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Biomedical subjects

R Pauwels

Publications and source records attributed to R Pauwels.

At least 19 recordsLinked to original sources
PubMed1992

Potent and selective inhibition of human immunodeficiency virus (HIV)-1 and HIV-2 replication by a class of bicyclams interacting with a viral uncoating event.

A series of bicyclams have been shown to be potent and selective inhibitors of human immunodeficiency virus (HIV). The compounds are inhibitory to the replication of various HIV-1 and HIV-2 strains in various human T-cell systems, including peripheral blood lymphocytes, at 0.14-1.4 microM, without being toxic to the host cells at 2.2 mM. The bicyclam JM2763 is active against 3'-azido-3'-deoxythymidine (zidovudine; AZT)-resistant HIV-1 strains and acts additively with AZT. Mechanism of action studies revealed that the bicyclams (i.e., JM2763) interact with an early event of the retrovirus replicative cycle, which could be tentatively identified as a viral uncoating event.

Antiviral Agents↗
PubMed1992

Kinetics of inhibition of endogenous human immunodeficiency virus type 1 reverse transcription by 2',3'-dideoxynucleoside 5'-triphosphate, tetrahydroimidazo-[4,5,1-jk][1,4]-benzodiazepin-2(1H)-thion e, and 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine derivatives.

Recently, tetrahydroimidazo-[4,5,1-jk][1,4]-benzodiazepin-2(1H)-one and -thione (TIBO) and 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) compounds have been shown to be potent, selective, and specific inhibitors of human immunodeficiency virus type 1 (HIV-1) replication in vitro. They interact with the reverse transcriptase of HIV-1 in a way different from that of previously studied reverse transcriptase (RT) inhibitors. We established an endogenous RT assay, starting from intact HIV-1 virions. This assay mimics the reverse transcription process in the HIV-infected cell more closely than RT assays with artificial templates. We investigated the inhibition of endogenous HIV-1 reverse transcription by the TIBO derivative (+)-(S)-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo [4,5,1-jk][1,4]-benzodiazepin-2(1H)-thione (R-82150) in comparison with the HEPT derivative 5-ethyl-1-ethoxymethyl-6-(phenylthio)uracil (E-EPU) and 2',3'-dideoxyguanosine 5'-triphosphate. The kinetics and characteristics of RT inhibition by TIBO in the endogenous RT assay were similar to those found previously for the exogenous RT assay (following addition of exogenous template/primer); thus, RT inhibition by TIBO was specific for HIV-1 and the extent of RT inhibition was dependent on which of the four substrates (dATP, dTTP, dGTP, and dCTP) was present in limited concentrations. Of the three enzymatic activities, RNA-dependent DNA polymerization was preferentially inhibited, and inhibition was not competitive with respect to the natural substrates. HIV-1 RT behaved as an allosteric enzyme, which means that positive cooperativity for binding of the substrate was observed. TIBO behaved as an allosteric inhibitor by causing a concentration-dependent decrease in this cooperativity.

Allosteric Regulation↗
PubMed1992

IgG subclass deficiency in children with recurrent bronchitis.

We studied the incidence of IgG subclass deficiency in children with recurrent bronchitis. Recurrent bronchitis was defined as three or more episodes a year during at least 2 consecutive years, of bronchopulmonary infection, productive cough with or without fever and/or diffuse râles by physical examination in the absence of asthma or atopy. Fifty three children were selected, of whom 30 (57%) were deficient in one of the IgG subclasses. None had an IgG1 deficiency. Nine (17%) were deficient in IgG2, 9 (17%) in IgG3 and 20 (38%) in IgG4. Isolated IgG subclass deficiencies were most frequently seen for IgG4 (14, 26%), less for IgG3 (6, 12%) and even less for IgG2 (4, 7%). Nine (17%) children were IgA deficient and 8 (15%) IgG deficient with a combined IgG subclass deficiency in 8 and 7 of them respectively. By subdivision into different age groups most patients were encountered in the youngest group. The mean content of IgG2, IgG3 and IgG4 in 3- to 4-year-old children with recurrent bronchitis was significantly lower than in the age matched controls. The mean value for IgG4 in the 5- to 6-year-olds was significantly lower than in the control group. This study demonstrates the correlation between recurrent bronchitis in childhood and IgG subclass deficiency. IgG subclass deficiency and recurrent bronchitis are both quite prominent phenomena in young children but rare in older children, suggesting a transient immaturity of the immune system as one of the possible pathogenetic factors. An IgA or an IgG deficiency is highly suggestive for the existence of a combined IgG subclass deficiency.

