Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We analyzed plasma HIV-1 from 27 antiretroviral drug-naive Ugandan adults. Previous subtype analysis of env and gag sequences from these samples identified subtypes A, C, D, and recombinant HIV-1. Sequences of HIV-1 protease and reverse transcriptase (RT) were obtained with a commercial HIV-1 genotyping system. Subtypes based on protease sequences differed from gag subtypes for 5 of 27 samples, demonstrating a high rate of recombination between the gag and pol regions. Protease and RT sequences were analyzed for the presence of amino acid polymorphisms at positions that are sites of previously characterized drug resistance mutations. At those sites, frequent polymorphisms were detected at positions 36 and 69 in protease and positions 179, 211, and 214 in RT. Subtype-specific amino acid motifs were identified in protease. Most of the subtype A sequences had the amino acids DKKM at positions 35, 57, 69, and 89, whereas most subtype D sequences had the amino acids ERHL at those positions. Detection of those polymorphisms may provide a useful approach for rapid identification of subtype A and D isolates in Uganda. This analysis significantly increases the number of Ugandan protease and RT sequences characterized to date and demonstrates successful use of a commercial HIV-1 genotyping system for analysis of diverse non-B HIV-1 subtypes.
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PMID:Analysis of HIV type 1 protease and reverse transcriptase in antiretroviral drug-naive Ugandan adults. 1082 87

Since the introduction of HIV-1 protease inhibitors as components of antiretroviral drug combination regimens, the clinical course of HIV disease and opportunistic infections has changed dramatically. Besides the favourable virological, immunological and clinical impact of highly active antiretroviral therapy (HAART), several adverse drug reactions have been observed in patients with HIV receiving therapy. Particularly, peripheral lipodystrophy, central adiposity, dyslipidaemia and insulin resistance have been described with a prevalence of up to 80% in patients infected with HIV, and attributed to almost all components of HAART. Hyperlipidaemia is characterised by an increase of low and very low density lipoprotein-cholesterol as well as apolipoproteins B and E. Several studies strongly suggest that there are either multiple syndromes or a variety of factors inducing different changes that influence the ultimate phenotype. Similarities between HIV-associated fat redistribution and metabolic abnormalities with both inherited lipodystrophies and benign symmetric lipomatosis suggest the pathophysiological involvement of, for example, nuclear factors like lamin A/C and drug-induced mitochondrial dysfunction. Moreover, there is some evidence that cytokines and hormones impair fat and glucose homeostasis in patients with HIV receiving HAART. Three years after the first description of HIV therapy-associated abnormal fat redistribution, there is still an ongoing discussion about the case definition, diagnostic procedure and treatment options for both body shape changes and metabolic disturbances. Regarding therapy, there is a major concern about possible complex pharmacological interactions and overlapping adverse effects between HAART and, for example, lipid-lowering therapy. In addition, the likely contribution of both nucleoside analogue reverse transcriptase inhibitors and protease inhibitors to the development of abnormal fat redistribution in patients with HIV limits options of changing to alternative effective antiretroviral drug combinations. Thus, the occurrence of hyperlipidaemia, maturity onset diabetes mellitus, and marked changes in body habitus resulted in important social and clinical consequences such as an increased risk of atherosclerosis. It also sheds new light on the use of protease inhibitors regarding risk factors for the initial treatment decision. In this article, we discuss the features, pathogenesis and treatment options for body fat redistribution and metabolic disturbances associated with HAART in HIV-1 infection.
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PMID:Lipodystrophy syndrome in HIV infection: what is it, what causes it and how can it be managed? 1091 32

