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

Changes in CD4+ T-cell surface marker phenotype and antigen receptor (TCR) repertoire were examined during the course of HIV infection and following therapy. A preferential decline in naive CD4+ T cells was noted as disease progressed. Following protease inhibitor therapy, naive CD4+ T cells increased only if they were present before initiation of therapy. Disruptions of the CD4+ TCR repertoire were most prevalent in patients with the lowest CD4+ T-cell counts. Antiviral or IL-12 therapy-induced increases in CD4+ T-cell counts led to only minor changes in previously disrupted repertoires. Thus, CD4+ T-cell death mediated by HIV-1 infection may result in a preferential decline in the number of naive CD4+ T cells and disruptions of the CD4+ T-cell repertoire that are not immediately corrected by antiviral or immune-based therapies.
 ...
PMID:HIV infection induces changes in CD4+ T-cell phenotype and depletions within the CD4+ T-cell repertoire that are not immediately restored by antiviral or immune-based therapies. 921 87

The processing of gag and gag-pol polyproteins by human immunodeficiency virus type 1 (HIV-1) protease is a crucial step in the formation of infectious HIV-1 virions. In this study, we examine whether particles produced in the presence of inhibitors of HIV-1 protease can subsequently undergo gag polyprotein cleavage with restoration of infectivity following removal of the inhibitors. Viral particles produced during 7 days of culture in the presence of the protease inhibitors KNI-272 (10 microM) and saquinavir (5 microM) contained predominantly p55gag polyprotein but little or no p24gag cleavage product. Following resuspension of the particles in medium free of the inhibitor, some gag polyprotein processing was detected in particles produced from the KNI-272-treated cells, but not from the saquinavir-treated cells within the first 3 h. However, the majority of the protein remained as p55gag throughout a 48-h experimental period. The infectivity (50% tissue culture infective dose per milliliter) of the viral particles from KNI-272-treated cells was 10(6)-fold lower than that of control particles and did not significantly increase over the 48 h after the inhibitor was removed, despite the apparent return of protease function in a subset of these virions. This failure to restore infectivity was due neither to a reduction in the number of particles produced by protease inhibitor-treated cells nor to a failure of HIV RNA to be packaged in the virions. These particles also failed to express the mature phenotype by electron microscopy. Thus, while some processing of the gag polyprotein can occur in isolated HIV virions, this does not appear to be sufficient to restore infectivity in the majority of particles. This finding suggests that there may be constraints on postbudding polyprotein processing in the production of viable particles. These results should have positive implications regarding the use of protease inhibitors as anti-HIV drugs.
 ...
PMID:Removal of human immunodeficiency virus type 1 (HIV-1) protease inhibitors from preparations of immature HIV-1 virions does not result in an increase in infectivity or the appearance of mature morphology. 914 62

We present several novel P1/P1' substituents that can replace the characteristic benzyl P1/P1' moiety of the cyclic urea based HIV protease inhibitor series. These substituents typically provide 5-10-fold improvements in binding affinity compared to the unsubstituted benzyl analogs. The best substituent was the 3,4-(ethylenedioxy)benzyl group. Proper balancing of the molecule's lipophilicity facilitated the transfer of this improved binding affinity into a superior cellular antiviral activity profile. Several analogs were evaluated further for protein binding and resistance liabilities. Compound 18 (IC90 = 8.7 nM) was chosen for oral bioavailability studies based on its log P and solubility profile. A 10 mg/kg dose in dogs provided modest bioavailability with Cmax = 0.22 microg/mL. X-ray crystallographic analysis of two analogs revealed several interesting features responsible for the 3,4-(ethylenedioxy)benzyl-substituted analog's potency: (1) Comparing the two complexes revealed two distinct binding modes for each P1/P1' substituent; (2) The ethylenedioxy moieties are within 3.6 A of Pro 81 providing additional van der Waals contacts missing from the parent structure; (3) The enzyme's Arg 8 side chain moves away from the P1 substituent to accommodate the increased steric volume while maintaining a favorable hydrogen bond distance between the para oxygen substituent and the guanidine NH.
 ...
PMID:Improved P1/P1' substituents for cyclic urea based HIV-1 protease inhibitors: synthesis, structure-activity relationship, and X-ray crystal structure analysis. 915 69

