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)

Proviral DNAs from 3 laboratory strains and 21 clinical isolates of HIV-1 were extracted from infected cells after proteinase K digestion and the protease gene was PCR amplified and sequenced directly by the Sanger method. In vitro susceptibilities of the virus isolates to protease inhibitors were determined by the ACTG/DoD consensus assay. Four different HIV protease inhibitors were tested including P9941, a C2 symmetrical diol (Du Pont-Merck); A80987, an asymmetric mono-ol (Abbott); XM323, a cyclic urea (Du Pont-Merck); and Ro31-8959, an asymmetric hydroxyethylene isostere (Roche). Maximum sequence variation was 10% at both the nucleic and amino acid levels. Purine-purine substitutions were most common. Five noncontiguous regions were conserved across all isolates and corresponded to amino acids 1-9 (amino terminal), 21-32 (catalytic site), 47-56 ("flap" region), 78-88 (substrate-binding region), and 94-99 (carboxy terminal). All clinical isolates demonstrated in vitro susceptibility to the protease inhibitors. There was no significant difference between the susceptibility of the reference strains and the clinical isolates. These data suggest that the variable regions of protease do not contain sites that are important for interactions with the inhibitors tested.
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PMID:Limited sequence diversity of the HIV type 1 protease gene from clinical isolates and in vitro susceptibility to HIV protease inhibitors. 773 83

A series of N1-methyl,N1-allyl,N1-(2-chloroethyl) and N1-propargyl urea and nitrosourea derivatives of diamino acids (L-ornithine and L-lysine) was synthesized and was shown to have weak activity in counteracting the cytopathic effects of the HIV-1 on a T4 lymphocyte cell line (CEM-IW). However, selected compounds may possess some immunomodulatory activity.
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PMID:Synthesis and anti-HIV activity of new urea and nitrosourea derivatives of diamino acids. 779 48

The pharmacokinetics of a series of novel cyclic, non-peptide inhibitors of HIV protease were studied in rats or dogs after intravenous and oral administration. Six symmetrically substituted cyclic urea compounds (XK234, XM311, XM320, XM321, XM323, and XM412), which effectively inhibited HIV virus replication, with IC90 values of 0.03-1.0 microM (0.017-0.76 microgram mL-1), were evaluated. Plasma concentrations were measured in rats and dogs using specific and sensitive HPLC methods. In rats, the maximum plasma concentrations of 0.21-1.88 micrograms mL-1 were detected within 1 h of oral administration of 10 mg kg-1 of the compounds. The elimination half-lives ranged from 1.25 to 3.3 h in rats and the absolute oral bioavailability ranged from 18 to 100%. In dogs, the maximum plasma concentration and absolute oral bioavailability were 4.37 micrograms mL-1 and 48%, 1.07 micrograms mL-1 and 16%, and 1.48 mg ML-1 and 38% for XK234, XM311, and XM323, respectively. The data demonstrated that the maximum plasma concentrations of these cyclic ureas were several times higher than the IC90 for inhibition of viral replication after single doses of 10 mg kg-1 in rats and dogs. With this combination of high potency against virus replication and good oral bioavailability, these cyclic ureas represent a new class of compounds that are suitable for development as therapeutic agents for the treatment of HIV-associated diseases.
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PMID:A pharmacokinetic evaluation of HIV protease inhibitors, cyclic ureas, in rats and dogs. 784 30

In previous papers, we have described the discovery of a new series of compounds, 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1 H)- ones, TlBO (1 and 1a), with potent anti-HIV-1 activity and the synthesis of analogues to better define the structure-activity relationships (SAR) in terms of changes in substituents at the N-6 position and variations of the five-membered urea ring as well as the seven-membered diazepine ring. This paper describes the synthesis of TlBO analogues with various substitutents on the aromatic ring and their SAR in terms of anti-HIV-1 properties. Substituents on the 8-position furnished the most rewarding results and gave a large improvement in potency versus the parent compound. These included halogen, thiomethyl, and methyl. Analogues like 8-cyano, -methoxy, and -acetylene were equipotent, while 8-amino, -acetylamino, -dimethylamino, and -nitro were inactive (Table 1). Substituents at the 9-position tended to have little effect on activity, and 10-substituents decreased activity. The 8-chloro compound 6a with IC50 = 0.0043 microM is currently under clinical development.
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PMID:Synthesis and anti-HIV-1 activity of 4,5,6,7-tetrahydro-5-methylimidazo-[4,5,1-jk][1,4]benzodiazepin- 2(1H)-one (TlBO) derivatives. 4. 787 44

