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hiv-1 reverse transcriptase and protease resistance mutations selected during 16-72 weeks of therapy in isolates from antiretroviral therapy-experienced patients receiving abacavir/efavirenz/amprenavir in the CNA2007 study

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ANTIVIRAL THERAPY 2003年第2期8卷 111-120页

作者： Ait-Khaled, M Rakik, A Griffin, P Stone, C Richards, N Thomas, D Falloon, J Tisdale, M GlaxoSmithKline Inc HIV Clin Dev & Med Affairs Europe Greenford Middx England GlaxoSmithKline Inc Int Clin Virol Stevenage Herts England GlaxoSmithKline Inc Stat Greenford Middx England GlaxoSmithKline Inc N Amer Med Affairs Res Triangle Pk NC USA NIAID NIH Bethesda MD 20892 USA

Objective: To determine hiv-1 reverse transcriptase (RT) and protease (PRO) mutations selected in isolates from antiretroviral therapy (ART)-experienced patients receiving an efavirenz/abacavir/amprenavir salvage regimen. Methods: Open-label, single arm of abacavir, 300 mg twice daily, amprenavir, 1200 mg twice daily and efavirenz, 600 mg once daily, in ART-experienced patients of which 42% were non-nucleoside reverse transcriptase inhibitor-naive. The virology population examined consisted of all patients who took at least 16 weeks of study drugs (n=74). Plasma population sequencing was carried out at baseline and last time point at which patients were still taking the three study drugs other ART. The median follow-up was 48 weeks (range week 16-72). Results: Baseline (n=73) and on-therapy (n=49) genotypes were obtained. By 48 weeks, 51% of isolates had >= 3 non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations. NNRTI mutations selected on therapy were K103N (51%), substitutions at position 190 (17/49, 35%): 6 to A (n=11) / S (n=4) / E (n=1) and T (n=1);L100I (37%) and V108I (20%) mutations. P225H was not observed in this study. L100I and G190A/S/E/T mutations were rarely detected in the same viral population and baseline Y181C favoured the 6190 mutations (OR=8.9, P < 0.001), rather than the L100I. The NRTI mutations selected were in accordance with abacavir known resistance profile, no new TAMs were observed, new L74V or I mutations developed in 39 and 16% of isolates, respectively, however, new M184V mutations were only detected in isolates from two patients, one of whom had added lamivudine + didanosine. M184V was common at baseline (55%) and maintained in 22/27 (81%) isolates (five of these 22 added lamivudine or didanosine, or both). The PRO mutations selected were in accordance with the distinct resistance profile of amprenavir compared with other protease inhibitors. Mutations D30N, G48V, N88D/S, L90M and I54V were de-selected, and mutations I50V,

关键词：抗逆转录病毒治疗高效苯并恶嗪类氨甲酸酯类队列研究抗药性病毒/遗传学药物疗法联合基因型 hiv感染/药物疗法 hiv蛋白酶/遗传学 hiv逆转录酶/遗传学 hiv-1/遗传学突变挽救疗法人类

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Site-specific incorporation of nucleoside analogs by hiv-1 reverse transcriptase and the template grip mutant P157S - Template interactions influence substrate recognition at the polymerase active site

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第1期275卷 359-366页

作者： Klarmann, GJ Smith, RA Schinazi, RF North, TW Preston, BD Univ Utah Dept Biochem Eccles Inst Human Genet Salt Lake City UT 84112 USA Univ Utah Dept Radiat Oncol Eccles Inst Human Genet Salt Lake City UT 84112 USA Univ Utah Huntsman Canc Inst Salt Lake City UT 84112 USA Emory Univ Sch Med Dept Pediat Decatur GA 30033 USA Emory Univ Sch Med Georgia Vet Affairs Res Ctr AIDS & HIV Invect Decatur GA 30033 USA Univ Calif Davis Ctr Comparat Med Davis CA 95616 USA

