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)

Recently, lamivudine used to treat patients with hepatitis B virus (HBV) infection was revealed to have potent antiviral activity. However, HBV resistance to lamivudine has been reported and shown to have amino acid substitutions in the methionine residue of the conserved tyrosine (Y), methionine (M), aspartate (D), aspartate (D) motif of RNA-dependent DNA polymerase. To explore the consequences of substitutions in this motif (YMDD), we made 7 variants by substituting the methionine of the YMDD motif with isoleucine (I), valine (V), alanine (A), leucine (L), lysine (K), arginine (R), and threonine (T). Replication ability of these variants was evaluated by transfection into human hepatoma cells. Sensitivity to lamivudine was tested for replication-competent variants. Four variants with hydrophobic substitutions (I, V, A, and L) remained replication-competent, whereas 3 others with hydrophilic substitutions (K, R, and T) exhibited impaired replication. Of the 4 replication-competent variants, 2 (I and V) were resistant, and 2 (A and L) were sensitive to lamivudine. Because the polymerase and the surface gene overlap, the introduction of these mutations affected the secretion of hepatitis B surface antigen (HBsAg), namely 4 variants (I, V, L, and R) secreted HBsAg, whereas 3 variants (A, K, and T) did not. Our study elucidated that only one amino acid substitution in the YMDD motif was sufficient to cause lamivudine resistance in vitro. As a result of replication competence and lamivudine sensitivity, only viruses having YIDD or YVDD sequences may appear during treatment with lamivudine. This in vitro system could be used to study HBV mutations, replication competence, and their susceptibility to antivirals.
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PMID:YMDD motif in hepatitis B virus DNA polymerase influences on replication and lamivudine resistance: A study by in vitro full-length viral DNA transfection. 1005 1

Lamivudine is effective in suppressing replication of hepatitis B virus (HBV). However, the emergence of HBV variants resistant to lamivudine is a concern. Lamivudine resistance has been attributed mainly to a substitution of isoleucine or valine for methionine at residue 550 (M550I or M550V) in the catalytic site of the virus polymerase. A substitution of methionine for leucine at residue 526 (L526M) has also been identified. To examine such virus genotypic mutations in Japanese patients, we studied five patients with chronic hepatitis B, who showed HBV breakthrough while on a 1-year lamivudine treatment. The entire nucleotide and deduced amino acid sequences of the proposed reverse transcriptase domain of the polymerase gene were determined on HBV DNA amplified by polymerase chain reaction from patient sera collected at the start and at the end of therapy. The HBV sequences from all five patients were of genotype C. In four patients, a substitution of valine or isoleucine for leucine at residue 426, which has not been reported previously, emerged in combination with M550I. One also harbored L526M. In the remaining patient, an alteration of leucine to methionine at residue 428 co-occurred with M550V. Longitudinal study of the mutations showed that the two or three mutations in each patient emerged almost simultaneously 4 weeks before or at the time of breakthrough and were replaced by wild-type virus after completing the therapy. Our results indicate that occurrence of HBV polymerase mutations at residue 426 in combination with M550I is frequent in Japanese or genotype C virus-in- fected patients who develop resistance to lamivudine.
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PMID:Novel patterns of amino acid mutations in the hepatitis B virus polymerase in association with resistance to lamivudine therapy in japanese patients with chronic hepatitis B. 1050 55

We describe a new human immunodeficiency virus type 1 (HIV-1) mutational pattern associated with phenotypic resistance to lamivudine (3TC) in the absence of the characteristic replacement of methionine by valine at position 184 (M184V) of reverse transcriptase. Combined genotypic and phenotypic analyses of clinical isolates revealed the presence of moderate levels of phenotypic resistance (between 4- and 50-fold) to 3TC in a subset of isolates that did not harbor the M184V mutation. Mutational cluster analysis and comparison with the phenotypic data revealed a significant correlation between moderate phenotypic 3TC resistance and an increased incidence of replacement of glutamic acid by aspartic acid or alanine and of valine by isoleucine at residues 44 and 118 of reverse transcriptase, respectively. This occurred predominantly in those isolates harboring zidovudine resistance-associated mutations (41L, 215Y). The requirement of the combination of mutations 41L and 215Y with mutations 44D and 44A and/or 118I for phenotypic 3TC resistance was confirmed by site-directed mutagenesis experiments. These data support the assumption that HIV-1 may have access to several different genetic pathways to escape drug pressure or that the increase in the frequency of particular mutations may affect susceptibility to drugs that have never been part of a particular regimen.
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PMID:A novel human immunodeficiency virus type 1 reverse transcriptase mutational pattern confers phenotypic lamivudine resistance in the absence of mutation 184V. 1068 19