N-acetyl-L-cysteine (NAC) has been proposed as a therapeutic agent for AIDS patients because it reduces human immunodeficiency virus type 1 (HIV-1) replication in stimulated T cells. However, NAC and glutathione enhanced acute HIV-1 replication in monocyte-derived macrophages. Buthionine sulfoximine did not affect NAC-mediated enhanced HIV-1 replication, indicating that the NAC-mediated effects are glutathione-independent. Superoxide dismutase and the hydroxyl radical scavengers dimethylthiourea and thiourea, but not urea, inhibited acute HIV-1 replication in macrophages. NAC reduced ferricytochrome c and increased dose-dependently Fe(III)-citrate and Fe(III)-EDTA-catalyzed hydroxyl radical formation in a system using glucose and glucose oxidase. Dimethylthiourea and thiourea, but not urea and superoxide dismutase, dose-dependently inhibited NAC-mediated enhancement of HIV-1 replication. These data suggest that oxygen radicals play an important role in self-sustained HIV-1 replication in macrophages and that oxygen radical scavengers other than NAC should be considered as therapeutic agents for AIDS patients.
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PMID:Role for oxygen radicals in self-sustained HIV-1 replication in monocyte-derived macrophages: enhanced HIV-1 replication by N-acetyl-L-cysteine. 799 46

Despite association with adverse clinical outcome, human immunodeficiency virus (HIV)-associated malnutrition has been relatively refractory to conventional nutrition management. Consequently, a prospective randomized trial was conducted to evaluate a new peptide-based enteral formula (NEF) in contrast to a standard enteral formula (SEF) in patients with HIV infection. Eighty early-stage largely asymptomatic patients were randomized into a dietary regimen supplemented with either a ready-to-feed NEF (18.7% protein, 65.5% carbohydrate, 15.8% fat; 1.28 kcal/ml) or SEF (14% protein, 55% carbohydrate, 31% fat; 1.06 kcal/ml). Patients received 2-3 8-oz cans of the NEF or SEF supplement per day for 6 mo. Parameters evaluated at 0 (baseline), 3, and 6 mo included adherence, weight change, anthropometric measurements, serum biochemical indices, gastrointestinal symptoms, physical performance, and intercurrent health events (including hospitalizations). For the 56 evaluable patients, those supplemented with NEF maintained their body weight significantly (p = 0.04) better, had significantly (p = 0.03) more stable triceps skin-fold measurements, and had significantly (p = 0.04) lower blood urea nitrogen than patients consuming the SEF supplement. Consumption of the NEF supplement was also associated with significantly reduced hospitalizations during the 3- to 6-mo evaluation period (p = 0.02). The NEF supplement was well tolerated and did not result in untoward clinical effects. These data suggest that supplemental use of an NEF provides superior nutritional management compared with an SEF for patients with early-stage HIV infection.
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PMID:Long-term effects of early nutritional support with new enterotropic peptide-based formula vs. standard enteral formula in HIV-infected patients: randomized prospective trial. 811 Nov 47