Studies of drug-resistant reverse transcriptases (RTs) reveal the roles of specific structural elements and amino acids in polymerase function. To characterize better the effects of RT/template interactions on dNTP substrate recognition, we examined the sensitivity of human immunodeficiency virus type 1 (hiv-1) RT containing a new mutation in a "template grip" residue (P157S) to the 5'-triphosphates of (-)-beta-2',3'-dideoxy-3'-thiacytidine (3TC), (-)-beta-2',3'-dideoxy-5-fluoro-3'-thiacytidine (FTC), and 3'-azido-3'-deoxythymidine (AZT). A primer extension assay was used to monitor quantitatively drug monophosphate incorporation opposite each of multiple target sites. Wild-type and P157S RTs had similar catalytic activities and processivities on heteropolymeric RNA and DNA templates. When averaged over multiple template sites, P157S RT was 2-7-fold resistant to the 5'-triphosphates of 3TC, FTC, and AZT, Each drug triphosphate inhibited polymerization more efficiently on the DNA template compared with an RNA template of identical sequence. Moreover, chain termination by 3TC and FTC was strongly influenced by template sequence context. Incorporation of FTC and 3TC monophosphate varied up to 10-fold opposite 7 different G residues in the DNA template, and the P157S mutation altered this site specificity. In summary, these data identify Pro(157) as an important residue affecting nucleoside analog resistance and suggest that interactions between RT and the template strand influence dNTP substrate recognition at the RT active site. Our findings are discussed within the context of the hiv-1 RT structure.

关键词：催化域胞苷三磷酸/类似物和衍生物胞苷三磷酸/代谢胞苷三磷酸/药理学双脱氧核苷酸类剂量效应关系药物抗药性 hiv逆转录酶/药物作用 hiv逆转录酶/遗传学 hiv逆转录酶/代谢 hiv-1/酶学拉米夫定/类似物和衍生物突变脯氨酸/遗传学逆转录酶抑制剂/代谢逆转录酶抑制剂/药理学硫代核苷类/代谢噻吩类胸腺嘧啶核苷酸类/代谢胸腺嘧啶核苷酸类/药理学转录遗传/药物作用扎昔他宾/类似物和衍生物扎昔他宾/代谢齐多夫定/类似物和衍生物齐多夫定/代谢齐多夫定/药理学

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Human immunodeficiency virus reverse transcriptase and protease sequence database

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NUCLEIC ACIDS RESEARCH 2000年第1期28卷 346-348页

作者： Shafer, RW Jung, DR Betts, BJ Xi, YO Gonzales, MJ Stanford Univ Med Ctr Div Infect Dis Dept Med Stanford CA 94305 USA Stanford Univ Dept Engn Stanford CA 94305 USA Stanford Univ Dept Comp Sci Stanford CA 94305 USA

The hiv RT and Protease Sequence Database is an online relational database that catalogs evolutionary and drug-related human immunodeficiency virus (hiv) reverse transcriptase (RT) and protease sequence variation (http://***), The database contains a compilation of nearly all published hiv RT and protease sequences including International Collaboration database submissions (e.g., GenBank) and sequences published in journal articles, Sequences are linked to data about the source of the sequence sample and the antiretroviral drug treatment history of the individual from whom the isolate was obtained, The database is curated and sequences are annotated with data from >230 literature references. Users can retrieve additional data and view alignments of sequence sets meeting specific criteria (e.g,, treatment history, subtype, presence of a particular mutation), A gene-specific sequence analysis program, new user-defined queries and nearly 2000 additional sequences were added in 1999.