Human immunodeficiency virus type 1 (HIV-1) rapidly develops resistance to lamivudine during monotherapy, typically resulting in the appearance at position 184 in reverse transcriptase (RT) of isoleucine instead of the wild-type methionine (M184I) early in therapy, which is later replaced by valine (M184V). M184V reduces viral susceptibility to drug in vitro by approximately 100-fold, but also results in a lower processivity of RT. We show that a drop in absolute viral fitness associated with the outgrowth of M184V results in a drop in viral load only in individuals with high CD4(+) counts, from whom we estimate the relative fitness of M184V in the presence of drug to be approximately 10% of that of the wild type prior to therapy. The timing of emergence of the M184V mutant varies widely between infected individuals. From analysis of the frequency of M184I and M184V mutants determined at multiple time points in seven individuals during lamivudine therapy, we estimated the fitness advantage of M184V over M184I during therapy to be approximately 23% on average. We have also estimated the average ratio of the frequencies of the two mutants prior to therapy to be 0. 2:1, with a range from 0.12:1 to 0.33:1. We have found that the differences between individuals in the rate of evolution of lamivudine resistance arise due to genetic drift affecting the relative frequency of M184I and M184V prior to therapy. These results show that stochastic effects can be significant in HIV evolution, even when there is large fitness difference between mutant and wild-type variants.
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PMID:Evolution of lamivudine resistance in human immunodeficiency virus type 1-infected individuals: the relative roles of drift and selection. 1086 35

The antiretroviral nucleoside analog 2',3'-dideoxy-3'-thiacytidine (3TC) is a potent inhibitor of wild-type human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). A methionine-to-valine or methionine-to-isoleucine substitution at residue 184 in the HIV-1 YMDD motif, which is located at the RT active site, leads to a high level of resistance to 3TC. We sought to determine whether 3TC can inhibit the replication of wild-type murine leukemia virus (MLV), which contains V223 at the YVDD active site motif of the MLV RT, and of the V223M, V223I, V223A, and V223S mutant RTs. Surprisingly, the wild type and all four of the V223 mutants of MLV RT were highly resistant to 3TC. These results indicate that determinants outside the YVDD motif of MLV RT confer a high level of resistance to 3TC. Therefore, structural differences among similar RTs might result in widely divergent sensitivities to antiretroviral nucleoside analogs.
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PMID:Wild-type and YMDD mutant murine leukemia virus reverse transcriptases are resistant to 2',3'-dideoxy-3'-thiacytidine. 1086 83