The entire nef gene sequence of HIV-2, NIH-Z strain, has been cloned into the pJL6 expression vector and used for the synthesis of a 23-kDa protein in E. coli. The expressed protein is a fusion between the N-terminal 13 amino acids of the cII gene, 8 amino acids resulting from the ligation procedure, and the 180 amino acids that comprise the HIV-2 Nef sequence from the NIH-Z strain. The bacterially expressed Nef protein has been purified to apparent homogeneity on analytical scale (10-20 micrograms) by a combination of sequential detergent extraction, gel filtration, and reversed-phase high-performance chromatography. The expressed Nef protein is highly susceptible to proteolysis (chymotryptic-like activity) and this property accounts for the low yield obtained by gel filtration and RP-HPLC. Larger amounts (> 100 micrograms) of the purified Nef protein have been produced by a purification procedure that employs sequential detergent extraction, chromatography on Q-Sepharose in the presence of 7 M urea, and chromatography on hydroxylapatite, also in 7 M urea. The purified HIV-2 Nef protein has been used for the production of polyclonal and monoclonal antibodies. The milder method of purification should facilitate structure-function studies of the Nef protein and its role in the life cycle of HIV.
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PMID:Purification of an Escherichia coli-expressed Nef protein from the human immunodeficiency virus-type 2. 814 39

Current methods to establish the duration of toxoplasma infection in pregnant women and for the diagnosis of toxoplasmosis in the neonate or HIV infected patient have significant limitations. We assessed the precision of a commercial ELISA for the detection of toxoplasma specific IgG and adapted the assay to measure avidity using an elution agent washing step. The sensitivity and specificity of the ELISA were 100 and 75% respectively and optimal measurement of avidity was achieved using 6 M urea as the elution agent. Toxoplasma lymphadenopathy of less than 3 months duration was associated with low avidity specific IgG but some discordant findings were recorded. Serial measurement of IgG avidity assisted the distinction between actively produced antibody in infants with congenital toxoplasmosis and passively acquired antibody of maternal origin in uninfected babies. There was no significant difference between avidity levels in HIV infected patients with or without cerebral toxoplasmosis.
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PMID:The diagnosis of toxoplasmosis using IgG avidity. 815 14

We have cloned a simian immunodeficiency virus (SIV) proteinase gene directly from proviral DNA of the infectious viral stock SIVmac251-32H (11/88 pool). The deduced amino acid sequence from this proteinase gene is similar to that for the published SIVmac239 molecular clone. SIVmac251-32H proteinase (SIV PR) and its flanking pol sequences were expressed in Escherichia coli as a fusion protein with most of the T7 bacteriophage gene 10 protein. The expressed protein formed cytoplasmic inclusion bodies which were solubilized in 8 M urea, and the recombinant SIV PR was refolded, yielding active, self-processed enzyme. The SIV PR was purified to homogeneity using a single pepstatin A affinity chromatography step, and had a specific peptidolytic activity of 20 mumol/min/mg. Enzymatic characteristics similar to those previously documented for other immunodeficiency virus proteinases (EC 3.4.23) were observed. These include an acidic pH optimum (pH 5.3), sensitivity to sodium chloride concentration, and complete inhibition by pepstatin A. In addition to these properties we have observed quantitative crystallization from low protein concentrations. We describe the first crystal habit for the proteinase from the HIV-2/SIV class of immunodeficiency virus, which is distinctly different from that for HIV-1 proteinase crystals.
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PMID:Purification of crystallizable recombinant SIVmac251-32H proteinase. 816 77

The negative factor, Nef, of HIV-1 was found to associate to an extent of 16-42% with the detergent insoluble cytoskeletal fraction of T lymphocytes. Furthermore, Escherichia coli expressed Nef protein was found to bind during in vitro reactions with the cytoskeletal matrix to an extent of 30-50%. Cytoskeletal association of Nef was significantly enhanced by myristoylation. The specificity of the myristoylation-enhanced binding was demonstrated by the lack of an effect of myristoylation on binding of the HIV-1 Gag protein to the cytoskeleton. Cytoskeletal binding was saturable, and inhibited by high concentrations of sodium chloride, or with SDS or urea. Binding of Nef to the cytoskeletal matrix may be important in mediating its effects on HIV-1 replication.
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PMID:Myristoylation-enhanced binding of the HIV-1 Nef protein to T cell skeletal matrix. 821 77


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