Evolution of antiviral resistance mutations and their biological and biophysical implications
Evolution of antiviral resistance mutations and their biological and biophysical implications
批准号:
10242909
负责人:
Ronald Levy
金额:
$117.56万
依托单位国家:
美国
项目类别:
财政年份:
2012
资助国家:
美国
项目状态:
已结题
起止时间:
2012-09-01 至 2023-08-31
关键词:
AddressAffectAmino Acid SequenceAmino AcidsAntiretroviral resistanceAntiviral resistanceBar CodesBiochemicalBioinformaticsBiologicalBiological AssayBiophysicsCapsidCharacteristicsClinicalCollaborationsComplementDataDevelopmentDrug ModelingsDrug resistanceEnzymesEvolutionFailureFundingGag PRGeneticGoalsHIVHIV InfectionsHIV-1IndividualIntegraseIntegration Host FactorsInvestigationLeadLengthLinkLinkage DisequilibriumLocationMeasuresMethodologyModelingMutationNational Institute of General Medical SciencesNaturePatientsPatternPeptide HydrolasesPharmaceutical PreparationsPharmacotherapyPositioning AttributeProbabilityProteinsRNA-Directed DNA PolymeraseResistanceResistance developmentRiskRoleSamplingSequence AlignmentStatistical MethodsStatistical ModelsStructureTechnologyTimeTreatment FailureValidationViralViral ProteinsVirusantiretroviral therapybasedatabase structuredeep sequencingexperiencefitnessgag Gene Productsinhibitor/antagonistinnovative technologiesinsightkinetic modelnext generation sequencingnovelpatient populationpol Gene Productspressureprospectiveresistance mutationresponsesingle moleculesmall moleculesuccesstherapy resistanttreatment responseviral fitnessvirology
中文摘要
摘要
正在接受抗逆转录病毒治疗的HIV-1选择与基因相关的突变,原因是
对蛋白质结构稳定性和功能的限制,这有助于健身。项目5的研究包括
与分析成对(或更高顺序)的抗逆转录病毒耐药突变及其
生物物理、生化和结构对抗药性和病毒适应性的综合影响。在过去
在资助期间,开发了新的统计方法来确定存在于
基因上没有关联的Gag和蛋白酶深度测序数据。Potts哈密顿概率模型
从蛋白酶序列比对中构建,以识别导致耐药性的突变模式。
为了扩展过去的发现,建议确定抗逆转录病毒耐药性的基因关联模式。
来自B分支或非B分支HIV感染患者的全长单个病毒的突变
抗逆转录病毒治疗。研究HIV蛋白中影响选择的结构限制因素
抗性突变,将利用序列和序列建立蛋白质序列共变的Potts模型
结构数据。一种新的全长测序方法与Torbett的病毒学专业知识相结合
利维的生物信息学和建模专业知识将与之相辅相成,以实现以下具体目标:
1)在纵向患者中鉴定HIV的基因连锁耐药突变(成对或更高顺序)
利用多读条形码辅助单分子测序(MRBASMS)的样品。协变
突变将使用前面描述的生物化学在功能和结构上进行表征,
生物物理和病毒学分析,以验证它们在耐药性上升中的作用。
2)将利用来自1)的全长和来自数据库的艾滋病毒序列数据和结构信息
构建药物朴素和药物相关的蛋白水解酶、逆转录酶、整合酶和
恶作剧。POTS模型将用于研究上位性突变组合对适应度的影响,如
以及预测艾滋病毒蛋白残留物存在耐药突变发展的风险。这些研究将
提供对HIV基因障碍的重要见解,这些障碍必须克服才能对多种病毒产生抵抗力
抑制剂组合。
来自纵向患者样本的HIV准种的MR BASMS测序将由Torbett和
萨拉菲亚诺斯和外部合作者劳斯(UTMB)。生化、结构和病毒学
突变协变量的验证将由Torbett、Sarafianos和Levy领导,并由
Levy将根据HIV序列数据和获得的蛋白质结构信息开发POTS模型
来自项目1、2和核心1。
英文摘要
ABSTRACT
HIV-1 under antiretroviral treatment selects for genetically-linked mutations that are correlated due to
constraints on protein structural stability and function, which contribute to fitness. Project 5 studies are
concerned with analyzing pairs (or higher-order) patterns of antiretroviral resistance mutations and their
combined biophysical, biochemical, and structural effects on drug-resistance and viral fitness. During the past
funding period, new statistical methods were developed to identify correlative mutational patterns present in
genetically unlinked Gag and protease deep sequencing data. Potts Hamiltonian probabilistic models were
constructed from protease sequence alignments to identify mutational patterns that lead to drug-resistance.
To extend the past findings, it is proposed to identify genetically-linked patterns of antiretroviral resistance
mutations from full-length, individual viruses from clade B or non-clade B HIV-infected patients during
antiretroviral treatment. To investigate structural constraints in HIV proteins that influence selection of
resistance mutations, Potts models of protein sequence covariation will be developed utilizing sequence and
structural data. The combination of a novel full-length sequencing approach and virology expertise by Torbett
will be complemented by bioinformatics and modeling expertise of Levy to serve the following specific aims:
1) Identify genetically-linked drug-resistance mutations (pairs or higher order) from HIV in longitudinal patient
samples utilizing Multi-read Barcode-Assisted Single Molecule Sequencing (MrBASMS). Covariant
mutations will be functionally and structurally characterized using previously described biochemical,
biophysical and virological assays to validate their role in the rise of drug resistance.
2) Both full-length, from 1), and HIV sequence data from databases and structural information will be utilized to
construct Potts models of drug naïve and drug-experienced protease, reverse transcriptase, integrase and
Gag. Potts models will be used to investigate the effects of epistatic mutational combinations on fitness, as
well as predict HIV protein residues at risk for drug-resistance mutation development. These studies will
provide critical insight into HIV genetic barriers that must be overcome to develop resistance to multiple
inhibitor combinations.