关键词：数据库事实型抗药性微生物/遗传学 hiv蛋白酶/化学 hiv蛋白酶/遗传学 hiv逆转录酶/化学 hiv逆转录酶/遗传学因特网突变用户计算机接口

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Uniquely altered DNA replication fidelity conferred by an amino acid change in the nucleotide binding pocket of human immunodeficiency virus type 1 reverse transcriptase

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JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第46期274卷 32924-32930页

作者： Lewis, DA Bebenek, K Beard, WA Wilson, SH Kunkel, TA NIEHS Struct Biol Lab NIH Res Triangle Pk NC 27709 USA

Arginine 72 in human immunodeficiency virus type I reverse transcriptase (RT), a highly conserved residue among retroviral polymerases and telomerases, forms part of the binding pocket for the nascent base pair. me show here that replacement of Arg(72) by alanine strongly alters fidelity in a highly unusual manner. R72A reverse transcriptase is a frameshift and base substitution anti-mutator polymerase whose increased fidelity results both from increased nucleotide selectivity and from a decreased ability to extend mismatched primer termini. Thus, Arg(72)-substrate interactions in wild-type human immunodeficiency virus type I RT can stabilize incorrect nucleotides allowing misinsertion and promoting extension of mismatched and perhaps misaligned template-primers. In contrast to the higher fidelity at most sites, R72A RT is highly error-prone for misincorporations opposite template T in the sequence context: 5'-C (T) under bar GG. Surprisingly this results mostly from a 1200-fold increase in the apparent K-m for correct dAMP incorporation. Thus, Arg(72) interactions with substrate are critical for the stability of the correct *** base pair when the 5'-C (T) under bar GG sequence is present in the binding pocket for the nascent base pair. Collectively, the data show that a mutant polymerase may yield higher than normal average replication fidelity, yet paradoxically place specific sequences at very high risk of mutation.

关键词：碱基配对碱基序列结合部位 DNA引物 DNA复制脱氧核糖核苷酸类/代谢 hiv逆转录酶/遗传学动力学模型分子分子序列数据突变底物特异性模板遗传人类

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New human immunodeficiency virus, type 1 reverse transcriptase (hiv-1 RT) mutants with increased fidelity of DNA synthesis - Accuracy, template binding, and processivity

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JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第39期274卷 27666-27673页

作者： Kim, B Ayran, JC Sagar, SG Adman, ET Fuller, SM Tran, NH Horrigan, J Univ Rochester Med Ctr Dept Microbiol & Immunol Rochester NY 14642 USA Univ Washington Dept Pathol Seattle WA 98195 USA Univ Washington Dept Biol Struct Seattle WA 98195 USA

Infidelity of DNA synthesis by human immunodeficiency virus, type 1 reverse transcriptase (HTV-1 RT) is a presumptive determinant of hiv-1 hypervariability and is incompletely understood at the mechanistic and structural levels. Amino acid substitution at only three residues, including Asp-76 (Kim, B., Hathaway, T. R., and Loeb, L. A (1996) Biochemistry 37, 5831-5839), is known to increase fidelity, We report here that substitution at Arg-78 can also increase accuracy. Mutant R78A RT showed reduced primer extension in misincorporation assays lacking a complementary dNTP and exhibited a 9-fold decrease in mutation frequency in the M13mp2 lacZ forward mutation assay. Previous structural studies indicate that Arg-78 and Asp-76 lie in a region that interacts with template nucleotides. Interestingly, R78A RT exhibited 6- to 8-fold decreases in binding affinity (K-d) for RNA and DNA templates relative to wild type RT. In contrast, D76V RT, which also increases fidelity (Kim ct al., 1996), showed a 6- to 7-fold increased affinity. The processivity of R78A RT on both RNA and DNA templates was substantially reduced relative to wild type RT, whereas the processivity of D76V RT was increased. We discuss relationships of fidelity, template binding, and processivity in these and other hiv RT mutants.

关键词：氨基酸取代精氨酸天冬氨酸碱基序列结合部位 DNA引物 DNA复制 DNA 病毒/生物合成 hiv逆转录酶/化学 hiv逆转录酶/遗传学 hiv逆转录酶/代谢 hiv-1/酶学模型分子分子序列数据诱变定点核酸构象聚合酶链反应蛋白质构象重组融合蛋白质类/生物合成重组蛋白质类/化学重组蛋白质类/代谢模板遗传 β半乳糖苷酶类/遗传学人类

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Characterization of active reverse transcriptase and nucleoprotein complexes of the yeast retrotransposon Ty3 in vitro

