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)

To examine the prevalence of drug resistance mutations among treatment-naive HIV/AIDS patients living in Liaoning province in China, the HIV-1 pol gene from plasma of 91 seropositive treatment-naive patients was amplified and sequenced. Three patients (3.3%) had an M46I amino acid substitution in the protease (PR) gene that decreased susceptibility to IDV, RTV, and NFV and one patient (1.1%) had an M184I amino acid substitution in the reverse transcriptase (RT) gene that confers high-level resistance to 3TC and FTC. Minor mutations were detected in high frequency in the PR gene. The frequencies of minor mutations to protease inhibitors (PI) were I93L (71.4%), L63P (62.6%), V77I (62.6%), M36I/V (33.0%), A71T/V (22.0%), K20R (6.6%), G16E (6.6%), and L10I (5.5%). The relatedness between subtypes and the frequencies of amino acid substitutions in PR were observed; 63P, 77I, and 71V/T were found in HIV-1 subtype B'/B, 16E, 36I, 20R/I, and 82I in non-B, except for CRF07_BC, 10I in subtype A, and 93L in non-A. Although the primary resistance of HIV-1 to antiretroviral drugs is low among the treatment-naive HIV-1 patients living in Liaoning province, the surveillance and monitoring of drug-resistant HIV-1 should be implemented regularly because of the increased access to antiretroviral therapy in China.
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PMID:Genotypic resistance mutations to antiretroviral drugs in treatment-naive HIV/AIDS patients living in Liaoning Province, China: baseline prevalence and subtype-specific difference. 1741 68

Apricitabine is a novel deoxycytidine analogue reverse transcriptase inhibitor that is under development for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Apricitabine is phosphorylated to its active triphosphate by deoxycytidine kinase, which is also responsible for the intracellular phosphorylation of lamivudine (3TC) and emtricitabine (FTC); hence, in vitro studies were performed to investigate possible interactions between apricitabine and these agents. Human peripheral blood mononuclear cells (PBMC) were incubated for 24 h with various concentrations of (3)H-labeled or unlabeled apricitabine, 3TC, or FTC. Intracellular concentrations of parent compounds and their phosphorylated derivatives were measured by high-performance liquid chromatography. In other experiments, viral reverse transcriptase activity was measured in PBMC infected with HIV-1 bearing M184V in the presence of various concentrations of apricitabine and 3TC. [(3)H]apricitabine and [(3)H]3TC were metabolized intracellularly to form mono-, di-, and triphosphates. 3TC and FTC (1 to 10 microM) produced concentration-dependent decreases in apricitabine phosphorylation; in contrast, apricitabine at concentrations of up to 30 muM had no effect on the phosphorylation of 3TC or FTC. The combination of apricitabine and 3TC reduced the antiviral activity of apricitabine against HIV-1: apricitabine concentrations producing 50% inhibition of viral reverse transcriptase were increased two- to fivefold in the presence of 3TC. These findings suggest that nucleoside reverse transcriptase inhibitors with similar modes of action may show biochemical interactions that affect their antiviral efficacy. It is therefore essential that potential interactions between combinations of new and existing agents be thoroughly investigated before such combinations are introduced into clinical practice.
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PMID:In vitro interactions between apricitabine and other deoxycytidine analogues. 1751 47

Emtricitabine (FTC) and lamivudine (3TC) are cytosine nucleoside analogues approved for use in HIV-1 infection. Both compounds select for the M184V/I mutation resulting in high-level resistance. This study compared the phenotypic resistance profiles of FTC and 3TC. Both compounds were tested against clinical samples submitted for routine resistance testing (PhenoSense HIV assay). We evaluated 306 viruses with nucleoside reverse transcriptase inhibitor mutations (NRTI-R) and 100 viruses without resistance mutations (WT). Seventy-two percent had > or = 1 thymidine analogue mutation (TAM), 21% had mixtures at M184, 14% had L74V and 7.5% had K65R. Results were expressed as fold change (FC) in 50% effective concentration compared with the NL4-3 reference. Concordance of FC was evaluated based on biological (99th percentile of the distribution of WT virus population) and clinical cutoffs (FC above which an optimal virological response declines). Against the WT viruses, FTC and 3TC had identical mean FC values relative to the NL4-3 reference of 0.9-fold +/- 0.2 and identical biological cutoffs of 1.4-fold against WT viruses. For NRTI-R isolates, there was a strong linear correlation between FTC and 3TC FC values (r2 = 0.94). Moreover, there was > 90% concordance in resistance calls based on either the biological (1.4-fold) or proposed clinical (3.5-fold) cutoffs among all NRTI-R isolates or isolates with M184V/I mixtures. In the absence of M184V/I, the majority of samples with resistance (> 3.5 FC) exhibited TAMs with a trend toward increased levels of cross-resistance with increasing numbers of TAMs. FTC and 3TC demonstrate nearly identical phenotypic resistance profiles and have the same biological cutoff in this panel of NRTI-R and WT clinical HIV-1 isolates.
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PMID:A comparison of the phenotypic susceptibility profiles of emtricitabine and lamivudine. 1804 62