We have recently reported that thiadiazole (TDA) derivatives are highly potent inhibitors of human immunodeficiency virus type 1 (HIV-1) replication. These compounds belong to the family of nonnucleoside reverse transcriptase inhibitors (NNRTIs). In an attempt to develop more effective and pharmacologically favorable compounds, novel TDA derivatives have been synthesized and examined for their anti-HIV-1 activity in vitro. Among them, RD4-2217 was found to be the most potent inhibitor of HIV-1 replication. It inhibited replication of the HTLV-IIIB strain in MT-4 cells at a concentration of 6 nM. RD4-2217 was also inhibitory to clinical isolates and zidovudine-resistant mutants of HIV-1. The combination of RD4-2217 with zidovudine or the protease inhibitor A-75925 synergistically inhibited HIV-1 replication. Studies on the emergence of drug-resistant mutants revealed that, although much higher concentrations (1-10 microM) were required, RD4-2217 completely suppressed the breakthrough of HIV-1 in the supernatants during long-term culturing of infected cells. Furthermore, RD4-2217 at low concentrations (10 or 100 nM), in combination with zidovudine, also completely inhibited viral breakthrough. In addition, RD4-2217 had lower lipophilicity and improved protein binding as compared to its congener RD4-2024 and loviride. These results suggest that RD4-2217, one of the TDA derivatives, is worth pursuing as a candidate drug for the treatment of HIV-1 infections.
 ...
PMID:Thiadiazole derivatives: highly potent and selective inhibitors of human immunodeficiency virus type 1 (HIV-1) replications in vitro. 915 3

Zalcitabine is a dideoxynucleoside antiretroviral agent that is phosphorylated to the active metabolite 2',3'-dideoxycytidine 5'-triphosphate (ddCTP) within both uninfected and HIV-infected cells. At therapeutic concentrations, ddCTP inhibits HIV replication by inhibiting the enzyme reverse transcriptase and terminating elongation of the proviral DNA chain. The results of 3 large pivotal trials comparing zidovudine monotherapy with combination therapy have now clearly established that zalcitabine plus zidovudine combination with an improvement in viral load and CD4+ cell count compared with zidovudine monotherapy. More recently, clinical end-point and surrogate marker data have established the efficacy of zalcitabine in combination with the protease inhibitor saquinavir in zidovudine-experienced patients. Other studies have demonstrated the utility of zalcitabine in combination with ritonavir and the nucleoside analogue lamivudine. Importantly, early use of zalcitabine in the treatment sequence does not appear to limit the therapeutic efficacy of subsequent therapy with other nucleoside analogues such as lamivudine. Peripheral neuropathy is the most frequent dose-limiting adverse effect associated with zalcitabine therapy and is generally reversible on discontinuation of treatment. Stomatitis and mouth ulcers may occur frequently with zalcitabine therapy but tend to resolve with continuing treatment. Haematological toxicity, which is a common adverse effect associated with zidovudine, is reported infrequently with zalcitabine. Overall, combination therapy with zalcitabine plus zidovudine or saquinavir has been shown to have a tolerability profile comparable to that of either agent alone, although treatment with zidovudine plus zalcitabine was associated with a significant increase in the incidence of haematological toxicity compared with zidovudine monotherapy in one study. Therefore, current data suggest that zalcitabine is a useful antiretroviral agent for inclusion as a component of initial double combination therapy with zidovudine or as part of triple combination therapy including zidovudine plus a protease inhibitor in the management of patients with HIV infection.
 ...
PMID:Zalcitabine. An update of its pharmacodynamic and pharmacokinetic properties and clinical efficacy in the management of HIV infection. 917 31

1. SC-52151, an HIV protease inhibitor, is mainly metabolized by CYP3A4 and is poorly bioavailable after oral administration. After i.v. administration of SC-52151 to the female beagle dog (2.5 mg/kg), SC-52151 was rapidly eliminated in plasma with an elimination half-life of about 1 h, a plasma clearance of 44 ml/min/kg and an apparent steady-state volume distribution of 2.2 litre/kg. The high value of plasma clearance of SC-52151 suggests an extensive hepatic first-pass metabolism since SC-52151 is highly protein bound and does not partition itself into red blood cells. 2. The extensive hepatic first-pass metabolism was reduced by coadministration of a CYP3A4 inhibitor, ketoconazole. 3. Dogs were dosed daily with ketoconazole at dose of 100 mg ketoconazole per dog (approximately 10 mg/kg) for 5 days prior to the initiation of coadministration of SC-52151 for 15 days. The doses used for SC-52151 was 0, 60 and 120 mg SC-52151/kg/day (divided t.i.d., 8-h dosing interval). Coadministration of ketoconazole improved the bioavailability of SC-52151 from 4.1 to 9.6% and also improved the Cmax of SC-52151 from 0.41 to 0.83 microgram/ml. 4. Although the absolute bioavailability of SC-52151 was still low (approximately 10%), the Cmax and AUC achieved in this study were satisfactory for conducting chronic toxicology studies. No toxicity associated with the coadministration of ketoconazole was evident. Results from this study suggest that coadministration of ketoconazole might be a practical approach to increase the exposure of SC-52151 in both preclinical and clinical studies.
 ...
PMID:Improvement of bioavailability of the HIV protease inhibitor SC-52151 in the beagle dog by coadministration of the CYP3A4 inhibitor, ketoconazole. 917 89