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JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第51期274卷 36643-36648页

作者： Cristofari, G Gabus, C Ficheux, D Bona, M Le Grice, SFJ Darlix, JL Ecole Normale Super Lyon INSERM LaboRetro Unite Virol HumaineU412 F-69364 Lyon 07 France Inst Biol & Chim Prot F-69367 Lyon France NCI Frederick Canc Res & Dev Ctr HIV Drug Resistance Program Div Basic SciNIH Frederick MD 21702 USA

Human immunodeficiency virus (hiv) and the distantly related yeast Ty3 retrotransposon encode reverse transcriptase (RT) and a nucleic acid-binding protein designated nucleocapsid protein (NCp) with either one or two zinc fingers, required for hiv-1 replication and Ty3 transposition, respectively. In vitro binding of hiv-1 NCp7 to viral 5' RNA and primer tRNA(3)(Lys) catalyzes formation of nucleoprotein complexes resembling the virion nucleocapsid. Nucleocapsid complex formation functions in viral RNA dimerization and tRNA annealing to the primer binding site (PBS). RT is recruited in these nucleoprotein complexes and synthesizes minus-strand cDNA initiated at the PBS. Recent results on yeast Ty3 have shown that the homologous NCp9 promotes annealing of primer tRNA(i)(Met) to a 5'-3' bipartite PBS, allowing RNA:tRNA dimer formation and initiation of cDNA synthesis at the 5' PBS (1), To compare specific cDNA synthesis in a retrotransposon and hiv-1, we have established a Ty3 model system comprising Ty3 RNA with the 5'-3' PBS, primer tRNA(i)(Met), NCp9, and for the first time, highly purified Ty3 RT. Here we report that Ty3 RT is as active as retroviral hiv-1 or murine leukemia virus RT using a synthetic template-primer system, Moreover, and in contrast to what was found with retroviral RTs, retrotransposon Ty3 RT was unable to direct cDNA synthesis by self-priming. We also show that Ty3 nucleoprotein complexes were formed in vitro and that the N terminus of NCp9, but not the zinc finger, is required for complex formation, tRNA annealing to the PBS, RNA dimerization, and primer tRNA-directed cDNA synthesis by Ty3 RT. These results indicate that NCp9 chaperones bona fide cDNA synthesis by RT in the yeast Ty3 retrotransposon, as illustrated for NCp7 in hiv-1, reinforcing the notion that Ty3 NCp9 is an ancestor of hiv-1 NCp7.

关键词：氨基酸序列真菌蛋白质类/遗传学 hiv逆转录酶/遗传学分子序列数据核蛋白类/遗传学反转录因子/遗传学酿酒酵母菌/酶学酿酒酵母菌/遗传学人类

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Mutations in the primer grip region of hiv reverse transcriptase can increase replication fidelity

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JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第40期274卷 28175-28184页

作者： Wisniewski, M Palaniappan, C Fu, ZP Le Grice, SFJ Fay, P Bambara, RA Univ Rochester Med Ctr Dept Biochem & Biophys Rochester NY 14642 USA Univ Rochester Dept Med Rochester NY 14642 USA Univ Rochester Ctr Canc Rochester NY 14642 USA Case Western Reserve Univ Sch Med Ctr AIDS Res Cleveland OH 44106 USA Case Western Reserve Univ Sch Med Div Infect Dis Cleveland OH 44106 USA