A large variety of natural products have been described as anti-HIV agents, and for a portion thereof the target of interaction has been identified. Cyanovirin-N, a 11-kDa protein from Cyanobacterium (blue-green alga) irreversibly inactivates HIV and also aborts cell-to-cell fusion and transmission of HIV, due to its high-affinity interaction with gp120. Various sulfated polysaccharides extracted from seaweeds (i.e., Nothogenia fastigiata, Aghardhiella tenera) inhibit the virus adsorption process. Ingenol derivatives may inhibit virus adsorption at least in part through down-regulation of CD4 molecules on the host cells. Inhibition of virus adsorption by flavanoids such as (-)epicatechin and its 3-O-gallate has been attributed to an irreversible interaction with gp120 (although these compounds are also known as reverse transcriptase inhibitors). For the triterpene glycyrrhizin (extracted from the licorice root Glycyrrhiza radix) the mode of anti-HIV action may at least in part be attributed to interference with virus-cell binding. The mannose-specific plant lectins from Galanthus, Hippeastrum, Narcissus, Epipac tis helleborine, and Listera ovata, and the N-acetylgl ucosamine-specific lectin from Urtica dioica would primarily be targeted at the virus-cell fusion process. Various other natural products seem to qualify as HIV-cell fusion inhibitors: the siamycins [siamycin I (BMY-29304), siamycin II (RP 71955, BMY 29303), and NP-06 (FR901724)] which are tricyclic 21-amino-acid peptides isolated from Streptomyces spp that differ from one another only at position 4 or 17 (valine or isoleucine in each case); the betulinic acid derivative RPR 103611, and the peptides tachyplesin and polyphemusin which are highly abundant in hemocyte debris of the horseshoe crabs Tachypleus tridentatus and Limulus polyphemus, i.e., the 18-amino-acid peptide T22 from which T134 has been derived. Both T22 and T134 have been shown to block T-tropic X4 HIV-1 strains through a specific antagonism with the HIV corecept or CXCR4. A number of natural products have been reported to interact with the reverse transcriptase, i.e., baicalin, avarol, avarone, psychotrine, phloroglucinol derivatives, and, in particular, calanolides (from the tropical rainforest tree, Calophyllum lanigerum) and inophyllums (from the Malaysian tree, Calophyllum inophyllum). The natural marine substance illimaquinone would be targeted at the RNase H function of the reverse transcriptase. Curcumin (diferuloylmethane, from turmeric, the roots/rhizomes of Curcuma spp), dicaffeoylquinic and dicaffeoylt artaric acids, L-chicoric acid, and a number of fungal metabolites (equisetin, phomasetin, oteromycin, and integric acid) have all been proposed as HIV-1 integrase inhibitors. Yet, we have recently shown that L-c hicoric acid owes its anti-HIV activity to a specific interaction with the viral envelope gp120 rather than integrase. A number of compounds would be able to inhibit HIV-1 gene expression at the transcription level: the flavonoid chrysin (through inhibition of casein kinase II, the antibacter ial peptides melittin (from bee venom) and cecropin, and EM2487, a novel substance produced by Streptomyces. (ABSTRACT TRUNCATED)
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PMID:Current lead natural products for the chemotherapy of human immunodeficiency virus (HIV) infection. 1093 47

Synthesis of the hepatitis B virus (HBV) DNA genome occurs within the viral nucleocapsid in a mechanistically ordered fashion. The nucleocapsid contains small pores that permit influx of nucleotide triphosphates and metabolites of nucleoside analogues such as lamivudine for DNA synthesis. Lamivudine is a potent inhibitor of HBV and human immunodeficiency virus (HIV) reverse transcriptases, but substitutions of isoleucine or valine for methionine within the tyrosine-methionine-aspartate-aspartate (YMDD) motif are associated with virologic and clinical resistance to lamivudine therapy. Under lamivudine selection pressure, the high viral production rate and the low fidelity viral polymerase contribute to frequent development of the YMDD mutants. However, the pattern and dynamics of emergence of the mutant viruses over the wild-type virus are determined by multiple factors including replication efficiency, host immune response, and availability of replication space. Structural modeling of HIV reverse transcriptase has permitted key insights into the molecular basis of lamivudine resistance of HBV based on evolutionary relatedness of HIV and HBV. The side groups of isoleucine and valine of the YMDD mutants sterically prevent lamivudine from appropriately configuring into the nucleotide binding site of the reverse transcriptase. Aminotransferase flares are associated with lamivudine therapy and may signify clinical resistance with emergence of YMDD mutants. They may also herald the recovery phase with seroconversion and viral clearance. Reconstitution of the endogenous anti-HBV immune response may be equally important in the control of viral replication by lamivudine and other nucleoside analogues.
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PMID:Molecular anatomy and pathophysiologic implications of drug resistance in hepatitis B virus infection. 1166 95

