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Biomedical subjects

H Thormar

Publications and source records attributed to H Thormar.

At least 19 recordsLinked to original sources
PubMed1995

Inhibitory effect of 9-(2-phosphonylmethoxyethyl)adenine on visna virus infection in lambs: a model for in vivo testing of candidate anti-human immunodeficiency virus drugs.

The acyclic nucleoside phosphonate analog 9-(2-phosphonylmethoxyethyl)adenine (PMEA) was recently found to be effective as an inhibitor of visna virus replication and cytopathic effect in sheep choroid plexus cultures. To study whether PMEA also affects visna virus infection in sheep, two groups of four lambs each were inoculated intracerebrally with 10(6.3) TCID50 of visna virus strain KV1772 and treated subcutaneously three times a week with PMEA at 10 and 25 mg/kg, respectively. The treatment was begun on the day of virus inoculation and continued for 6 weeks. A group of four lambs were infected in the same way but were not treated. The lambs were bled weekly or biweekly and the leukocytes were tested for virus. At 7 weeks after infection, the animals were sacrificed, and cerebrospinal fluid (CSF) and samples of tissue from various areas of the brain and from lungs, spleen, and lymph nodes were collected for isolation of virus and for histopathologic examination. The PMEA treatment had a striking effect on visna virus infection, which was similar for both doses of the drug. Thus, the frequency of virus isolations was much lower in PMEA-treated than in untreated lambs. The difference was particularly pronounced in the blood, CSF, and brain tissue. Furthermore, CSF cell counts were much lower and inflammatory lesions in the brain were much less severe in the treated lambs than in the untreated controls. The results indicate that PMEA inhibits the propagation and spread of visna virus in infected lambs and prevents brain lesions, at least during early infection. The drug caused no noticeable side effects during the 6 weeks of treatment.

Adenine↗
PubMed1995

Inhibition of visna virus replication and cytopathic effect in sheep choroid plexus cell cultures by selected anti-HIV agents.

Several anti-HIV agents were tested against visna virus replication and cytopathic effect (CPE) in sheep choroid plexus cell cultures. Sulphated polysaccharides (i.e., dextran sulphate, pentosan polysulphate and heparin) and plant lectins, which inhibit viral adsorption and fusion, were found to be 10- to 40-fold less active against visna virus than against HIV. Bicyclam derivatives were at least 250-fold less active against visna virus and the highly HIV-1 specific TIBO derivatives were without a significant inhibitory effect on visna virus at subtoxic concentrations. In contrast, several 2',3'-dideoxynucleosides and acyclic nucleoside phosphonate analogues, which inhibit reverse transcription, were found to be very effective inhibitors of visna virus replication and viral CPE in cell culture.

Animals↗
PubMed1994

Inactivation of enveloped viruses in human bodily fluids by purified lipids.

Antimicrobial lipids are found in mucosal secretions and are one of a number of nonimmunologic and nonspecific protective factors found at mucosal surfaces. Lipids can inactivate enveloped viruses, bacteria, fungi, and protozoa. Lipid-dependent antimicrobial activity at mucosal surfaces is due to certain monoglycerides and fatty acids that are released from triglycerides by lipolytic activity. Medium chain length antiviral lipids can be added to human blood products that contain HIV-1 and HIV-2 and reduce the cell-free virus concentration by as much as 11 log10 TCID50/ml. The presence of lipids does not interfere with most clinical assays performed on human blood samples. Antimicrobial lipids can disrupt cell membranes and therefore lyse leukocytes which potentially carry virus. Genital mucosal epithelial cells should be protected from damage by the mucous layer. Preliminary studies indicate that lipids decrease sperm motility and viability suggesting that lipids may potentially be used as combination spermicidal and virucidal agents.

Antiviral Agents↗
PubMed1994

Inactivation of visna virus and other enveloped viruses by free fatty acids and monoglycerides.