Mutations in the primer grip region of human immunodeficiency virus reverse transcriptase (hiv-RT) affect its replication fidelity. The primer grip region (residues 227-235) correctly positions the 3'-ends of primers. Point mutations were created by alanine substitution at positions 224-235, Error frequencies were measured by extension of a dG:dA primer-template mismatch. Mutants E224A, P225A, P226A, L228A, and E233A were approximately equal to the wild type in their ability to extend the mismatch. Mutants F227A, W229A, M230A, G231A, and Y232A extended 40, 66, 54, 72, and 76% less efficiently past a dG:dA mismatch compared with the wild type. We also examined the misinsertion rates of dG, dC, or dA across from a DNA template dA using RT mutants F227A and W229A Mutant W229A exhibited high fidelity and did not produce a dC:dA or dC:dA mismatch. Interestingly, mutant F227A displayed high fidelity for dG:dA and dC:dA mismatches but low fidelity for dA:dA misinsertions, This indicates that F227A discriminates against particular base substitutions. However, a primer extension assay with three dNTPs showed that F227A generally displays higher fidelity than the wild type RT. Clearly, primer grip mutations can improve or worsen either the overall or base-specific fidelity of hiv-RT, We hypothesize that wild type RT has evolved to a fidelity that allows genetic variation without compromising yield of viable viruses.

关键词：碱基错配 DNA引物 DNA复制 hiv逆转录酶/遗传学诱变模板遗传

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Highly specific recognition of primer RNA structures for 2′-OH priming reaction by bacterial reverse transcriptases

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JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第44期274卷 31236-31244页

作者： Inouye, S Hsu, MY Xu, AG Inouye, M Robert Wood Johnson Med Sch Dept Biochem Piscataway NJ 08854 USA

A minor population of Escherichia coli contains retroelements called retrons, which encode reverse-transcriptases (RT) to synthesize peculiar satellite DNAs called multicopy single-stranded DNA (msDNA). These RTs recognize specific RNA structures in their individual primer-template RNAs to initiate cDNA synthesis from the 2'-OH group of a specific internal G residue (branching G residue). The resulting products (msDNA) consist of RNA and single-stranded DNA, sharing hardly any sequence homology. Here, we investigated how RT-Ec86 recognizes the specific RNA structure in its primer-template RNA. On the basis of structural comparison with hiv-1 RT, domain exchanges were carried out between two E. coli RTs, RT-Ec86 and RT-Ec73. RT-Ec86 (320 residues) and RT-Ec78 (316 residues) share only 71 identical residues (22%), From the analysis of 10 such constructs, the C-terminal 91-residue sequence of RT-Ec86 was found to be essential for the recognition of the unique stem-loop structure and the branching G residue in the primer-template RNA for retron-Ec86. Using the SELEX (systematic evolution of ligands by exponential enrichment) method with RT-Ec86 and primer RNAs containing random sequences, the identical stem-loop structure (including the 3-U loop) to that found in the retron-Ec86 primer-template RNA was enriched. In addition, the highly conserved 4-base sequence (UAGC), including the branching G residue, was also enriched, These results indicate that the highly diverse C-terminal region recognizes specific stem-loop structures and the branching G residue located upstream of the stem-loop structure. The present results with seemingly primitive RNA-dependent DNA polymerases provide insight into the mechanisms for specific protein RNA recognition.

关键词：氨基酸序列碱基序列 DNA 单链定向分子进化大肠杆菌/酶学 hiv逆转录酶/遗传学 hiv逆转录酶/代谢配体分子序列数据核酸构象蛋白质结合 RNA/化学 RNA/代谢 RNA 细菌/化学 RNA 细菌/代谢 RNA指导的DNA聚合酶/遗传学 RNA指导的DNA聚合酶/代谢重组融合蛋白质类/代谢反转录因子底物特异性

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Residues in the αH and αI helices of the hiv-1 reverse transcriptase thumb subdomain required for the specificity of RNase H-catalyzed removal of the polypurine tract primer

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JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第28期274卷 19885-19893页

作者： Powell, MD Beard, WA Bebenek, K Howard, KJ Le Grice, SFJ Darden, TA Kunkel, TA Wilson, SH Levin, JG NICHD Genet Mol Lab NIH Bethesda MD 20892 USA NIEHS Struct Biol Lab NIH Res Triangle Pk NC 27709 USA NIEHS Genet Mol Lab NIH Res Triangle Pk NC 27709 USA Case Western Reserve Univ Ctr AIDS Res Cleveland OH 44106 USA