The recombinant virus assay (RVA) is a method for assessing the susceptibility of human immunodeficiency virus type 1 (HIV-1) plasma isolates to antiretroviral drugs. The RVA involves the production of viable virus in vitro by homologous recombination of RT-PCR products from plasma virus with a noninfectious reverse transcriptase (RT) or protease (PR)-deleted cloned HIV-1 provirus. In this study, we have constructed RVA plasmids with contiguous deletions in RT, PR, and the p7/p1 and p1/6 gag protease cleavage sites (CS). The deletions in these plasmids allow generation of recombinant viruses with all loci currently identified as important for resistance to anti-HIV-1 drugs being derived from the clinical isolate, including CS mutations that compensate for the reduced fitness of viruses resistant to protease inhibitors (Doyon et al., J Virol 1996:70:3763-3769). We have also used these new constructs to generate viruses with or without compensatory CS mutations, and examined the effects on fitness. In the case of an indinavir-selected virus, fitness was restored close to that of a wild type virus when a vector deleted in the CS and PR was used. With an amprenavir-selected isolate, virus fitness was incompletely restored by including the CS, and this defect appeared to be partially due to reduced infectivity of the virions. We conclude that the CS mutations were required for optimum detection of resistance in the RVA, but that virus fitness can remain compromised even in the presence of compensatory CS mutations.
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PMID:HIV type 1 protease cleavage site mutations and viral fitness: implications for drug susceptibility phenotyping assays. 1095 90

The recognition sequences for substrate cleavage by aspartic protease of HIV-1 are diverse and cleavage specificities are controlled by complex interactions between at least six amino acids around the cleavage site. We have identified 45 efficiently cleaved peptide substrates of HIV-1 protease (PR) using substrate phage display, an approach that can elucidate both context-dependent and context-independent preferences at individual subsites of a protease substrate. Many of the selected peptides were cleaved more efficiently and had lower K(m) values than physiologically relevant substrates of HIV-1 PR. Therefore, mutations occurring in the cleavage sites of the Gag and Gag-pol polyproteins of HIV-1 could significantly lower the K(m) values to better compete against drugs for protease binding while maintaining cleavage rates necessary for viral replication. The most efficiently cleaved peptide substrate derived from these phage, Ac-GSGIF*LETSL-NH(2), was cleaved 60 times more efficiently and had a K(m) approximately 260 times lower than a nine-amino-acid peptide based on the natural reverse transcriptase/integrase cleavage site when assayed at pH 5.6, 0.2 M NaCl. The peptide substrates selected served as frameworks for synthesis of tight binding reduced amide inhibitors of HIV-1 PR. The results show that the most efficiently cleaved substrates serve as the best templates for synthesis of the tightest binding inhibitors. Thus, defining changes in substrate preferences for drug-resistant proteases may aid in the development of more efficacious inhibitors.
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PMID:Identification of efficiently cleaved substrates for HIV-1 protease using a phage display library and use in inhibitor development. 1096 81

The aim of this preliminary experimental study was to test the stability of cryopreservation straws to human immunodeficiency virus-1 (HIV-1). Three kinds of straws were tested: four polyvinyl chloride (PVC), four polyethylene terephthalate glycol (PETG) and 20 high-security ionomeric resin (IR). The PVC and PETG straws were sealed ultrasonically, and the IR straw by thermosoldering. Each sealed straw was cut in half to produce two demi-straws and then filled with 100 microl of HIV-1-containing supernatant (reverse transcriptase activity: 15 000 c.p.m./50 microl). The unsealed cotton end of PVC and PETG straws and the two halves of the IR straws (cotton and plastic plug ends) were tested. Each demi-straw was two- thirds submerged in RPMI medium at 37 degrees C, and RPMI samples were withdrawn on days 3, 7 and 11. Viral RNA was extracted from the medium and then amplified by reverse transcriptase-polymerase chain reaction (RT-PCR) followed by nested PCR using primers specific to HIV-1 protease. On day 7, no HIV-1 RNA was detected in any of the different samples of medium that had surrounded the unsealed PVC and PETG straws with cotton ends, but three IR specimens were positive. On day 11, PVC and PETG remained negative but HIV-1 RNA was detected in RPMI samples for two more IR demi-straws (n = 5). In conclusion, under these experimental conditions (at 37 degrees C), the unsealed cotton end PVC, PETG and thermosoldered cotton end IR demi-straws appeared to be safe for HIV-1, while IR straws, sealed or unsealed with a plastic plug and with unsealed cotton ends, leaked.
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PMID:Safety of cryopreservation straws for human gametes or embryos: a preliminary study with human immunodeficiency virus-1. 1100 96

