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A S Tyms

Publications and source records attributed to A S Tyms.

At least 37 records · Page 2Linked to original sources
PubMed1990

Inhibition of glycoprotein processing and HIV replication by castanospermine analogues.

Inhibitors of glycoprotein processing enzymes have been shown to have activity against HIV. Several analogues of the known glucosidase I inhibitor, castanospermine (CAST), were synthesized and evaluated for their inhibitory effect on glucosidases and for antiviral activity against Moloney murine leukemia virus (MOLV) and HIV-1. The most effective analogue was 6-O-butanoyl CAST (B-CAST, MDL 28,574) with an IC50 of 0.05 micrograms/mL against MOLV. A correlation between inhibition of glucosidase I and MOLV replication was observed. This analogue was further evaluated against HIV-induced syncytial formation in HeLa T4+ cells and against productive infection in JM cells infected with HIV 1 (GB8 strain). B-CAST showed an IC50 of 0.3 micrograms/mL in the HeLa T4+ assay, compared to CAST at 11 micrograms/mL. The compound also was more potent (IC50:0.15 micrograms/mL) than CAST (4-6 micrograms/mL) in JM cells. The antiretroviral activity of B-CAST was further confirmed in Friend leukemia virus (FLV) infection in mice. B-CAST showed equivalent activity to AZT and was more potent than CAST in inhibiting FLV-induced splenomegaly in mice. The data presented herein suggest the potential of these novel glucosidase inhibitors as anti-HIV agents.

Animals↗
PubMed1989

The herpes simplex virus type 1 immediate-early protein ICP27 is obligately required for the accumulation of a cellular protein during viral infection.

Lytic infection with herpes virus type 1 (HSV-1) causes the accumulation of a 40-kDa cellular protein (p40) which is also overexpressed in cultured cells transformed by HSV or other agents and in human cervical tumors. Accumulation of p40 is dependent upon viral protein synthesis but not viral DNA replication in the infected cell and occurs in the HSV-1 mutants tsK and tsLB2 in which only a defective ICP4 protein and the four other immediate-early proteins are synthesized. By using a panel of HSV-1 strains, each defective in one of these four proteins, we show that only a mutation in the gene encoding ICP27 abolishes p40 accumulation. The defect in this mutant virus can be rescued by a plasmid encoding ICP27 alone indicating that ICP27 is obligately required for p40 accumulation. The significance of this effect as one aspect of the interaction of viral control proteins with cellular genes is discussed.

Animals↗
PubMed1989

Cytomegalovirus and the acquired immunodeficiency syndrome.

The acquired immunodeficiency syndrome (AIDS) is complex in nature with one major aetiological factor but with numerous other agents exploiting the immune incompetence. Cytomegaloviruses (CMV) form a little-defined group of viruses which naturally persist in man and respond readily to the relaxation in immune surveillance. A role for CMV and other herpesviruses in potentiating the underlying infection with human immune deficiency virus (HIV) cannot be totally excluded but CMV is well established as a major opportunist in AIDS. They are considered responsible for a range of diseases in AIDS patients including retinitis, gastrointestinal disease, pneumonitis and, less frequently, encephalitis. The pyrophosphate analogue foscarnet (phosphonoformate) and the deoxyguanosine analogue ganciclovir have both been used to treat CMV infections in AIDS patients. Results of uncontrolled studies have indicated efficacy with both drugs but the work with ganciclovir is particularly encouraging. This communication provides a review of CMV infections in AIDS patients with special reference to the experiences to-date in the use of ganciclovir and foscarnet.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Inhibition of HIV replication by amino-sugar derivatives.

The plant alkaloids castanospermine, dihydroxymethyldihydroxypyrrolidine and deoxynojirimycin have recently been shown to have potential anti-HIV activity [(1987) Proc. Natl. Acad. Sci. USA 84, 8120-8124; (1987) Nature 330, 74-77; (1987) Lancet i, 1025-1026]. They are thought to act by inhibiting alpha-glucosidase I, an enzyme involved in the processing of N-linked oligosaccharides on glycoproteins. We report here the relative efficacy of a spectrum of amino-sugar derivatives as inhibition of HIV cytopathicity. Several alpha-glucosidase inhibitors and alpha-fucosidase inhibitors were found to be active at concentrations which were non-cytotoxic.

Amino Sugars↗
PubMed1988

Loss of cytomegalovirus infectivity after treatment with castanospermine or related plant alkaloids correlates with aberrant glycoprotein synthesis.

Many plants contain polyhydroxyalkaloids which are potent inhibitors of glucosidases, enzymes involved in oligosaccharide trimming. These are important in determining the final configuration of specific glycoproteins. Human cytomegalovirus (CMV) encodes a number of glycoproteins, some of which ultimately reside in the outer envelope of the mature virion and are important for virus infectivity. Treatment with three polyhydroxyalkaloids, castanospermine (CAST), deoxynojirimycin (DNJ) and 2R,5R-dihydroxymethyl-3R,4R-dihydroxypyrrolidine (DMDP) blocked the growth of infectious virus, as determined by yield reduction and plaque reduction assays. However, in the presence of CAST, CMV infected cells continued to shed virions into the extracellular medium, as determined by electron microscopy. Envelope glycoproteins of virions produced after treatment with CAST (2.5 mM) were immunoprecipitated with a monoclonal antibody (F5) specific for the gcI family of glycoproteins. Analysis by PAGE-SDS showed an absence of gcI complex 2 (gp52 disulphide-linked to gp130) with a proportional increase in gcI complex 1 (gp52 disulphide-linked to gp95). The results indicated that gp130 alone, or linked to gp52, was important for CMV infectivity. As well as being potential targets for antiviral agents against CMV, inhibitors of glycoprotein trimming reactions may define components of the virion surface important for infectivity.