Bronchitis↗
PubMed1992

Resistance of human immunodeficiency virus type 1 reverse transcriptase to TIBO derivatives induced by site-directed mutagenesis.

The reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) is the target enzyme for the tetrahydro-imidazo[4,5,1-jk][1,4]- benzodiazepin-2(1H)one and thione (TIBO) derivatives, a class of highly potent and selective anti-HIV agents that specifically inhibit HIV-1 but not HIV-2 replication. The amino acid sequence divergence may be held responsible for the differential sensitivity of HIV-1 RT and HIV-2 RT to the TIBO derivatives. Using site-directed mutagenesis, we have introduced several amino acid substitutions in the conserved regions of HIV-1 RT. Where applicable, the amino acids were replaced by the corresponding amino acids present in HIV-2 RT. The amino acid residues Y181 and Y188 appeared to be critical for the anti-HIV-1 RT activity of the TIBO derivatives, since substitution of these residues by the corresponding HIV-2 amino acids I181 and L188 resulted in a virtual loss of TIBO sensitivity without loss of enzymatic activity.

Antiviral Agents↗
PubMed1992

Presence of class II histocompatibility DR proteins on the envelope of human immunodeficiency virus demonstrated by FACS analysis.

Depending on the cell line used for virus propagation, human immunodeficiency virus (HIV) particles may possess class II MHC proteins, as demonstrated by FACS analysis. HLA-DR appeared in high amounts at the HIV envelope, if the virus was grown in HLA-DR+ cells, but was absent if the virus had been grown in HLA-DR- cells. No other cellular constituents, including HLA-DQ and HLA-DP, were detected in these virions. The presence of HLA-DR in the virion envelope itself in preparations used for diagnostic purposes may explain some of the false-positive results obtained in earlier serological tests for HIV infection. Possible implications of these virus-associated cellular antigens in the immunopathogenesis of AIDS should be considered.

Cells, Cultured↗
PubMed1992

Different pattern of activity of inhibitors of the human immunodeficiency virus in lymphocytes and monocyte/macrophages.

Monocyte/macrophages (M/M) are important targets for HIV in the body, and represent the majority of cells infected by the virus in some body compartments such as the central nervous system (CNS). M/M can be different from T-lymphocytes in terms of surface antigens, cell replication and drug metabolism. Thus, we evaluated, in M/M and in T-lymphocytes, the pattern of viral inhibition induced by various anti-HIV drugs, and assessed some of the mechanisms of action related to such antiviral activity. Inhibitors of HIV binding on CD4 receptors have similar activity in M/M and T-lymphocytes, while AZT and other dideoxynucleosides (ddN) are in general more active against HIV in M/M than in T-lymphocytes. This phenomenon can be related to the increased ratio in M/M of ddN-triphosphate/deoxynucleoside-triphosphate, and can at least in part explain the ability of zidovudine and didanosine in improving neurological dysfunctions in AIDS patients. Moreover, the antiviral activity of AZT (but not of other ddN- or HIV-binding inhibitors) is potently enhanced by cytokines like granulocyte-macrophage colony stimulating factor (GM-CSF) in M/M, while anti-HIV activity of TIBO compounds in M/M is not down-modulated by GM-CSF and other cytokines. Finally, non-toxic concentrations of adriamycin, an anticancer drug reported to be active against DNA viruses, can inhibit HIV replication in M/M (but not in T-lymphocytes). Taken together, these results suggest that M/M are selective targets for HIV with peculiarities different from those of T-lymphocytes. Thus, promising anti-HIV compounds should be evaluated both in T-cells and in M/M before reaching clinical trials. This may help in selecting drugs with good chances of being effective in patients with HIV-related disease.