Within the past few years encouraging progress has been made in the treatment of HIV-1 infection, largely due to the combined use of HIV-1 protease inhibitors with nucleoside and non-nucleoside reverse transcriptase inhibitors. Despite this, HIV-1 infection is still a major global problem and the emergence of a drug resistant virus is ever present. There is a continuing need to develop new therapeutic strategies as well as improve upon all forms of existing therapies for the treatment of this viral infection. It has now been almost a decade since the first demonstration that ribozymes can effectively inhibit HIV-1 infectious spread in cell culture. Since then, ribozymes have progressed into human clinical trials primarily through gene therapy approaches. This progression brings ribozymes into the forefront as an important addition to the growing arsenal of anti-HIV-1 weapons. The following review covers the developments in anti-HIV-1 ribozyme usage over the past decade and summarizes the current state of ribozyme development for the purpose of inhibiting HIV-1 infection.
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PMID:Ribozyme therapy for HIV infection. 1103 99

We prospectively followed 20 consecutive patients with human immunodeficiency virus type 1 (HIV-1) with viral loads of <200 RNA copies/mL. These patients had been treated with 2 nucleoside reverse transcriptase inhibitors and > or =1 HIV-1 protease inhibitor for > or =3 months; they developed body changes consistent with lipodystrophy and requested they be switched from protease inhibitor to efavirenz. At baseline and every 3 months, we assessed the following: body mass index, waist-to-hip ratio, regional fat thickness (assessed by sonography), fasting total and high-density lipoprotein cholesterol, triglycerides, glucose, insulin, CD4(+) cells, and viral load. At baseline, hypertriglyceridemia (> or =200 mg/dL) was present in 17 (85%) patients, hypercholesterolemia (> or =200 mg/dL) in 14 (70%), and impaired fasting glucose (> or =110 mg/dL) in 8 (40%); CD4(+) T cells were 280x10(6) cells/L (range, 64-942x10(6) cells/L). HIV-1 RNA had been at <200 copies/mL for a median of 14 months (range, 3-24 months). Six months after switching to efavirenz, there was a reduction in triglyceride levels (a decrease of 31%; P=.03) and fasting insulin resistance index (a decrease of 28%; P=.03), but total and high-density lipoprotein cholesterol and glucose did not change. Waist-to-hip ratio decreased from 0.92 to 0.87 (P=.06). Subcutaneous fat thickness did not change. CD4(+) cells remained stable (363x10(6) cells/L; range, 102-741x10(6) cells/L; P=.65). Nineteen patients (95%) had HIV-1 RNA levels that remained at <200 copies/mL. Although CD4(+) response and viral suppression remained preserved after 6 months of switching from protease inhibitor to efavirenz, the benefits of this approach on the evolution of lipodystrophy were limited, and our findings do not support its routine recommendation to treat lipodystrophy.
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PMID:Impact of switching from human immunodeficiency virus type 1 protease inhibitors to efavirenz in successfully treated adults with lipodystrophy. 1107 62