The development of new nucleoside analogs, that inhibit the HBV reverse transcriptase activity, such as lamivudine, famciclovir and others, has provided recently an alternative to interferon therapy for chronic hepatitis B. However, due to the kinetics of viral replication with a high rate of virus production, a relatively long half-life of virus (CCC) DNA in the nucleus of infected hepatocytes, long-term antiviral therapy with a reverse transcriptase inhibitor is required to eradicate viral infection. Recently, it has been reported that lamivudine therapy for chronic hepatitis B in immune competent patients may be associated with the selection of resistant strains in aproximately 20% of the patients after 12 months of therapy. Sequence analysis of the reverse transcriptase domain of resistant viral strains, at the time of viral breakthrough, revealed the occurrence of mutations located in the YMDD motif within the C domain of the viral enzyme with a methionine to valine (M552V) or to isoleucine (M5521) change. Recent reports on larger series of patients pointed that other mutations residing outside of the C domain but mainly in the B domain of the viral polymerase (L528M) could be associated with these mutations in the YMDD motif. The lamivudine resistant mutants, selected in vivo, can be classified in 2 main groups: group I with a double mutation L528M and M552V, and group II with a single mutation M5521. In vitro studies performed in cell culture showed that these mutants have a decreased replication capacity and are indeed resistant to lamivudine. With the development of new antiviral options, genotyping assays and quantitative determination of viremia with highly sensitive assay are clearly warranted for an optimal monitoring of antiviral therapy of chronic hepatitis B. In view of the experimental and clinical data, the capacity of new antiviral strategies based on combination of new inhibitors, including adefavir and entecavir, with immune modulators needs to be further evaluated in animal models and clinical trials to prevent the emergence of resistant viral strains.
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PMID:Detection of hepatitis B virus resistance to antivirals. 1139 61

When human immunodeficiency virus type 1 (HIV-1) is selected for resistance to 3TC, the methionine normally present at position 184 is replaced by valine or isoleucine. Position 184 is the X of the conserved YXDD motif; positions 185 and 186 form part of the triad of aspartic acids at the polymerase active site. Structural and biochemical analysis of 3TC-resistant HIV-1 reverse transcriptase (RT) led to a model in which a beta-branched amino acid at position 184 would act as a steric gate. Normal deoxynucleoside triphosphates (dNTPs) could still be incorporated; the oxathiolane ring of 3TCTP would clash with the beta branch of the amino acid at position 184. This model can also explain 3TC resistance in feline immunodeficiency virus and human hepatitis B virus. However, it has been reported (14) that murine leukemia viruses (MLVs) with valine (the amino acid present in the wild type), isoleucine, alanine, serine, or methionine at the X position of the YXDD motif are all resistant to 3TC. We prepared purified wild-type MLV RT and mutant MLV RTs with methionine, isoleucine, and alanine at the X position. The behavior of these RTs was compared to those of wild-type HIV-1 RT and of HIV-1 RT with alanine at the X position. If alanine is present at the X position, both MLV RT and HIV-1 RT are relatively resistant to 3TCTP in vitro. However, the mutant enzymes were impaired relative to their wild-type counterparts; there appears to be steric hindrance for both 3TCTP and normal dNTPs.
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PMID:YADD mutants of human immunodeficiency virus type 1 and Moloney murine leukemia virus reverse transcriptase are resistant to lamivudine triphosphate (3TCTP) in vitro. 1141 98

Reactivation of chronic hepatitis B virus (HBV) infection is a major cause of morbidity and mortality after renal transplantation. Although lamivudine is an effective treatment for chronic hepatitis B, the development of drug resistance due to mutations in the tyrosine-methionine-aspartate-aspartate (YMDD) motif is a major concern, especially in immunosuppressed patients who require prolonged therapy. Treatment with famciclovir has not been effective in the majority of patients who developed lamivudine resistance due to methionine-to-valine mutation at position 550, because this mutation has been uniformly associated with leucine-to-methionine mutation at position 526, a mutation that is associated with resistance to famciclovir. We describe a renal transplant recipient with an uncommon lamivudine-resistant HBV variant, in which methionine-to-valine/isoleucine mutation at position 550 was associated with wild-type sequence at position 526. The severe hepatitic flare consequent to the lamivudine resistance in this patient was successfully treated with famciclovir, indicating that both M550V and M550I mutants with preserved wild-type sequence at position 526 of HBV reverse transcriptase are susceptible to famciclovir. Our experience shows that famciclovir can be useful in selected patients with otherwise potentially fatal hepatitic flares related to lamivudine resistance, and that analysis of mutations in the HBV variant can be helpful in the choice of antiviral therapy.
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PMID:Efficacy of famciclovir in the treatment of lamivudine resistance related to an atypical hepatitis B virus mutant. 1179 96


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