Adenine↗
PubMed1992

Differential inhibitory effects of TIBO derivatives on different strains of simian immunodeficiency virus.

Recently, several classes of compounds have been shown to be extremely selective inhibitors of human immunodeficiency virus type 1 (HIV-1) replication in vitro. These include the tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-one and -thione (TIBO), 1-(2-hydroxyethoxymethyl)-6-(phenylthio)-thymine (HEPT), dipyridodiazepinone, pyridinone and bis(heteroaryl)piperazine derivatives. The hallmark of these new antiviral compounds is a specific interaction with reverse transcriptase (RT) of HIV-1. They are inactive against HIV-2 and any other viruses tested. Here we describe that, in addition to the HIV-1 strains, two simian immunodeficiency virus (SIV) strains from African green monkeys (SIVagm3 and SIVagmTYO-1) are also sensitive to the TIBO class of compounds. TIBO and HEPT derivatives block the replication of SIVagm in cell culture at micromolar concentrations. Kinetics of inhibition of SIVagm RT by TIBO are competitive with respect to the natural substrate (dGTP). Amino acid alignments and site-directed mutagenesis point to the critical role of amino acid residues Y181 and Y188 in the sensitivity of HIV-1 RT and SIVagm RT to inhibition by the TIBO derivatives. Antiviral efficacy studies with this range of compounds and using sensitive SIV strains are now feasible in monkeys.

Amino Acid Sequence↗
PubMed1992

Cell type-specific anti-human immunodeficiency virus type 1 activity of the transactivation inhibitor Ro5-3335.

The drug Ro5-3335 [7-chloro-5-(2-pyrryl)-3H-1,4-benzodiazepin-2(H)-one] inhibits human immunodeficiency virus type 1 (HIV-1) gene expression at the transcriptional level through interference with Tat-mediated transactivation (M.-C. Hsu, A. D. Schutt, M. Holly, L. W. Slice, M. I. Sherman, D. D. Richman, M. J. Potash, and D. J. Volsky, Science 254:1799-1802, 1991). We confirmed this specific inhibitory effect in a quantitative bioassay based on transactivation of a chimeric gene comprising the HIV-1 long terminal repeat promoter fused to the lacZ gene of Escherichia coli and transfected in a HeLa cell line expressing Tat. Ro5-3335 was found to inhibit HIV-1 long terminal repeat-driven lacZ gene expression at a 50% inhibitory concentration of 0.5 microM. The in vitro anti-HIV-1 activity of Ro5-3335 was highly dependent on the nature of the host cells. The highest selectivity index, 50, was found in phytohemagglutinin-stimulated peripheral blood lymphocytes. The selectivity index was between 1 and 10 in the CD4+ T-cell lines CEM, MOLT-4 (clone 8), and HUT-78. In MT-4 and MT-2 cells, Ro5-3335 had no inhibitory effect on HIV-1 replication. The absence of anti-HIV-1 activity of Ro5-3335 in MT-4 cells was confirmed by using different parameters of virus replication and different multiplicities of infection. In persistently HIV-1-infected HUT-78/IIIB/LAI cells, Ro5-3335 failed to demonstrate any activity at subtoxic concentrations. The cytotoxicity of Ro5-3335 was significantly lower in peripheral blood lymphocytes than in the CD4+ T-cell lines.

Antiviral Agents↗
PubMed1992

Primary pulmonary Hodgkin's disease.

