Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

IgG antibodies against Pneumocystis carinii (P. carinii) were detected by an ELISA method using urea-extracted material from human and rat P. carinii as the antigen. Carbohydrate formed a major part of the antigen responsible for reactivity in the ELISA assay, since periodate treatment reduced the reactivity of most sera tested. Cross-reactivity between human and rat P. carinii was detected. However, human serum recognized antigens specific for human P. carinii. With the ELISA method IgG antibody levels were compared between blood donors (n = 40), asymptomatic HIV-antibody positive patients (n = 30) and AIDS patients with (n=22) and without previous P. carinii pneumonia (PCP) (n=21). HIV-infected patients had significantly lower antibody reactivity against the microorganism compared with blood donors. Among HIV-antibody positive patients the highest antibody reactivity was seen in PCP patients. The antibody response to PCP was impaired, since an equal number of patients had an increase and a decrease in antibody reactivity. In conclusion, carbohydrate formed an important part of the P. carinii immunogenic antigen. Cross-reactivity between rat and human P. carinii was demonstrated, but reactivity was somewhat lower using antigen from rats. The antibody level was lower in HIV-infected patients and the ability to mount an antibody response to the infection was impaired, suggesting that the poor antibody response may contribute to the liability of HIV-infected patients to have PCP.
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PMID:Low levels of IgG antibodies against pneumocystis carinii among HIV-infected patients. 1006 52

The further development of allosteric HIV-1 RT inhibitors in the urea analogue series of PETT (phenylethylthiazolylthiourea) derivatives is described here. The series includes derivatives with an ethyl linker (1-5) and racemic (6-16) and enantiomeric (17-20) cis-cyclopropane compounds. The antiviral activity was determined both at the RT level and in cell culture on both wild-type and mutant forms of HIV-1. Most compounds have anti-HIV-1 activity on the wt in the nanomolar range. Resistant HIV-1 was selected in vitro for some of the compounds, and the time for resistant HIV-1 to develop was longer for urea-PETT compounds than it was for reference compounds. Preliminary pharmacokinetics in rats showed that compound 18 is orally bioavailable and penetrates well into the brain. The three-dimensional structure of complexes between HIV-1 RT and two enantiomeric compounds (17 and 18) have been determined. The structures show similar binding in the NNI binding pocket. The propionylphenyl moieties of both inhibitors show perfect stacking to tyrosine residues 181 and 188. The cyclopropyl moiety of the (+)-enantiomer 18 exhibits optimal packing distances for the interactions with leucine residue 100 and valine residue 179.
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PMID:Urea-PETT compounds as a new class of HIV-1 reverse transcriptase inhibitors. 3. Synthesis and further structure-activity relationship studies of PETT analogues. 1051 85

Carnitine is a well-known cofactor for the beta-oxidation of long-chain fatty acid. It also plays a role in transport of acetyl moity for fatty acid and cholesterol synthesis, excretion of organic acid and xenobiotic acid as carnitine ester, and control of ratio of acetylCoA to CoA. Therapeutic effect of acetylcarnitine on Alzheimer disease and HIV-infection, and aberrant incorporation acetylcarnitine into brain under chronic fatigue syndrome have been reported. Carnitine deficiency causes hyperammonemia through suppression of gene expression of urea cycle enzymes. On the other hand, a large amount of carnitine has a therapeutic effect on hyperammonemia by still unclear mechanism. These suggest carnitine as a multifunctional biofactor.
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PMID:[Carnitine as a vitamin-like biofactor]. 1054 Aug 73

Increased prevalence of anti-phospholipid antibodies (aPL) and increased levels of lipid peroxidation have been described in patients with HIV infection. To assess the binding specificity and avidity of aPL antibodies in HIV infection, sera from 44 HIV-1 infected patients were evaluated for antibodies to cardiolipin (aCL), phosphatidyl serine (aPS), phosphatidyl inositol (aPI) and phosphatidyl choline (aPC) using enzyme linked immunosorbent assay (ELISA) methods. Sera from 30 patients with systemic lupus erythematosus (SLE), but without features of anti-phospholipid syndrome (APS) (SLE/non APS), six with SLE and secondary APS, (SLE/APS) and 11 with primary APS (PAPS) were also evaluated as controls. The resistance of the aPL antibody binding to dissociating agents was evaluated by treating the ELISA wells, after serum incubation with 2 M urea or 0.6 M NaCl for 10 min. An anti-beta2-glycoprotein-I (beta2-GPI) ELISA was used to assess serum reactivity against beta2-GPI, a plasma protein considered as the true antigen of aCL antibodies occurring in APS and SLE patients. The prevalence of aCL, aPS, aPI and aPC antibodies in HIV-1 infection was 36%, 56%, 34% and 43% respectively, which was comparable to that found in SLE/APS and PAPS patients and significantly higher than that observed in SLE/non-APS patients. Anti-beta2-GPI antibodies occurred in 5% of HIV-1 infected vs. 17% in SLE/non-APS (P=0.11), 50% in SLE/APS (P=0.009) and 70% in PAPS patients (P=0.0014). A significant decrease of aPL binding after urea and NaCl treatment was observed in the sera of HIV-1-infected, compared to that of APS patients, indicating that aPL antibodies from HIV-1 infected individuals have low resistance to dissociating agents. In conclusion, aPL antibodies (1) occur in HIV-1 infection; (2) tend to recognize various phospholipids but not beta2-GPI; and (3) are of low resistance to dissociating agents-a finding probably reflecting low antibody avidity. Finally, these, like the autoimmune-type aCL antibodies, tend to recognize the oxidized CL-a finding probably indicating autoantibody generation as a result of neoepitope formation by oxidized PLs.
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PMID:Anti-phospholipid antibodies in HIV infection and SLE with or without anti-phospholipid syndrome: comparisons of phospholipid specificity, avidity and reactivity with beta2-GPI. 1055 Feb 22