During retrovirus replication, reverse transcriptase (RT) must specifically interact with the polypurine tract (PPT) to generate and subsequently remove the RNA primer for plus-strand DNA synthesis. We have investigated the role that human immunodeficiency virus-1 RT residues in the alpha H and alpha I helices in the thumb subdomain play in specific RNase H cleavage at the 3'-end of the PPT;an in vitro assay modeling the primer removal step was used. Analysis of alanine-scanning mutants revealed that a subgroup exhibits an unusual phenotype in which the PPT is cleaved up to seven bases from its 3'-end. Further analysis of alpha H mutants (G262A, K263A, N265A, and W266A) with changes in residues in or near a structural motif known as the minor groove binding track showed that the RNase H activity of these mutants is more dramatically affected with PPT substrates than with non-PPT substrates. Vertical scan mutants at position 266 were all defective in specific RNase H cleavage, consistent with conservation of tryptophan at this position among lentiviral RTs, Our results indicate that residues in the thumb subdomain and the minor groove binding track in particular, are crucial for unique interactions between RT and the PPT required for correct positioning and precise RNase H cleavage.

关键词：丙氨酸/遗传学碱基序列 DNA/生物合成 hiv逆转录酶/化学 hiv逆转录酶/遗传学 hiv-1/酶学动力学模型分子分子序列数据突变核酸构象蛋白质结构二级 RNA/代谢核糖核酸酶H/代谢底物特异性色氨酸/遗传学人类

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Lamivudine (3TC) resistance in hiv-1 reverse transcriptase involves steric hindrance with β-branched amino acids

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 1999年第18期96卷 10027-10032页

作者： Sarafianos, SG Das, K Clark, AD Ding, JP Boyer, PL Hughes, SH Arnold, E Ctr Adv Biotechnol & Med Piscataway NJ 08854 USA Rutgers State Univ Dept Chem Piscataway NJ 08854 USA NCI Frederick Canc Res & Dev Ctr Adv Biosci Labs Basic Res Program Frederick MD 21702 USA

An important component of triple-drug anti-AIDS therapy is 2',3'-dideoxy-3'-thiacytidine (3TC, lamivudine). Single mutations at residue 184 of the reverse transcriptase (RT) in hiv cause high-level resistance to 3TC and contribute to the failure of anti-AIDS combination therapy. We have determined crystal structures of the 3TC-resistant mutant hiv-1 RT (M184I) in both the presence and absence of a DNA/DNA template-primer, In the absence of a DNA substrate, the wild-type and mutant structures are very similar. However, comparison of crystal structures of M184I mutant and wild-type hiv-1 RT with and without DNA reveals repositioning of the template-primer in the M184I/DNA binary complex and other smaller changes in residues in the dNTP-binding site. On the basis of these structural results, we developed a model that explains the ability of the 3TC-resistant mutant M184I to incorporate dNTPs but not the nucleotide analog 3TCTP. In this model, steric hindrance is expected for NRTIs with beta- or L- ring configurations, as with the enantiomer of 3TC that is used in therapy. Steric conflict between the oxathiolane ring of 3TCTP and the side chain of P-branched amino acids (Val, Ile, Thr) at position 184 perturbs inhibitor binding, leading to a reduction in incorporation of the analog. The model can also explain the 3TC resistance of analogous hepatitis B polymerase mutants. Repositioning of the template-primer as observed in the binary complex (M184I/DNA) may also occur in the catalytic ternary complex (M184I/DNA/3TCTP) and contribute to 3TC resistance by interfering with the formation of a catalytically competent closed complex.

关键词：别构调节氨基酸序列氨基酸取代保守序列二聚作用抗药性微生物 hiv逆转录酶/化学 hiv逆转录酶/遗传学 hiv逆转录酶/代谢 hiv-1/药物作用 hiv-1/酶学 hiv-1/遗传学拉米夫定/化学拉米夫定/药理学大分子物质模型分子分子序列数据核酸构象点突变蛋白质构象 RNA 病毒/化学 RNA 病毒/代谢模板遗传人类

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