Human milk was found to become antiviral during storage at 4 degrees C because of the release of fatty acids by lipolysis. The stored milk caused more than a 10,000-fold inactivation of visna virus during incubation at 37 degrees C for 30 minutes. Medium-chain saturated and long-chain unsaturated fatty acids inactivated visna virus and other enveloped viruses causing more than a 3000-fold to 10,000-fold reduction in virus titer. 1-Monoglycerides and ethers of medium-chain fatty acids were more antiviral than the corresponding free fatty acids. Antiviral fatty acids were found to affect the viral envelope, causing leakage and, at higher concentrations, a complete disintegration of the envelope and the viral particles. Lipids commonly found in natural products could possibly be used as antiviral agents against enveloped viruses.

Animals↗
PubMed1993

Inhibition of visna virus replication by 2',3'-dideoxynucleosides and acyclic nucleoside phosphonate analogs.

A series of acyclic nucleoside phosphonate (ANP) and 2',3'-dideoxynucleoside (ddN) derivatives were evaluated for their inhibitory effects on visna virus replication and maedi/visna virus-induced syncytium formation in sheep choroid plexus cells. Most ANP derivatives inhibited virus replication and syncytium formation within a concentration range of 0.2 to 1.8 microM. Among the most active ANP derivatives ranked (R)-9-(2-phosphonomethoxypropyl)adenine, (R)-9-(2-phosphonomethoxypropyl)-2,6-diaminopurine, and (S)-9-(3-fluoro-2-phosphonomethoxypropyl)adenine. Of the ddN derivatives, 2',3'-dideoxycytidine (ddCyd) proved to be the most inhibitory to visna virus-induced syncytium formation (50% effective concentration, 0.02 microM). The purine ddN analogs (i.e., 2',3'-dideoxyinosine, 2',3'-dideoxyadenosine, 2',3'-dideoxyguanosine, and 2,6-diaminopurine-2',3'-dideoxyribosine) were 10- to 30-fold less effective, and the thymidine derivatives 2',3'-didehydro-2',3'-dideoxythymidine (D4T) and 3'-azido-2',3'-dideoxythymidine (AZT) were more than 500-fold less inhibitory to visna virus than ddCyd. The 5'-triphosphate forms of AZT and D4T were 100- to 600-fold more inhibitory to visna virus particle-derived reverse transcriptase than was the 5'-triphosphate of ddCyd. The apparent discrepancy between the inhibitory effects of these ddN derivatives on virus replication and viral reverse transcriptase activity most likely reflects differences in the metabolic conversion of ddCyd versus D4T and AZT in sheep choroid plexus cells.

Animals↗
PubMed1990

Measles virus-specific immunoglobulin D antibody in cerebrospinal fluid and serum from patients with subacute sclerosing panencephalitis and multiple sclerosis.

Quantitation of measles-specific immunoglobulin D (IgD) antibody was carried out in cerebrospinal fluid (CSF) and serum samples from 18 patients with subacute sclerosing panencephalitis (SSPE), 12 patients with multiple sclerosis (MS) and seven normal controls with high measles antibody titers in serum, using polyclonal and monoclonal antibodies specific for human IgD and enzyme-linked immunosorbent assay. Measles-specific IgD activity was significantly higher in CSF and serum from SSPE patients compared to that found in patients with MS or normal controls. The IgD antibody to measles virus was not due to high levels of measles-specific IgG since significant measles IgD activity was found after eluting IgG from SSPE serum. The increased level of measles-specific IgD found in SSPE sera is consistent with the levels observed in patients with acute and chronic viral infections.

Enzyme-Linked Immunosorbent Assay↗
PubMed1990

Antiviral and antibacterial lipids in human milk and infant formula feeds.

Human milk and two infant formula feeds were tested for antiviral and antibacterial activity before being given to 21 low birthweight (LBW) infants; neither was present. When samples were aspirated from the stomachs of the infants within one to three hours of feeding, however, they reduced titres of enveloped virus and also killed both Staphylococcus epidermidis and Escherichia coli. The lipid fraction of the gastric aspirate from an infant who had been given human milk as well as those from four infants who had been given a conventional LBW infant formula feed, showed antiviral and antibacterial activities at least equal to the activities of the unfractionated aspirates. There was no consistent difference in antiviral or antibacterial activity of either the stomach aspirates or the lipid fractions of these aspirates between infants given human milk and those given formula feeds. The antiviral and antibacterial activities of the gastric aspirates seem to result from intragastric production of monoglycerides and fatty acids from the triglyceride content of the ingested feeds.