Emivirine (EMV), formerly known as MKC-442, is 6-benzyl-1-(ethoxymethyl)-5-isopropyl-uracil, a novel nonnucleoside reverse transcriptase inhibitor that displays potent and selective anti-human immunodeficiency virus type 1 (HIV-1) activity in vivo. EMV showed little or no toxicity towards human mitochondria or human bone marrow progenitor cells. Pharmacokinetics were linear for both rats and monkeys, and oral absorption was 68% in rats. Whole-body autoradiography showed widespread distribution in tissue 30 min after rats were given an oral dose of [(14)C]EMV at 10 mg/kg of body weight. In rats given an oral dose of 250 mg/kg, there were equal levels of EMV in the plasma and the brain. In vitro experiments using liver microsomes demonstrated that the metabolism of EMV by human microsomes is approximately a third of that encountered with rat and monkey microsomes. In 1-month, 3-month, and chronic toxicology experiments (6 months with rats and 1 year with cynomolgus monkeys), toxicity was limited to readily reversible effects on the kidney consisting of vacuolation of kidney tubular epithelial cells and mild increases in blood urea nitrogen. Liver weights increased at the higher doses in rats and monkeys and were attributed to the induction of drug-metabolizing enzymes. EMV tested negative for genotoxic activity, and except for decreased feed consumption at the high dose (160 mg/kg/day), with resultant decreases in maternal and fetal body weights, EMV produced no adverse effects in a complete range of reproductive toxicology experiments performed on rats and rabbits. These results support the clinical development of EMV as a treatment for HIV-1 infection in adult and pediatric patient populations.
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PMID:Safety assessment, in vitro and in vivo, and pharmacokinetics of emivirine, a potent and selective nonnucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1. 1060 32

We report in this paper the design, by means of computational techniques, of new cyclic urea inhibitors of the HIV aspartic protease. The relationship between the complexation energies of the enzyme with known inhibitors and the experimentally determined log K(i) have been studied and used to predict inhibition constants for new inhibitors.
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PMID:Computational design of new cyclic urea inhibitors for improved binding of HIV-1 aspartic protease. 1067 13

Skeletal muscle tissue from SIV-infected macaques was previously found to contain abnormally high sulfate and low glutathione levels indicative of an excessive cysteine catabolism. We now confirm the peripheral tissue as a site of massive cysteine catabolism in HIV infection and have determined the urinary loss of sulfur per time unit. The comparison of the sulfate concentrations of the arterial and venous blood from the lower extremities of 16 symptomatic HIV+ patients and 18 HIV- control subjects (study 1) revealed (1) that the peripheral tissue of HIV+ patients with or without highly active antiretroviral therapy (HAART) releases large amounts of sulfate and (2) that plasma sulfate, thioredoxin, and interleukin-6 levels are elevated in these patients. A complementary investigation of 64 asymptomatic HIV+ patients and 65 HIV- subjects (study 2) revealed increased plasma sulfate levels in the asymptomatic patients. The analysis of the daily urinary excretion of sulfate and urea of another group of 19 HIV+ patients and 22 healthy HIV- subjects (study 3) confirmed (1) that HIV+ patients experience a massive loss of sulfur and (2) that this loss is not ameliorated by HAART. The sulfur loss of asymptomatic patients was equivalent to a mean loss of about 10 g of cysteine per day. If extrapolated, this would correspond to an alarming negative balance of approximately 2 kg of cysteine per year under the assumption that the normal sulfate excretion equivalent to approximately 3 g of cysteine per day is balanced by a standard Western diet. The abnormally high sulfate/urea ratio suggests that this process drains largely the glutathione pool.
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PMID:Massive loss of sulfur in HIV infection. 1071 Feb 8

