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sequence and structure based models of HIV-1 protease and reverse transcriptase drug resistance

BMC GENOMICS 2013年第4期14卷 1-13页

作者： Masso, Majid Vaisman, Iosif I. George Mason Univ Sch Syst Biol Lab Struct Bioinformat Manassas VA 20110 USA

Background: Successful management of chronic human immunodeficiency virus type 1 (HIV-1) infection with a cocktail of antiretroviral medications can be negatively affected by the presence of drug resistant mutations in the viral targets. These targets include the HIV-1 protease (PR) and reverse transcriptase (RT) proteins, for which a number of inhibitors are available on the market and routinely prescribed. Protein mutational patterns are associated with varying degrees of resistance to their respective inhibitors, with extremes that can range from continued susceptibility to cross-resistance across all drugs. Results: Here we implement statistical learning algorithms to develop structure-and sequence-based models for systematically predicting the effects of mutations in the PR and RT proteins on resistance to each of eight and eleven inhibitors, respectively. Employing a four-body statistical potential, mutant proteins are represented as feature vectors whose components quantify relative environmental perturbations at amino acid residue positions in the respective target structures upon mutation. Two approaches are implemented in developing sequence-based models, based on use of either relative frequencies or counts of n-grams, to generate vectors for representing mutant proteins. To the best of our knowledge, this is the first reported study on structure-and sequence-based predictive models of HIV-1 PR and RT drug resistance developed by implementing a four-body statistical potential and n-grams, respectively, to generate mutant attribute vectors. Performance of the learning methods is evaluated on the basis of tenfold cross-validation, using previously assayed and publicly available in vitro data relating mutational patterns in the targets to quantified inhibitor susceptibility changes. Conclusion: Overall performance results are competitive with those of a previously published study utilizing a sequence-based strategy, while our structure-and sequence-based mod

关键词： Support Vector Machine Random Forest Support Vector Regression reverse transcriptase sequence Random Forest Classification

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A comparative analysis of HIV drug resistance interpretation based on short reverse transcriptase sequences versus full sequences

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AIDS RESEARCH AND THERAPY 2010年第1期7卷 1-9页

作者： Steegen, Kim Bronze, Michelle Van Craenenbroeck, Elke Winters, Bart Van der Borght, Koen Wallis, Carole L. Stevens, Wendy de Wit, Tobias F. Rinke Stuyver, Lieven J. Tibotec Virco Virol BVBA Dept Infect Dis & Biomarkers Beerse Belgium Univ Witwatersrand Dept Mol Med & Hematol Johannesburg South Africa Tibotec Virco Virol BVBA Dept Res Informat & Integrat Genom Beerse Belgium Tibotec Virco Virol BVBA Dept Clin Virol Beerse Belgium Univ Witwatersrand Dept Mol Med & Hematol Fac Hlth Sci Johannesburg South Africa Natl Hlth Lab Serv Johannesburg South Africa PharmAccess Fdn Dept Hlth Intelligence Amsterdam Netherlands Univ Amsterdam Acad Med Ctr Amsterdam Inst Global Hlth & Dev NL-1105 AZ Amsterdam Netherlands Contract Lab Serv Johannesburg South Africa Ctr Rech Publ Sante Luxembourg Luxembourg PharmAccess Fdn Amsterdam Netherlands Univ Med Ctr Utrecht Dept Virol Utrecht Netherlands Tibotec Virco Virol BVBA Beerse Belgium Univ Witwatersrand Wits Hlth Consortium Johannesburg South Africa

Background: As second-line antiretroviral treatment (ART) becomes more accessible in resource-limited settings (RLS), the need for more affordable monitoring tools such as point-of-care viral load assays and simplified genotypic HIV drug resistance (HIVDR) tests increases substantially. The prohibitive expenses of genotypic HIVDR assays could partly be addressed by focusing on a smaller region of the HIV reverse transcriptase gene (RT) that encompasses the majority of HIVDR mutations for people on ART in RLS. In this study, an in silico analysis of 125,329 RT sequences was performed to investigate the effect of submitting short RT sequences (codon 41 to 238) to the commonly used virco (R) TYPE and Stanford genotype interpretation tools. Results: Pair-wise comparisons between full-length and short RT sequences were performed. Additionally, a non-inferiority approach with a concordance limit of 95% and two-sided 95% confidence intervals was used to demonstrate concordance between HIVDR calls based on full-length and short RT sequences. The results of this analysis showed that HIVDR interpretations based on full-length versus short RT sequences, using the Stanford algorithms, had concordance significantly above 95%. When using the virco (R) TYPE algorithm, similar concordance was demonstrated (>95%), but some differences were observed for d4T, AZT and TDF, where predictions were affected in more than 5% of the sequences. Most differences in interpretation, however, were due to shifts from fully susceptible to reduced susceptibility (d4T) or from reduced response to minimal response (AZT, TDF) or vice versa, as compared to the predicted full RT sequence. The virco (R) TYPE prediction uses many more mutations outside the RT 41-238 amino acid domain, which significantly contribute to the HIVDR prediction for these 3 antiretroviral agents. Conclusions: This study illustrates the acceptability of using a shortened RT sequences (codon 41-238) to obtain reliable genotype inte