The HIV-1 reverse transcriptase (RT) resistance mutations K65R and M184V occur individually and in combination, and can contribute to decreased treatment responses in patients. In order to understand how these mutations interact with one another to confer drug resistance, the susceptibilities and underlying resistance mechanisms of these mutants to nucleoside RT inhibitors (NRTIs) were determined. Virus carrying K65R have reduced susceptibility to most NRTIs, but retain full susceptibility to zidovudine (AZT). M184V mutants have reduced susceptibility to lamivudine (3TC), emtricitabine (FTC) and didanosine (ddl), and contribute to reduced susceptibility to abacavir; however, they remain fully susceptible to tenofovir (TFV), AZT and stavudine (d4T). In cell culture, the K65R+M184V virus showed slightly increased susceptibility to TFV, AZT and d4T compared with K65R alone, but showed further decreases in susceptibility to 3TC, FTC, ddl and abacavir. There are two major biochemical mechanisms of resistance: altered NRTI binding/incorporation and altered NRTI excision after incorporation. For most NRTIs, the primary mechanism of resistance by K65R, M184V and K65R+M184V mutant RTs is to disrupt the NRTI-binding/incorporation steps. In the case of AZT, however, decreased binding/incorporation by K65R and K65R+M184V was counteracted by decreased AZT excision resulting in wild-type susceptibility. For TFV, decreased excision by K65R and K65R+M184V may partially counteract the K65R-driven decrease in incorporation relative to wild-type resulting in only low levels of TFV resistance. The K65R-mediated effect on decreasing NRTI excision was stronger than for M184V. These studies show that both mechanisms of resistance (binding/incorporation and excision) must be considered when defining resistance mechanisms.
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PMID:The balance between NRTI discrimination and excision drives the susceptibility of HIV-1 RT mutants K65R, M184V and K65r+M184V. 1832 Sep 35

Preexposure prophylaxis (PrEP) with antiretroviral drugs constitutes a promising strategy for HIV prevention. Potent PrEP regimens with reverse transcriptase inhibitors can prevent detectable SHIV infection in a repeated low-dose macaque model that resembles human transmission, supporting plans to quickly move this approach into human trials. However, the possibility remains that extremely low levels of virus replication could nonetheless occur during PrEP and seed viral reservoirs in tissues. Therefore, seemingly protected macaques may harbor occult virus that may be initially contained by cytotoxic T cells, but could emerge later. To explore this possibility, we studied whether CD8(+) cells suppress viremia in four rhesus macaques apparently protected by daily or intermittent Truvada (FTC and tenofovir) during 14 low-dose, rectal SHIV(SF162P3) challenges and during a subsequent drug washout period. CD8(+) cells were efficiently ablated with antibodies in these and two additional control macaques that were previously infected but had reached undetectable virus set points. During 4 weeks of follow-up, all four macaques remained free of plasma viremia and provirus in blood lymphocytes. In contrast, plasma viremia resurged to 10(6) to 10(7) copies per milliliter within 2 weeks in both control macaques. Thus, these results indicate that the undetectable viremia in the PrEP-protected macaques was not due to CD8(+) cells that were containing a low-level infection. Rather, the PrEP treatment created conditions in which infection was prevented, eliminated, or controlled by unknown mechanisms. These data provide important information for PrEP usage to prevent HIV transmission, and fully support the continued pursuit of PrEP prevention measures in humans.
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PMID:Short communication: no evidence of occult SHIV infection as demonstrated by CD8+ cell depletion after chemoprophylaxis-induced protection from mucosal infection in rhesus macaques. 1837 May 90

Highly active antiretroviral therapy has significantly reduced HIV-related morbidity and mortality. Increasingly, fixed-dose antiretroviral combinations with equal or greater potency than traditional antiretrovirals, along with fewer side effects, reduced toxicity, and simplified dosing convenience are being utilized. Tenofovir-emtricitabine (TDF-FTC) represents one of the more recent fixed-dose combinations. In combination with either a ritonavir-boosted protease inhibitor or a non-nucleoside reverse transcriptase inhibitor, TDF-FTC is a preferred choice in recent treatment guidelines on the basis of demonstrated potency in randomized clinical trials, one-pill-a-day dosing convenience, and relatively low toxicity. In addition, the drug is active against hepatitis B virus. Caution must be exercised in patients with renal insufficiency, or when the drug is used with certain other drugs. This manuscript reviews the use of TDF-FTC in the treatment of HIV.
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PMID:Review of tenofovir-emtricitabine. 1851 68