Antiviral Agents↗
PubMed1989

Immunoglobulin G subclass antibodies to measles virus in patients with subacute sclerosing panencephalitis or multiple sclerosis.

Mouse monoclonal antibodies specific for human immunoglobulin G (IgG) subclasses and a sensitive immunoassay were used to evaluate the IgG subclass antibody response to measles virus antigens in cerebrospinal fluid and serum samples from 20 patients with subacute sclerosing panencephalitis (SSPE), 12 patients with multiple sclerosis (MS), and 11 controls with high measles virus antibody titers in serum. In patients with SSPE, measles virus-specific antibodies were found mainly in the IgG1 subclass and the IgG subclass distribution remained unchanged, irrespective of the clinical stage or duration of the disease. In patients with MS and in controls, measles virus activity was also associated mainly with IgG1. However, the activity was significantly lower than that found in patients with SSPE. The results suggest that there is no primary abnormality in humoral immune response to measles virus in patients with MS. The disproportionately high levels of the measles virus-specific IgG1 subclass found in patients with SSPE may be due to persistent antigenic stimulation or reflect a defect in immunoregulatory mechanisms in response to viral infection.

Adolescent↗
PubMed1988

Transmission of measles virus encephalitis to ferrets by intracardiac inoculation of a cell-associated SSPE virus strain.

Ferret fibroblasts infected with a cell-associated strain of subacute sclerosing panencephalitis virus were inoculated into the hearts of ferrets in order to study whether the virus can spread from the blood to the brain in this animal model. Five of 21 inoculated ferrets developed encephalitis 5-7 days later and were sacrificed. Sick animals showed inflammatory lesions in the brain, both perivascular cuffings and infiltration of inflammatory cells in the choroid plexus and meninges. Virus was isolated in cell cultures from various parts of the brain and virus antigen was found by immunostaining, particularly in the cortex. Virus was not detected in inflammatory cells by immunostaining but in situ hybridization with a cDNA probe demonstrated measles virus RNA in neurons and glia cells surrounding perivascular inflammatory cuffings and in a lymph node of one ferret. Ferrets inoculated into the heart with cell-associated SSPE virus seem to be a suitable animal model to study how the virus spreads from the blood to the brain.

Animals↗
PubMed1987

Measles virus matrix protein gene expression in a subacute sclerosing panencephalitis patient brain and virus isolate demonstrated by cDNA hybridization and immunocytochemistry.

Subacute sclerosing panencephalitis (SSPE) is a rare, fatal disease of children caused by a persistent measles virus infection of the central nervous system. A defect in synthesis of measles virus matrix (M) protein may be a factor in virus persistence in the brain. This study details attempts to detect expression of M protein in the brain of an SSPE patient, in the cell-associated virus isolated from this brain, and in brains of ferrets inoculated with the isolate. In situ hybridization with a tritiated cloned cDNA probe was used to search for RNA encoding M protein. Immunostaining with monospecific antiserum and the avidin-biotin-peroxidase technique was done to locate the polypeptide. The data obtained indicate that although nucleotide sequences coding for M protein were detected in the patient and ferret brains, expression of M protein in these tissues could not be detected. In the culture SSPE virus isolate, the results were the same until the infected cells were examined by electron microscopy and a very limited expression of M protein was revealed. This suggests either diminished synthesis and/or rapid degradation of M protein in this cell-associated virus strain.

Adolescent↗
PubMed1987

Inactivation of enveloped viruses and killing of cells by fatty acids and monoglycerides.