关键词： Call Change reverse transcriptase sequence Resistance Prediction Phenotypic Drug Susceptibility Reference Strain sequence

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BMC PLANT BIOLOGY 2010年第1期10卷 1-10页

作者： Zedek, Frantisek Smerda, Jakub Smarda, Petr Bures, Petr Masaryk Univ Dept Bot & Zool CS-61137 Brno Czech Republic

Background: Transposable elements (TEs) are considered to be an important source of genome size variation and genetic and phenotypic plasticity in eukaryotes. Most of our knowledge about TEs comes from large genomic projects and studies focused on model organisms. However, TE dynamics among related taxa from natural populations and the role of TEs at the species or supra-species level, where genome size and karyotype evolution are modulated in concert with polyploidy and chromosomal rearrangements, remain poorly understood. We focused on the holokinetic genus Eleocharis (Cyperaceae), which displays large variation in genome size and the occurrence of polyploidy and agmatoploidy/symploidy. We analyzed and quantified the long terminal repeat (LTR) retrotransposons Ty1-copia and Ty3-gypsy in relation to changes in both genome size and karyotype in Eleocharis. We also examined how this relationship is reflected in the phylogeny of Eleocharis. Results: Using flow cytometry, we measured the genome sizes of members of the genus Eleocharis (Cyperaceae). We found positive correlation between the independent phylogenetic contrasts of genome size and chromosome number in Eleocharis. We analyzed PCR-amplified sequences of various reverse transcriptases of the LTR retrotransposons Ty1-copia and Ty3-gypsy (762 sequences in total). Using real-time PCR and dot blot approaches, we quantified the densities of Ty1-copia and Ty3-gypsy within the genomes of the analyzed species. We detected an increasing density of Ty1-copia elements in evolutionarily younger Eleocharis species and found a positive correlation between Ty1-copia densities and C-/n-values (an alternative measure of monoploid genome size) in the genus phylogeny. In addition, our analysis of Ty1-copia sequences identified a novel retrotransposon family named Helos1, which is responsible for the increasing density of Ty1-copia. The transition: transversion ratio of Helos1 sequences suggests that Helos1 recently transposed in

关键词： Genome Size Transposable Element Long Terminal Repeat Long Terminal Repeat Retrotransposons reverse transcriptase sequence

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Repetitive part of the banana (Musa acuminata) genome investigated by low-depth 454 sequencing

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BMC PLANT BIOLOGY 2010年第1期10卷 1-10页

作者： Hribova, Eva Neumann, Pavel Matsumoto, Takashi Roux, Nicolas Macas, Jiri Dolezel, Jaroslav Acad Sci Czech Republ Inst Plant Mol Biol Ctr Biol CZ-37005 Ceske Budejovice Czech Republic Natl Inst Agrobiol Sci Tsukuba Ibaraki 3058602 Japan Biovers Int Commod Livelihoods Programme F-34397 Montpellier 5 France Inst Expt Bot Lab Mol Cytogenet & Cytometry CZ-77200 Olomouc Czech Republic

Background: Bananas and plantains (Musa spp.) are grown in more than a hundred tropical and subtropical countries and provide staple food for hundreds of millions of people. They are seed-sterile crops propagated clonally and this makes them vulnerable to a rapid spread of devastating diseases and at the same time hampers breeding improved cultivars. Although the socio-economic importance of bananas and plantains cannot be overestimated, they remain outside the focus of major research programs. This slows down the study of nuclear genome and the development of molecular tools to facilitate banana improvement. Results: In this work, we report on the first thorough characterization of the repeat component of the banana (M. acuminata cv. 'Calcutta 4') genome. Analysis of almost 100 Mb of sequence data (0.15x genome coverage) permitted partial sequence reconstruction and characterization of repetitive DNA, making up about 30% of the genome. The results showed that the banana repeats are predominantly made of various types of Ty1/copia and Ty3/gypsy retroelements representing 16 and 7% of the genome respectively. On the other hand, DNA transposons were found to be rare. In addition to new families of transposable elements, two new satellite repeats were discovered and found useful as cytogenetic markers. To help in banana sequence annotation, a specific Musa repeat database was created, and its utility was demonstrated by analyzing the repeat composition of 62 genomic BAC clones. Conclusion: A low-depth 454 sequencing of banana nuclear genome provided the largest amount of DNA sequence data available until now for Musa and permitted reconstruction of most of the major types of DNA repeats. The information obtained in this study improves the knowledge of the long-range organization of banana chromosomes, and provides sequence resources needed for repeat masking and annotation during the Musa genome sequencing project. It also provides sequence data for isolation of DNA ma