Unique viral variants and resistance mutations may occur in the genital tract of HIV-2 ARV-naive infected women. We sequenced and phylogenetically analyzed protease (PR), reverse transcriptase (RT), and envelope (ENV) from PBMC and genital tract samples from four ARV-naive women in Senegal. HIV-2 protease polymorphisms that predict HIV-1 protease inhibitor (PI) resistance were common. Two subjects had protease mutations (T77I and I64V) in genital tract samples that were not found in PBMCs. One subject had the HIV-2 reverse transcriptase M184I mutation in CVL DNA (but not PBMCs) that is known to confer 3TC/FTC resistance in HIV-2. In another subject, the reverse transcriptase A62V mutation was also found in CVL-RNA but not PBMCs. We found no significant difference in ENV variants between PBMCs and the genital tract. HIV-2 RT and PR mutations in the genital tract of ARV-naive females may have implications for transmitted HIV-2 resistance and ARV therapy.
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PMID:HIV type 2 protease, reverse transcriptase, and envelope viral variation in the PBMC and genital tract of ARV-naive women in Senegal. 1854 24

The huge improvement in the therapeutic arsenal for HIV infection has led to HIV becoming a chronic disease. Like us, our patients are aging and their life expectancy is close to that of the general population. Consequently, we need safe, easily administered drugs with interactions that can be controlled and the least possible impact on highly prevalent comorbidities such as atherosclerosis or coinfection with hepatotropic viruses. Drugs should fit the patient's lifestyle without affecting quality of life and, above all, be free of effects leading to stigma, such as lipoatrophy, a major concern for most recently diagnosed patients. The choice of the two nucleoside analogue reverse transcriptase inhibitors used at the start of antiretroviral therapy should be based on careful evaluation of the abundant data accumulated on all these determining factors which are heralding a new era in the control of HIV infection. Thus, in this scenario, thymidine analogues have been relegated to alternative use. Fixeddose combinations of tenofovir and emtricitabine (TDF/FTC) or abacavir and lamivudine (ABC/3TC) are the backbone of choice when initiating antiretroviral therapy. Direct comparative data are still scarce but suggest similar virological efficacy, with highly preliminary data suggesting some disadvantages associated with the use of ABC/3TC. After excluding patients at risk of hypersensitivity to ABC, both combinations are well tolerated, but TDF/FTC is associated with a better lipid profile. Recent data from the Data Collection on Adverse Events of Anti-HIV drugs (DAD) study show an unexpected association of ABC with increased cardiovascular risk and thus more detailed studies are required.
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PMID:[Are all analogue combinations equal?]. 1919 37

Abstract Between November 2006 and June 2007, HIV-1 reverse transcriptase (RT) and protease (PR) genes of 67 ARV-naive Cambodian patients were amplified and sequenced. At inclusion, the median age and duration of HIV infection were 28 and 1.1 years, respectively. The median CD4 and HIV-1 RNA were 611 cells/ml [IQR: 525-759] and 4.0 log(10) copies/ml [IQR: 3.4-4.6]. Among 67 HIV-1 strains, 95.5% were CRF 01_AE viruses (n = 64) whereas three clustered with subtype B. RT analysis indicated that only 1 patient out of 67, presenting K103N and M184V mutations, was resistant to NVP/EFV and 3TC/FTC. No primary resistance to protease inhibitors was detected in 59 amplified protease genes. The 1.49% (IC 95%: 0.04-8.04%) prevalence of transmitted drug-resistant strains in drug-naive patients was low in our study. Surveys of drug-resistant transmitted viruses should be regularly performed regarding the increasing access to HAART in Cambodia.
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PMID:Low prevalence of drug resistance transmitted virus in HIV Type 1-infected ARV-naive patients in Cambodia. 1938 23

The HIV-1 reverse transcriptase inhibitors tenofovir (TFV), emtricitabine (FTC), and lamivudine (3TC) are widely used in the treatment of HIV-1-infected persons and are now being considered as chemoprophylactic drugs for the prevention of sexual HIV transmission. Assays that measure these drugs after either oral or topical application are critical to the understanding of the pharmacokinetic profiles of the drugs and allow a rational design of chemoprophylaxis modalities for evaluation in macaque models and human trials. We developed a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS-MS) method for sensitive measurement of FTC, 3TC, and TFV in plasma from macaques. To achieve detection limits of 10 pg on column, the plasma analytes were measured using acidic mobile phase and positive electrospray ionization MS-MS detection. However, this caused various chromatographic peak distortions, which were minimized by using mobile phase additives that induced ion-pairing interactions. Chromatographic peak tailing was minimized by adjusting the organic mobile phase concentration while considering the simultaneous effect of organic content on buffer and analyte pKa. Injection solution interferences were corrected by chromatographic peak focusing using column switching. The final method provides simultaneous measurement of all three analytes with a wide linear range of 1-3000 ng/mL using 0.1 mL plasma (10 pg on column) and coefficients of variation from 5% to 15% in the high ng/mL concentration range and from 16% to 20% in the low ng/mL concentration range.
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PMID:Effect of mobile phase pH and organic content on LC-MS analysis of nucleoside and nucleotide HIV reverse transcriptase inhibitors. 1947 4


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