26 months after the onset of alcohol-induced pain, a diagnosis of primary pulmonary Hodgkin's (PPHD) disease could be made in a 34-year-old woman. Standard radiology of the thorax remains normal up to 18 months after the onset of symptoms. A short review of the literature concerning PPHD is given.

Adult↗
PubMed1992

Mechanism of anti-human immunodeficiency virus action of polyoxometalates, a class of broad-spectrum antiviral agents.

Various polyoxometalates proved inhibitory to the replication of a number of enveloped DNA and RNA viruses, i.e., herpesviruses (herpes simplex and cytomegalo), togaviruses (Sindbis), paramyxoviruses (respiratory syncytial), rhabdoviruses (vesicular stomatitis), arenaviruses (Junin and Tacaribe), and retroviruses [human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2), simian immunodeficiency virus, and murine sarcoma virus]. The most potent compounds, i.e., JM1590 [K13[Ce(SiW11O39)2]. 26H2O] and JM2766 [K6[BGa(H2O)W11O39]. 15H2O], inhibited HIV-1 and simian immunodeficiency virus at concentrations as low as 0.008-0.8 microM. The polyoxometalates also inhibited giant cell formation in co-cultures of HIV-infected HUT-78 cells and uninfected MOLT-4 cells. Studies designed to unravel the mechanism of action of these compounds revealed that they inhibit the reverse transcriptase activity associated with HIV. The polyoxometalates also proved inhibitory to the binding of HIV-1 virions to the cells. From "time of addition" experiments, whereby the polyoxometalates were added at different times after virus infection, their mechanism of anti-HIV action could be attributed to inhibition of virus-cell binding. There was a good correlation (r = 0.84) between the inhibitory effects of the compounds on HIV-1-induced cytopathicity and their inhibitory effects on syncytium formation and a close correlation (r = 0.902) between their inhibitory effects on syncytium formation and their interaction with gp120, whereas there was no correlation between their anti-HIV-1 activity and their inhibitory effects on HIV-1 reverse transcriptase. In flow cytometric studies, the compounds did not interfere with the binding of OKT4A/Leu-3a monoclonal antibody to the CD4 receptor of uninfected cells, but they inhibited binding of anti-gp120 monoclonal antibody to HIV-1-infected cells. Thus, the binding of the polyoxometalates to the viral envelope glycoprotein gp120 is responsible for their anti-HIV activity.

Antiviral Agents↗
PubMed1992

Allosteric inhibition of human immunodeficiency virus type 1 reverse transcriptase by tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one and -thione compounds.

The reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) is present in virions and infected cells as an heterodimer (p66/p51). A new class of potent and selective HIV-1 inhibitors, the tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one and -thione (TIBO) derivatives, were found to exert their antiviral activity by interacting with monomeric HIV-1 RT (p66) in a way different from that of previously studied RT inhibitors such as azidothymidine 5'-triphosphate. Upon examination of the kinetic properties of the heterodimeric HIV-1 RT and its inhibition by TIBO compounds, a positive cooperativity between the subunits of the enzyme with regard to the 2'-deoxynucleoside 5'-triphosphates and the template/primer was observed. The cooperativity with respect to the template/primer may result from a progressive dimerization in the presence of increasing concentrations of the template/primer, a process referred to as polysteric linkage. Because the cooperativity of p66/p51 was abolished in the presence of TIBO, these compounds behave as allosteric inhibitors.

Benzodiazepines↗
PubMed1992

Common features in the interaction of tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one and -thione and 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine derivatives with the human immunodeficiency virus type 1 reverse transcriptase.