关键词： Mitotic Chromosome reverse transcriptase sequence reverse transcriptase Domain Single Copy sequence Distinct Evolutionary Lineage

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Subtype-associated differences in HIV-1 reverse transcription affect the viral replication

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RETROVIROLOGY 2010年第1期7卷 1-18页

作者： Iordanskiy, Sergey Waltke, Mackenzie Feng, Yanjun Wood, Charles Univ Nebraska Sch Biol Sci Nebraska Ctr Virol Ken Morrison Life Sci Res Ctr Lincoln NE 68583 USA George Washington Univ Med Ctr Dept Microbiol Immunol & Trop Med Washington DC 20037 USA Russian Acad Med Sci DI Ivanovsky Inst Virol Moscow Russia

Background: The impact of the products of the pol gene, specifically, reverse transcriptase (RT) on HIV-1 replication, evolution, and acquisition of drug resistance has been thoroughly characterized for subtype B. For subtype C, which accounts of almost 60% of HIV cases worldwide, much less is known. It has been reported that subtype C HIV-1 isolates have a lower replication capacity than B;however, the basis of these differences remains unclear. Results: We analyzed the impact of the pol gene products from HIV-1 B and C subtypes on the maturation of HIV virions, accumulation of reverse transcription products, integration of viral DNA, frequency of point mutations in provirus and overall viral replication. Recombinant HIV-1 viruses of B and C subtypes comprising the pol fragments encoding protease, integrase and either the whole RT or a chimeric RT from different isolates of the C and B subtypes, were used for infection of cells expressing CXCR4 or CCR5 co-receptors. The viruses carrying different fragments of pol from the isolates of B and C subtypes did not reveal differences in Gag and GagPol processing and viral RNA incorporation into the virions. However, the presence of the whole RT from subtype C, or the chimeric RT containing either the polymerase or the connection and RNase H domains from C isolates, caused significantly slower viral replication regardless of B or C viral backbone. Subtype C RT carrying viruses displayed lower levels of accumulation of strong-stop cDNA in permeabilized virions during endogenous reverse transcription, and decreased accumulation of both strong-stop and positive strand reverse transcription products in infected cells and in isolated reverse transcription complexes. This decreased accumulation correlated with lower levels of viral DNA integration in cells infected with viruses carrying the whole RT or RT domains from subtype C isolates. The single viral genome assay analysis did not reveal significant differences in the frequen

关键词： Chimeric Virus reverse Transcription Product reverse transcriptase sequence reverse transcriptase Domain Polymerase Domain

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Higher levels of Zidovudine resistant HIV in the colon compared to blood and other gastrointestinal compartments in HIV infection

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RETROVIROLOGY 2010年第1期7卷 1-13页

作者： van Marle, Guido Church, Deirdre L. Nunweiler, Kali D. Cannon, Kris Wainberg, Mark A. Gill, M. John Univ Calgary Dept Microbiol & Infect Dis Calgary AB Canada Univ Calgary Dept Pathol & Lab Med Calgary AB Canada Univ Calgary Dept Med Calgary AB Canada Calgary Lab Serv Calgary AB Canada McGill Univ Jewish Gen Hosp Lady Davis Inst AIDS Ctr Montreal PQ H3T 1E2 Canada McGill Univ Dept Microbiol & Immunol Montreal PQ Canada