Lipids in fresh human milk do not inactivate viruses but become antiviral after storage of the milk for a few days at 4 or 23 degrees C. The appearance of antiviral activity depends on active milk lipases and correlates with the release of free fatty acids in the milk. A number of fatty acids which are normal components of milk lipids were tested against enveloped viruses, i.e., vesicular stomatitis virus, herpes simplex virus, and visna virus, and against a nonenveloped virus, poliovirus. Short-chain and long-chain saturated fatty acids had no or a very small antiviral effect at the highest concentrations tested. Medium-chain saturated and long-chain unsaturated fatty acids, on the other hand, were all highly active against the enveloped viruses, although the fatty acid concentration required for maximum viral inactivation varied by as much as 20-fold. Monoglycerides of these fatty acids were also highly antiviral, in some instances at a concentration 10 times lower than that of the free fatty acids. None of the fatty acids inactivated poliovirus. Antiviral fatty acids were found to affect the viral envelope, causing leakage and at higher concentrations, a complete disintegration of the envelope and the viral particles. They also caused disintegration of the plasma membranes of tissue culture cells resulting in cell lysis and death. The same phenomenon occurred in cell cultures incubated with stored antiviral human milk. The antimicrobial effect of human milk lipids in vitro is therefore most likely caused by disintegration of cellular and viral membranes by fatty acids. Studies are needed to establish whether human milk lipids have an antimicrobial effect in the stomach and intestines of infants and to determine what role, if any, they play in protecting infants against gastrointestinal infections.

Animals↗
PubMed1986

Membrane-disruptive effect of human milk: inactivation of enveloped viruses.

Fresh human milk treated with antibody to secretory IgA had no effect on viral infectivity but became antiviral after 1 hr in the stomachs of suckling infants. Antiviral activity also appeared in fresh milk stored at 4 C for at least two days. The antiviral activity, which reduced titers of virus by as much as 10,000-fold, only affected enveloped viruses and was localized in the milk lipid fraction. Its appearance in stored milk was apparently due to fatty acids released by the activity of milk lipases, particularly lipoprotein lipase. Antiviral activity in the infants' stomach, however, most likely resulted from the activity of gastric and lingual lipases on milk triglycerides and caused the release of antiviral fatty acids. Milk and stomach contents that were antiviral also lysed cultured cells by disruption of their plasma membrane. Cell lysis was also caused by purified linoleic acid, which is a normal constituent of human milk triglycerides.

Antibodies, Anti-Idiotypic↗
PubMed1985

Demonstration of immunoglobulin in brains of ferrets inoculated with an SSPE strain of measles virus: use of protein A conjugated to horseradish peroxidase.

Measles virus-specific immunoglobulin G (IgG) has been found in the brains of patients with subacute sclerosing panencephalitis (SSPE), a slowly progressing central nervous system (CNS) disease affecting children. IgG/albumin ratios indicate that the antibodies are probably synthesized in the CNS. In a ferret model system, protein A conjugated to horseradish peroxidase (PrAPx) was used to localize Ig's in brains of animals inoculated with a cell associated strain of SSPE. Ig's were found in plasma cells in various stages of antibody production both in perivascular inflammatory lesions and scattered throughout the cerebral cortex. These findings offer corroborative evidence that the Ig found in SSPE ferret brain and CSF is actively synthesized within the CNS. Antibody was also demonstrated in glial and neuronal cell bodies and processes and in postsynaptic profiles. These are the same sites where measles virus antigens are most frequently found and suggests the possibility of immune complex formation.

Animals↗
PubMed1985

Localization of measles virus antigens in subacute sclerosing panencephalitis in ferrets.

Young adult male ferrets were inoculated intracerebrally (i.c.) with a cell-associated encephalitogenic subacute sclerosing panencephalitis (SSPE) virus strain to study the pathogenesis of the disease at the ultrastructural level. Most became acutely ill in 8-13 days. Areas of the brain were examined with indirect immunoperoxidase labeling techniques to detect measles antigen. None of these animals showed the characteristic viral nucleocapsids or marked inflammatory response associated with SSPE. However, all had positive immunolabeling of unstructured virus antigen, especially in post-synaptic regions in all areas of the brain that were examined. One ferret, immunized with measles vaccine 40 days prior to challenge with SSPE, became ill 18 days post inoculation (p.i.). Perivascular cuffings of inflammatory cells and large cytoplasmic inclusions of fuzzy nucleocapsids were found in the brain and spinal cord. The study indicates that ferrets which become acutely ill after inoculation with cell-associated SSPE virus do so before there is a marked cellular immune response or formation of virus nucleocapsids.

Animals↗