Alkaloids↗
PubMed1988

Characterization of cytomegalovirus isolates from patients with AIDS by DNA restriction analysis.

Thirty-seven isolates of cytomegalovirus (CMV) were obtained from a group of 20 promiscuous homosexual men, either suffering from the acquired immunodeficiency syndrome (AIDS) at the time of CMV isolation, or who developed AIDS subsequently. The isolates of CMV were characterized by the method of DNA restriction analysis. All epidemiologically unrelated strains of CMV exhibited different fragment migration patterns and no one strain appeared to be associated with AIDS or any particular disease pattern in these patients. Sequential isolates of CMV were obtained from nine patients in the study group either from different sites at the same time or from the same site on different dates. In the case of seven of the men, viruses with minor differences in restriction profile were obtained, possibly representing sub-populations of an endogenous strain of CMV. In two of the patients, reinfection with different strains was apparent. We conclude that reinfections with CMV in AIDS patients can occur, but the isolation of strains exhibiting major differences in genome structure seen by restriction enzyme analysis was uncommon.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Cellular polypeptides overexpressed after herpes simplex infection permit virus subtyping and may help diagnose cervical cancer.

The synthesis of cellular macromolecules is inhibited after infection with herpes simplex viruses (HSV) although certain host proteins accumulate to high concentrations as identified by monoclonal antibody TG7A. By western blotting, a polypeptide with a relative molecular weight of 90 kilodaltons was identified in cells infected with type 2 viruses and a polypeptide of 40 kilodaltons relative molecular weight in type 1 infected cells, and virus typing was confirmed by restriction enzyme analysis of viral DNA. Thirty seven clinical isolates from the genital region were subtyped as HSV type 2 and 18 from the orofacial region as type 1 by the different intracellular location of the 90 kilodalton and 40 kilodalton proteins seen on immunofluorescent staining of cells infected with HSV. Expression of these proteins has been associated with cellular transformation due to gene products of HSV or other viruses. Overexpression of the cellular proteins identified by TG7A reactivity was shown to be a marker for cells in cervical smears from patients with CIN III that appeared to be dyskaryotic. Little or no reaction was observed in squamous epithelial cells found in normal or abnormal smears.

Antibodies, Monoclonal↗
PubMed1987

Fine structure of cells infected with human cytomegalovirus after treatment with 9-(1,3-dihydroxy-2-propoxymethyl)guanine.

Infection with human cytomegalovirus (CMV) is characterized by cytological changes which are readily visualized by electron microscopy using ultrathin sections of infected cells. Treatment of such cells with 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG), a potent inhibitor of CMV, is effective when initiated at early or late times after infection and the response to such treatment has been studied by fine structural analysis. Inhibition of viral DNA synthesis by DHPG treatment (50 microM) late in virus infection resulted in a cessation of virus growth accompanied by a lack of development and possible regression in skein-like intranuclear inclusions together with a depletion in cytoplasmic dense bodies. Such changes were accompanied by the appearance of nuclear dense bodies. These were also present when virus growth was reduced (5 microM-DHPG) rather than completely inhibited (50 microM-DHPG) by treatment initiated from the time of infection. The nuclear bodies were predominantly of a reticular type structure after the early treatment but mainly of a homogeneous form when virus growth was interrupted at late times. Their presence appeared to be connected with the ability of infected cells to initiate the synthesis of late proteins and their morphology may relate to the extent of such protein synthesis. Unlike cytoplasmic dense bodies, provisional findings on the characterization of the nuclear bodies suggested that the 69K matrix protein was not present in abundance.

Acyclovir↗
PubMed1987

Synthesis of cytomegalovirus DNA is an antiviral target late in virus growth.

The mechanism of action of 9-(1,3-dihydroxypropoxymethyl)guanine (DHPG) and phosphonoformic acid (PFA) but not 5-fluorouridinedeoxyribose (FUdR), provides selective action against cytomegalovirus (CMV)-coded events and this was used to demonstrate that the synthesis of viral DNA was continuous during the extended phase of virus growth. The synthesis de novo of viral DNA was measured by restriction enzyme analysis after exposure to [32P]orthophosphate and its interruption by DHPG or PFA resulted in a cessation in the extrusion of infective virus from treated cells. The rate of decline in infectivity appeared to correspond to the failure of cells to maintain the synthesis of late proteins once DNA synthesis was blocked. Thus, regulation of late protein synthesis appeared to be linked to synthesis de novo of viral DNA even at late stages in CMV growth. The synthesis of the polyamines spermidine and spermine, considered obligatory for CMV growth, was unaffected by early or late inhibition of viral DNA and this showed that some virus-induced events were unaffected by the restriction on virus growth by DHPG. This provided evidence that polyamine biosynthesis was a target independent of viral DNA synthesis per se, which may be important in future considerations of combined drug therapies.

Acyclovir↗
PubMed1987

Asymptomatic shedding and subsequent transmission of genital herpes simplex virus.

We report the transmission of genital herpes simplex virus (HSV) infection from an asymptomatic woman shedding virus from the cervix to two male sexual partners and further transmission from these two men while their infection was in the prodromal phase. The value of the restriction enzyme analysis of viral deoxyribonucleic acid (DNA) is presented. Guidelines regarding the management of patients who are found to be asymptomatic shedders of HSV are discussed.

Adult↗
PubMed1986

Polyamine inhibitors.

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Acquired Immunodeficiency Syndrome↗