The MrBASMS sequencing of HIV quasispecies from longitudinal patient samples will be led by Torbett and
Sarafianos, along with outside collaborator Routh (UTMB). The biochemical, structural and virological
validation of mutational covariants will be led by Torbett, Sarafianos and Levy, along with assistance from
Core 2. Levy will develop Potts models from HIV sequence data and protein structural information obtained
from Projects 1, 2, and Core 1.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Mechanisms of HIV fitness and drug resistance inferred from high-resolution molecular dynamics and sequence co-variation models
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批准号:10750627
-
项目类别:
-
资助金额:$69.11万
-
财政年份:2023
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负责人:Ronald Levy
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依托单位:
Mapping Fitness and Free Energy Landscapes of Proteins
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批准号:10609895
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项目类别:
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资助金额:$37.13万
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财政年份:2019
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负责人:Ronald Levy
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依托单位:
Mapping Fitness and Free Energy Landscapes of Proteins
-
批准号:9906947
-
项目类别:
-
资助金额:$37.13万
-
财政年份:2019
-
负责人:Ronald Levy
-
依托单位:
Mapping Fitness and Free Energy Landscapes of Proteins
-
批准号:10577469
-
项目类别:
-
资助金额:$21.46万
-
财政年份:2019
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负责人:Ronald Levy
-
依托单位:
Mapping Fitness and Free Energy Landscapes of Proteins
-
批准号:10402303
-
项目类别:
-
资助金额:$37.13万
-
财政年份:2019
-
负责人:Ronald Levy
-
依托单位:
Computer Cluster for Computational Biology and Biophysics
-
批准号:8826397
-
项目类别:
-
资助金额:$44.23万
-
财政年份:2015
-
负责人:Ronald Levy
-
依托单位:
Evolution of antiviral resistance mutations and their biological and biophysical implications
-
批准号:10363026
-
项目类别:
-
资助金额:$64.71万
-
财政年份:2012
-
负责人:Ronald Levy
-
依托单位:
Computer Simulations of Protein Structure and Dynamics
-
批准号:7932626
-
项目类别:
-
资助金额:$14.53万
-
财政年份:2009
-
负责人:Ronald Levy
-
依托单位:
ATLR 9 AGONIST, COMBINED WITH LOCAL RADIATION IN RECURRENT LOW-GRADE LYMPHOMAS
-
批准号:7605212
-
项目类别:
-
资助金额:$4.45万
-
财政年份:2007
-
负责人:Ronald Levy
-
依托单位:
CLINICAL TRIAL: KLH WITH GM-CSF, IN PATIENTS WITH FOLLICULAR NON-HODGKIN'S LYMPH
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批准号:7717852
-
项目类别:
-
资助金额:$0.05万
-
财政年份:2007
-
负责人:Ronald Levy
-
依托单位:
CLINICAL TRIAL: ATLR 9 AGONIST, COMBINED WITH LOCAL RADIATION IN RECURRENT LOW-G
-
批准号:7717872
-
项目类别:
-
资助金额:$0.98万
-
财政年份:2007
-
负责人:Ronald Levy
-
依托单位:
Computer Cluster for Computational and Structural Biology
-
批准号:7217100
-
项目类别:
-
资助金额:$29.09万
-
财政年份:2007
-
负责人:Ronald Levy
-
依托单位:
KLH WITH GM-CSF, IN PATIENTS WITH FOLLICULAR NON-HODGKIN'S LYMPHOMA
-
批准号:7605175
-
项目类别:
-
资助金额:$0.64万
-
财政年份:2007
-
负责人:Ronald Levy
-
依托单位:
VACCINE THERAPY FOR MULTIPLE MYELOMA ALLOGENEIC DENDRITIC CELLS
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批准号:7605222
-
项目类别:
-
资助金额:$0.94万
-
财政年份:2007
-
负责人:Ronald Levy
-
依托单位:
PATIENTS WITH STABLE OR PROGRESSIVE GRADE 1 OR 2 FOLLICULAR B-CELL LYMPHOMAS
-
批准号:7605251
-
项目类别:
-
资助金额:$0.35万
-
财政年份:2007
-
负责人:Ronald Levy
-
依托单位:
ATLR 9 AGONIST, COMBINED WITH LOCAL RADIATION IN RECURRENT LOW-GRADE LYMPHOMAS
-
批准号:7375281
-
项目类别:
-
资助金额:$0.53万
-
财政年份:2005
-
负责人:Ronald Levy
-
依托单位:
VACCINE THERAPY FOR MULTIPLE MYELOMA UTILIZING ALLOGENEIC DENDRITIC CELLS
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批准号:7375297
-
项目类别:
-
资助金额:$0.22万
-
财政年份:2005
-
负责人:Ronald Levy
-
依托单位:
PROTOCOL G2002-09: A PHASE II STUDY TO EVALUATE THE SAFETY AND EFFICACY
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批准号:7375226
-
项目类别:
-
资助金额:$1.25万
-
财政年份:2005
-
负责人:Ronald Levy
-
依托单位:
IMMUNOTHERAPY IN PATIENTS WITH FOLLICULAR NON-HODGKIN'S LYMPHOMA
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批准号:7375218
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项目类别:
-
资助金额:$2.05万
-
财政年份:2005
-
负责人:Ronald Levy
-
依托单位:
Training for Integrative Proteomics Technologies(RMI)
-
批准号:6951837
-
项目类别:
-
资助金额:$11.62万
-
财政年份:2004
-
负责人:Ronald Levy
-
依托单位:
海外基金