Nelfinavir is a protease inhibitor which shows good inhibitory activity against HIV-1. The pattern of HIV-1 resistance to nelfinavir is different from that seen with other protease inhibitors. In healthy male volunteers, administration of single 400 and 800mg doses of nelfinavir with food resulted in area under the plasma concentration-time curve values that were 27 to 50% higher than those achieved in fasted volunteers who received the same doses of the drug. Reductions in plasma HIV RNA to below detectable levels (detection limit 500 copies/ml) were achieved in some patients (number not reported) after 28 days' treatment with nelfinavir 500, 600 or 750 mg twice daily, or 500, 750 or 1000 mg 3 times daily. Combination therapy with nelfinavir and stavudine produced greater reductions in plasma HIV RNA levels that stavudine monotherapy in patients who had not previously received stavudine treatment; mean increases in CD4+ cell counts were also greater in the combination treatment group than in monotherapy recipients. Plasma HIV RNA decreased to below detectable levels in 11 of 12 patients with early onset HIV infection who received a triple regimen of nelfinavir, zidovudine and lamivudine for 16 weeks.
 ...
PMID:Nelfinavir. 921 Oct 82

Seminal viral load is likely to be directly related to the sexual transmissibility of human immunodeficiency virus type 1 (HIV-1). However, it is not clear whether the level of HIV-1 in semen varies with the stage of infection and whether antiretroviral therapy reduces seminal viral load. A nucleic acid sequence-based amplification (NASBA) technique was used to quantify HIV-1 RNA as an indicator of infectious viral load in semen and blood plasma of homosexual men with different stages and durations of HIV-1 infection. The median viral load in a cross section of 34 men was 11,000 HIV-1 RNA copies/ml (range, <400 to 1.3 x 10(7) copies/ml) in whole semen and 5,238 HIV-1 RNA copies/ml (range, <400 to 2.8 x 10(5) copies/ml) in seminal plasma, which is 10- to 1,000-fold higher than previous estimates. Viral loads in whole semen and seminal plasma were strongly correlated with blood plasma viral load (P < 0.001) but not with blood CD4+ T-cell count (P = 0.420). Longitudinal analysis of eight subjects who progressed to AIDS showed that seminal viral load increased in most cases, with viral load consistently higher in blood plasma than in semen. Viral loads in semen and blood plasma decreased markedly in six other patients following initiation of potent combination therapy with a protease inhibitor (indinavir) and a nonnucleoside reverse transcriptase inhibitor (DMP-266). These findings have important implications for the biology of sexual transmission of HIV-1 and its potential reduction by antiretroviral therapy.
 ...
PMID:High viral load in semen of human immunodeficiency virus type 1-infected men at all stages of disease and its reduction by therapy with protease and nonnucleoside reverse transcriptase inhibitors. 922 32

A sensitive stereospecific high-performance liquid chromatographic assay for the quantitation of the enantiomers of 4-cyano-N-(3-(cyclopropyl-(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H- cycloocta(b)pyran-3-yl)methyl)phenyl)benzenesulfonamide (PNU-103017) (I), an HIV protease inhibitor, in plasma of rat, dog and human was developed. The procedure involved an acetonitrile-aided protein precipitation followed by solid-phase extraction (SPE) of I from plasma into ethanol. Stereospecific separation was accomplished on a Pirkle-concept chiral column (Regis S,S-Whelk-01, 250x4.6 mm I.D.) with a mobile phase of absolute ethanol-0.1% acetic acid in hexane (30:70, v/v). The eluate was monitored by UV absorbance (295 nm). Linear calibration curves were obtained in the range of 0.2 to 500 microM, with a lower limit of quantitation of 0.1-0.2 microM for both enantiomers in either rat, dog or human plasma. Intra- and inter-assay precision and assay accuracy were demonstrated to be acceptable for the stereoselective pharmacokinetic analysis of I in plasma.
 ...
PMID:Stereospecific determination of an HIV aspartyl protease inhibitor, PNU-103017, in rat, dog and human plasma using a Pirkle-concept high-performance liquid chromatographic column. 923 60

A great deal has been learned over the past 1 to 2 years about treatment of HIV infection. Viral load testing now provides a reliable method of assessing the effectiveness of any treatment regimen. And it is now clear that triple combinations of drugs (typically two nucleoside analogues and one protease inhibitor) are producing excellent reductions in viral load with concomitant elevations in CD4+ counts. This new triple-approach drug regimen has demonstrated clear advantage in delaying disease progression in persons in very early or late stages of the disease.
 ...
PMID:Understanding strategies for treating HIV. 923 82


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>