Several strategies for evaluation of the protein-ligand binding free energies are examined. Particular emphasis is placed on the Linear Response Approximation (LRA) (Lee et. al., Prot Eng 1992;5:215-228) and the Linear Interaction Energy (LIE) method (Aqvist et. al., Prot Eng 1994;7:385-391). The performance of the Protein Dipoles Langevin Dipoles (PDLD) method and its semi-microscopic version (the PDLD/S method) is also considered. The examination is done by using these methods in the evaluating of the binding free energies of neutral C2-symmetric cyclic urea-based molecules to Human Immunodeficiency Virus (HIV) protease. Our starting point is the introduction of a thermodynamic cycle that decomposes the total binding free energy to electrostatic and non-electrostatic contributions. This cycle is closely related to the cycle introduced in our original LRA study (Lee et. al., Prot Eng 1992;5:215-228). The electrostatic contribution is evaluated within the LRA formulation by averaging the protein-ligand (and/or solvent-ligand) electrostatic energy over trajectories that are propagated on the potentials of both the polar and non-polar (where all residual charges are set to zero) states of the ligand. This average involves a scaling factor of 0.5 for the contributions from each state and this factor is being used in both the LRA and LIE methods. The difference is, however, that the LIE method neglects the contribution from trajectories over the potential of the non-polar state. This approximation is entirely valid in studies of ligands in water but not necessarily in active sites of proteins. It is found in the present case that the contribution from the non-polar states to the protein-ligand binding energy is rather small. Nevertheless, it is clearly expected that this term is not negligible in cases where the protein provides preorganized environment to stabilize the residual charges of the ligand. This contribution can be particularly important in cases of charged ligands. The analysis of the non-electrostatic term is much more complex. It is concluded that within the LRA method one has to complete the relevant thermodynamic cycle by evaluating the binding free energy of the "non-polar" ligand, l;, where all the residual charges are set to zero. It is shown that the LIE term, which involves the scaling of the van der Waals interaction by a constant beta (usually in the order of 0.15 to 0.25), corresponds to this part of the cycle. In order to elucidate the nature of this non-electrostatic term and the origin of the scaling constant beta, it is important to evaluate explicitly the different contributions to the binding energy of the non-polar ligand, DeltaG(bind,l;). Since this cannot be done at present (for relatively large ligands) by rigorous free energy perturbation approaches, we evaluate DeltaG(bind,l;) by the PDLD approach, augmented by microscopic calculations of the change in configurational entropy upon binding. This evaluation takes into account the van der Waals, hydrophobic, water penetration and entropic contributions, which are the most important free energy contributions that make up the total DeltaG(bind,l;). The sum of these contributions is scaled by a factor straight theta and it is argued that obtaining a quantitative balance between these contributions should result in straight theta = 1. By doing so we should have a reliable estimate of the value of the LIE beta and a way to understand its origin. The present approach gives straight theta values between 0.5 and 0.73, depending on the approximation used. This is encouraging but still not satisfying. Nevertheless, one might be able to use our PDLD approach to estimate the change of the LIE straight theta between different protein active sites. It is pointed out that the LIE method is quite similar to our original approach where the electrostatic term was evaluated by the LRA method and the non-electrostatic term by the PDLD method (with its vdw, solvation,
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PMID:Examining methods for calculations of binding free energies: LRA, LIE, PDLD-LRA, and PDLD/S-LRA calculations of ligands binding to an HIV protease. 1081 21

Integration of a DNA copy of the HIV-1 genome is required for viral replication and pathogenicity, and this highly specific molecular process is mediated by the virus-encoded integrase protein. The requirement for integration, combined with the lack of a known analogous process in mammalian cells, makes integrase an attractive target for therapeutic inhibitors of HIV-1 replication. While many reports of HIV-1 IN inhibitors exist, no such compounds have yet emerged to treat HIV-1 infection. As such, new classes of integrase inhibitors are needed. We have combined molecular modeling and combinatorial chemistry to identify and develop a new class of HIV-1 integrase inhibitors, the Carbonyl J [N,N'-bis(2-(5-hydroxy-7-naphthalenesulfonic acid)urea] derivatives. This new class includes a number of compounds with sub-micromolar IC(50) values for inhibiting purified HIV-1 integrase in vitro. Herein we describe the chemical characteristics that are important for integrase inhibition and cell toxicity within the Carbonyl J derivatives. Copyright 2000 Academic Press.
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PMID:Carbonyl J Derivatives: A New Class of HIV-1 Integrase Inhibitors. 1091 52

We report the case of a 40-year-old-man who developed febrile cytolysis as the presenting sign of hemorragic fever with renal syndrome (HFRS). On admission, he had fever (40 degrees C) and epigastric pain. The AST level was at 2N, the ALT at 3N. There was a thrombocytopenia (61 000/mm(3)) without anemia or hyperleukocytosis. Three days after admission, the platelet count decreased to 40 000/mm(3), serum urea and creatinine increased from normal rate to 10.8mmol/l, 204.0 micromol/l, respectively. The HIV, HBV, HCV, leptospirosis antibodies were negative. The Hantavirus serology was positive (Ig G: 1/512). This case suggests that HFRS should be entertained as a possible cause of cytolysis with thrombocytopenia in patients with fever and no initial sign of renal involvement in North-Eastern France.
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PMID:[Febrile cytolysis disclosing hemorrhagic fever with renal syndrome]. 1117 12


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