Recently, several classes of compounds have been shown to be potent, selective, and specific inhibitors of human immunodeficiency virus type 1 replication in vitro. These include the tetrahydroimidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-one and -thione (TIBO) and the 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) derivatives. Both the TIBO and HEPT derivatives specifically inhibit human immunodeficiency virus type 1 reverse transcriptase (RT). From a comparative study of the characteristics of RT inhibition by TIBO and HEPT, and from the competition between TIBO and HEPT for RT inhibition, we infer that both classes of compounds, although structurally unrelated, are targeted at the same site of the enzyme. Detailed functional and kinetic analyses indicate that this target site is functionally and possibly also spatially related to the substrate binding site.

Antiviral Agents↗
PubMed1992

Perinatal manifestations of maternal yellow nail syndrome.

A term female firstborn infant had unexplained nonimmune fetal hydrops and recurrent left chylothorax at 4 weeks of age. A few months before conception, her mother had had acute dystrophic nail changes and is being treated for recurrent sinusitis, bronchiectasis, and a deficiency of serum IgG2. We suggest that they both suffer from a dominantly inherited congenital lymphedema syndrome known as 'yellow nail dystrophy.' Prenatal manifestation of this disorder has not been reported previously. The child's anthropometric and neurological development was normal at 1 year of age, whereas mild ankle edema and marbling of the skin of the limbs were salient clinical findings. Inherited lymphedema leading to nonimmune fetal hydrops also has been recognized in chromosomal disorders, Noonan's syndrome, multiple pterygium syndrome, pulmonary lymphangiectasis, and mixed-vessel lymphatic dysfunction. Indicators of parental lymphedema are not on record in those instances.

Chylothorax↗
PubMed1991

An antiviral target on reverse transcriptase of human immunodeficiency virus type 1 revealed by tetrahydroimidazo-[4,5,1-jk] [1,4]benzodiazepin-2 (1H)-one and -thione derivatives.

Screening of pharmacologically acceptable prototype compounds has recently led to the discovery of a series of ultraselective inhibitors of human immunodeficiency virus (HIV)-1 replication, the tetrahydroimidazo[4,5,1-jk] [1,4]-benzodiazepin-2(1H)-one and -thione (TIBO) derivatives. The TIBO compounds completely suppress the formation of proviral DNA in acutely infected cells, as revealed by polymerase chain reaction (PCR) analysis. TIBO derivatives are inhibitory to the reverse transcriptase (RT) of HIV-1 but not that of HIV-2 or other retroviruses. The inhibition is most effective with poly(C)-oligo(dG) as the template/primer, and it is selectively directed against the RNA-dependent DNA polymerase activity and not the accompanying DNA-dependent DNA polymerase and ribonuclease H activity of HIV-1 RT. Kinetic studies point to an uncompetitive inhibition with regard to the template/primer. TIBO compounds are active against HIV-1 replication through a unique interaction with HIV-1 RT. The experimental data indicate the existence of a target on HIV-1 RT that is responsible for the inhibition of replication and a mode of action unrelated to that of previously studied RT inhibitors.

Antiviral Agents↗
PubMed1991

A TIBO derivative, R82913, is a potent inhibitor of HIV-1 reverse transcriptase with heteropolymer templates.

R82913, (+)-S-4,5,6,7-tetrahydro-9-chloro-5-methyl-6-(3-methyl-2-butenyl)- imidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-thione (a TIBO derivative), inhibited the replication of thirteen different strains of HIV-1 in CEM cells with a median IC50 of 0.15 microM. The concentration of compound that killed 50% of the cells was much higher (46 microM), indicating that R82913 has a high selectivity index. R82913 was 20-fold more potent than AZT-TP in the inhibition of HIV-1 reverse transcriptase in an assay using a naturally occurring template (ribosomal RNA) that more accurately resembles native viral RNA than a synthetic homopolymer. With this template, R82913 inhibited HIV-1 reverse transcriptase with an ID50 (0.01 microM) that is equal to, or lower than, the IC50 for this compound in all of our cell culture assays (0.01-0.65 microM). R82913 has no effect on the replication of HIV-2 in CEM cells and does not inhibit the reverse transcriptase from this virus.

Base Sequence↗