virus (NDV) haemolysis by bivalent cations.

The capacity of paramyxoviruses for haemolysis (hl) is enhanced after treatment with physical agents and complement (C'). Bivalent cations in the medium inhibit HL. The inhibition is proportional to the molar concentrations, and is graded Ba++ greater than Ca++ greater than Mg++. Substitution of the bivalent cations with K+ and re-incubation leads to reappearance of HL, but in reverse order. It is postulated that bivalent cations inhibit HL mainly by stabilising the virus membrane integrated into the erythrocyte membrane and slowing down the permeability rates. This inhibition is removed on substitution with monovalent cations. The bivalent cations also reversibly inhibit the permeability of the transferred C' lesion.