Background: The gut-associated lymphoid tissue (GALT) is the largest lymphoid organ infected by human immunodeficiency virus type 1 (HIV-1). It serves as a viral reservoir and host-pathogen interface in infection. This study examined whether different parts of the gut and peripheral blood lymphocytes (PBL) contain different drug-resistant HIV-1 variants. Methods: Gut biopsies (esophagus, stomach, duodenum and colon) and PBL were obtained from 8 HIV-1 infected preHAART (highly active antiretroviral therapy) patients at three visits over 18 months. Patients received AZT, ddI or combinations of AZT/ddI. HIV-1 reverse transcriptase (RT)-coding sequences were amplified from viral DNA obtained from gut tissues and PBL, using nested PCR. The PCR fragments were cloned and sequenced. The resulting sequences were subjected to phylogenetic analyses, and antiretroviral drug mutations were identified. Results: Phylogenetic and drug mutation analyses revealed differential distribution of drug resistant mutations in the gut within patients. The level of drug-resistance conferred by the RT sequences was significantly different between different gut tissues and PBL, and varied with antiretroviral therapy. The sequences conferring the highest level of drug-resistance to AZT were found in the colon. Conclusion: This study confirms that different drug-resistant HIV-1 variants are present in different gut tissues, and it is the first report to document that particular gut tissues may select for drug resistant HIV-1 variants.

关键词： Peripheral Blood Lymphocyte reverse transcriptase sequence Antiviral Drug Resistance reverse transcriptase Code reverse transcriptase Code Region

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Host sequence motifs shared by HIV predict response to antiretroviral therapy

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BMC MEDICAL GENOMICS 2009年第1期2卷 1-14页

作者： Dampier, William Evans, Perry Ungar, Lyle Tozeren, Aydin Drexel Univ Bossone Res Ctr 711 Ctr Integrated Bioinformat Philadelphia PA 19104 USA Univ Penn Genom & Computat Biol & Dept Comp & Informat Sci Philadelphia PA 19104 USA

Background: The HIV viral genome mutates at a high rate and poses a significant long term health risk even in the presence of combination antiretroviral therapy. Current methods for predicting a patient's response to therapy rely on site-directed mutagenesis experiments and in vitro resistance assays. In this bioinformatics study we treat response to antiretroviral therapy as a two-body problem: response to therapy is considered to be a function of both the host and pathogen proteomes. We set out to identify potential responders based on the presence or absence of host protein and DNA motifs on the HIV proteome. Results: An alignment of thousands of HIV-1 sequences attested to extensive variation in nucleotide sequence but also showed conservation of eukaryotic short linear motifs on the protein coding regions. The reduction in viral load of patients in the Stanford HIV Drug Resistance Database exhibited a bimodal distribution after 24 weeks of antiretroviral therapy, with 2,000 copies/ml cutoff. Similarly, patients allocated into responder/non-responder categories based on consistent viral load reduction during a 24 week period showed clear separation. In both cases of phenotype identification, a set of features composed of short linear motifs in the reverse transcriptase region of HIV sequence accurately predicted a patient's response to therapy. Motifs that overlap resistance sites were highly predictive of responder identification in single drug regimens but these features lost importance in defining responders in multi-drug therapies. Conclusion: HIV sequence mutates in a way that preferentially preserves peptide sequence motifs that are also found in the human proteome. The presence and absence of such motifs at specific regions of the HIV sequence is highly predictive of response to therapy. Some of these predictive motifs overlap with known HIV-1 resistance sites. These motifs are well established in bioinformatics databases and hence do not require identifi

关键词： Human Immunodeficiency Virus miRNA Binding Site Phenotype Classification reverse transcriptase sequence Human Immunodeficiency Virus Protein

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Potential impact of stress activated retrotransposons on genome evolution in a marine diatom

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BMC GENOMICS 2009年第1期10卷 1-19页

作者： Maumus, Florian Allen, Andrew E. Mhiri, Corinne Hu, Hanhua Jabbari, Kamel Vardi, Assaf Grandbastien, Marie-Angele Bowler, Chris Ecole Normale Super CNRS UMR8186 F-75230 Paris France J Craig Venter Inst San Diego CA 92121 USA INRA Versailles Grignon Inst Jean Pierre Bourgin Lab Biol Cellulaire F-78026 Versailles France Rutgers State Univ Inst Marine & Coastal Sci Environm Biophys & Mol Ecol Grp New Brunswick NJ 08901 USA Staz Zool Anton Dohrn I-80121 Naples Italy