Ritonavir is a potent, orally bioavailable inhibitor of HIV-1 protease. Our investigators undertook a retrospective study to compare the effectiveness of ritonavir (600mg twice daily) associated with 2 reverse transcriptase inhibitors (RTIs) in 38 patients in 3 situations. Group I patients previously treated with 2 RTIs, Group II treatment-naive patients, and Group III patients previously treated with 2 RTIs and saquinavir. Routine hematological and biochemical studies, HIV-1 viremia, and CD4+ lymphocyte counts were performed before and after ritonavir. In Group I, the median of HIV-1 RNA plasma levels decreased from 4.8 to 3.4 log(10) copies/mL, in Group II from 5.9 to 2.9 log(10) copies/mL, and in Group III from 5.2 to 4.1 log(10) copies/mL. (p=0.003, p=0.014, p=0.002, respectively, Wilcoxon signed rank test). The median increases of CD4(+) cells occurred as follows: in Group I from 173 to 282 cells/mm(3), in Group II from 92 to 254 cell/mm(3), and in Group III from 68 to 133 cell/mm(3) (p=0.002, p=0.008, p<0.001, respectively, Wilcoxon signed rank test). In Group II the mean weight increased from 55.2 +/-14.3 kg to 59.4+/-15.7 kg and, in Group III, from 62.2+/-10.5 kg to 67.5+/-12 kg (p = 0.026, p = 0.002, respectively, paired T test). Patients in Group I presented no weight gain. Mild reversible hypertriglyceridemia occurred in 6 of 38 patients. The results of this study showed that ritonavir is a good choice for treatment naive patients and as a sequential option, not only after 2 RTIs, but also after a 3 drug regimen with saquinavir.
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PMID:Comparison of Ritonavir in a First Choice Three Drug Regimen, After Two Nucleoside Analogues and in Saquinavir Experienced Patients. 1110 13

Lopinavir is a protease inhibitor with high specificity for HIV-1 protease. Ritonavir strongly inhibits lopinavir metabolism; coadministration of lopinavir and ritonavir in healthy volunteers increased the area under the lopinavir plasma concentration-time curve >100-fold. Trough plasma concentration: antiviral 50% effective concentration ratio for lopinavir was >75 for wild-type HIV at the dose used in clinical trials, compared to values of < or = 4 for other commonly used protease inhibitors. Coformulated lopinavir and ritonavir (lopinavir/ ritonavir) 400/100mg twice daily for 48 weeks suppressed HIV replication in significantly more antiretroviral-naive patients than nelfinavir 750mg 3 times daily (all patients also received stavudine and lamivudine). Suppression of viral replication was observed in most protease inhibitor-experienced patients with lopinavir/ ritonavir (400/100, 400/200 or 533/133mg twice daily for 48 or 96 weeks) in combination with > or = 2 nucleoside reverse transcriptase inhibitors (NRTIs) and either efavirenz or nevirapine. 48 weeks of treatment with twice daily lopinavir/ ritonavir (230/57.5 or 300/75 mg/m2 for the first 12 weeks and then 300/75 mg/m2) in combination with 1 or2 NRTIs, with or without nevirapine, suppressed viral replication in the majority of antiretroviral-naive and -experienced paediatric patients (aged 6 months to 12 years). Diarrhoea, nausea and asthenia were the most frequently reported adverse effects in patients receiving lopinavir/ritonavir-based regimens. Elevated total cholesterol, triglyceride and hepatic enzyme levels were also reported.
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PMID:Lopinavir. 1115 17

The emergence of mutations encoding drug resistance is supposed to be a significant limitation to the clinical efficacy of inhibitor compounds directed against specific HIV-1 enzymatic targets. We have used a commercial test (Visible Genetics Inc., Paris, France) to study the prevalence of mutations occurred in HIV-1 protease and reverse transcriptase (RT) genes in 93 HIV-1 infected patients treated with at least one regimen containing a protease inhibitor (PI) and failing to the current therapeutic regimen. Protease mutations conferring resistance to at least one PI were detected in 46/93 (49.4%) of strains, 25 (26.8%) of which showed resistance to all PIs. Reverse transcriptase mutations conferring resistance to at least one RT inhibitor were detected in 57/93 (61.2%) of strains, 18 (19.3%) of which showed resistance to all RT inhibitors. The most frequent RT mutations were T215Y/F, M41L, and M184V (41.9, 40.8, and 40.8%, respectively), while L63P, L10R/V, and A71V/T (58, 41.9, and 34.4%, respectively) were the most represented protease substitutions. We have found no mutations encoding for multiple dideoxynucleoside resistance (Q151M or T69SS). Twelve of our patients (12.9%) had no mutation encoding drug resistance and were completely sensitive to all RT and protease inhibitors. Therefore, not all virological failures are caused by HIV-1 genomic resistance.
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PMID:Analysis of HIV-1 mutation patterns in patients failing antiretroviral therapy. 1117 Feb 34


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