Background: Transposable elements (TEs) are mobile DNA sequences present in the genomes of most organisms. They have been extensively studied in animals, fungi, and plants, and have been shown to have important functions in genome dynamics and species evolution. Recent genomic data can now enlarge the identification and study of TEs to other branches of the eukaryotic tree of life. Diatoms, which belong to the heterokont group, are unicellular eukaryotic algae responsible for around 40% of marine primary productivity. The genomes of a centric diatom, Thalassiosira pseudonana, and a pennate diatom, Phaeodactylum tricornutum, that likely diverged around 90 Mya, have recently become available. Results: In the present work, we establish that LTR retrotransposons (LTR-RTs) are the most abundant TEs inhabiting these genomes, with a much higher presence in the P. tricornutum genome. We show that the LTR-RTs found in diatoms form two new phylogenetic lineages that appear to be diatom specific and are also found in environmental samples taken from different oceans. Comparative expression analysis in P. tricornutum cells cultured under 16 different conditions demonstrate high levels of transcriptional activity of LTR retrotransposons in response to nitrate limitation and upon exposure to diatom-derived reactive aldehydes, which are known to induce stress responses and cell death. Regulatory aspects of P. tricornutum retrotransposon transcription also include the occurrence of nitrate limitation sensitive cis-regulatory components within LTR elements and cytosine methylation dynamics. Differential insertion patterns in different P. tricornutum accessions isolated from around the world infer the role of LTR-RTs in generating intraspecific genetic variability. Conclusion: Based on these findings we propose that LTR-RTs may have been important for promoting genome rearrangements in diatoms.

关键词： Centric Diatom Decadienal reverse transcriptase sequence Rice Tungro Bacilliform Virus Copia Lineage

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How Athila retrotransposons survive in the Arabidopsis genome

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BMC GENOMICS 2008年第1期9卷 1-14页

作者： Marco, Antonio Marin, Ignacio CSIC Inst Biomed Valencia Valencia Spain Arizona State Univ Biodesign Inst Ctr Evolutionary Funct Genom Tempe AZ 85287 USA

Background: Transposable elements are selfish genetic sequences which only occasionally provide useful functions to their host species. In addition, models of mobile element evolution assume a second type of selfishness: elements of different familes do not cooperate, but they independently fight for their survival in the host genome. Results: We show that recombination events among distantly related Athila retrotransposons have led to the generation of new Athila lineages. Their pattern of diversification suggests that Athila elements survive in Arabidopsis by a combination of selfish replication and of amplification of highly diverged copies with coding potential. Many Athila elements are non-autonomous but still conserve intact open reading frames which are under the effect of negative, purifying natural selection. Conclusion: The evolution of these mobile elements is far more complex than hitherto assumed. Strict selfish replication does not explain all the patterns observed.

关键词： Active Element Active Copy reverse transcriptase sequence Defective Copy Athila Element

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Genome-wide changes in expression profile of murine endogenous retroviruses (MuERVs) in distant organs after burn injury

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BMC GENOMICS 2007年第1期8卷 1-15页

作者： Lee, Young-Kwan Chew, Alex Fitzsimon, Lauren Thomas, Rita Greenhalgh, David Cho, Kiho Univ Calif Davis Inst Pediat Regenerat Med Shriners Hosp Children N Calif Sacramento CA 95817 USA Univ Calif Davis Dept Surg Sacramento CA 95817 USA

Background: Previous studies have shown that burn-elicited stress signals alter expression of certain murine endogenous retroviruses (MuERVs) in distant organs of mice. These findings suggest that MuERVs may participate in a network of pathophysiologic events during post-burn systemic response. To gain a better understanding of the biological roles of MuERVs in post-burn systemic response, we examined the genome-wide changes in the MuERV expression profiles in distant organs and the biological properties of the putative-burn related MuERVs were characterized. Results: Female C57BL/6J mice were subjected to an approximately 18% total body surface area flame burn and tissues (liver, lung, and kidney) were harvested at 3 hours and 24 hours after injury. The changes in the MuERV expression profiles in these tissues were examined by RT-PCR using a primer set flanking the non-ecotropic MuERV U3 promoter region within the 3' long terminal repeat. There were differential changes in the expression profiles of MuERV U3 regions after injury in all three tissues examined. Subsequently, a total of 31 unique U3 promoter sequences were identified from the tissues of both burn and no burn mice. An analysis of viral tropisms revealed that putative MuERVs harboring these U3 promoter sequences were presumed to be either xenotropic or polytropic. Some putative transcription regulatory elements were present predominantly in U3 promoter sequences isolated from burn and no burn mice, respectively. In addition, in silico mapping using these U3 sequences as a probe against the mouse genome database identified 59 putative MuERVs. The biological properties (coding potentials for retroviral polypeptides, primer binding sites, tropisms, branching ages, recombination events, and neighboring host genes) of each putative MuERV were characterized. In particular, 16 putative MuERVs identified in this study retained intact coding potentials for all three retroviral polypeptides (gag, pol, and env). N

关键词： Host Gene Direct Repeat Mouse Genome Database reverse transcriptase sequence Transcription Regulatory Element

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