Clinical DataSample Core-Resistance Driven Structural Design for HIV Therapeutics

临床数据 HIV 治疗的核心电阻驱动结构设计样本

• 批准号: 7434201
• 负责人: David James Looney
• 金额: $ 4.91万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-18 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7434201
• 关键词: Address; Adherence; Algorithms; Bioinformatics; California; Clinical; Clinical Data; Clinical Treatment; Clinical Trials; Controlled Clinical Trials; Data; Data Set; Drug Combinations; Drug Formulations; Drug resistance; Endopeptidases; Enzymes; Event; Evolution; Failure; Gagging; HIV; HIV Protease; HIV-1; Human; Hybrids; Immunologics; In Vitro; Individual; Investigation; Laboratories; Lead; Link; Modeling; Molecular Structure; Mutation; Outcome; Patients; Pattern; Peptide Hydrolases; Pharmaceutical Preparations; Polymerase Chain Reaction; Population; Protease Gene; Protease Inhibitor; Purpose; RNA; Randomized Controlled Clinical Trials; Replicon; Resistance; Sampling; Sequential Treatment; Site; Specimen; Structural Models; Structure; Study models; Suggestion; T-Lymphocyte Subsets; Testing; Therapeutic; Treatment Failure; Treatment Protocols; Veterans; Viral; Work; abstracting; base; clinical research site; cohort; design; experience; inhibitor/antagonist; interest; novel; pol genes; resistance mechanism; response; success

The overall purpose of the Clinical Data and Sample Core (Clinical Core) is to provide relevant clinical data to Project 1, "Computational and Bioinformatics modeling and analysis of HIV Protease drug resistance", and data and specimens to Project 4, "Structure-based Mechanisms for Resistance to PR Inhibitors". Clinical experience often differs from that of controlled clinical trials, and the evolution of resistance to protease inhibitor drugs (Pis) seen in clinical settings may differ that selected in vitro or in the homogenous populations in randomized trials. This may be particularly true with respect to highly treatment-experienced individuals with persistent virological failure. We hypothesize that modeling limited data sets from clinical cohort(s) will lead to new predictions concerning evolution of resistance that can in turn be tested in laboratory models. Similarly, it is hypothesized that both unique patterns of mutations within the HIV protease as well as compensatory mutations outside the protease region may correlate with success or failure of PI containing regimens,and that specific strains from clinical trial samples can be identified to test this hypothesis in vitro. ; Specifically, the Clinical Core will: (1) Implement human use projects to obtain and abstract limited data sets suitable for modeling and/or other analysis by Project 1 which include HIV genotypic (sequence as well as interpretation) data, immunologic (T-cell subset), virological (HIV RNA), and treatment (sequential treatment regimen) from three clinical sites in Southern California and a "salvage" trial in highly advanced patients (Options in Managment with Antiretrovirals - OPTIMA, substudy), and (2) Identify and characterize (PCR amplifcation and sequencing of gag-pol) samples from clinical trials (OPTIMA substudy, Drug Adherence in HIV-infected Veterans) likely to contain suitable mutations for study by Project 4.

临床数据和样本核心(临床核心)的总体目的是提供相关的临床数据 项目1，“艾滋病毒蛋白水解酶耐药性的计算和生物信息学建模与分析”，以及 项目4，“基于结构的PR抑制剂抗性机制”的数据和样本。 临床经验往往不同于对照临床试验，并且耐药的演变 在临床环境中看到的蛋白酶抑制剂药物(PI)可能不同于在体外或在均相中选择的药物 随机试验中的人群。对于有丰富治疗经验的人来说，情况可能尤其如此 患有持续性病毒学故障的个体。我们假设对有限的临床数据集进行建模 队列(S)将导致关于耐药性进化的新预测，这些预测反过来可以在 实验室模型。类似地，假设HIV病毒内的两种独特的突变模式 蛋白水解酶以及蛋白水解酶区域外的补偿性突变可能与成功或 含有PI的方案失败，临床试验样本中的特定菌株可以被鉴定出来进行检测 这一假说在体外。 ； 具体地说，临床核心将：(1)实施人类使用项目，以获取和提取有限的数据集 适用于项目1的建模和/或其他分析，包括HIV基因类型(序列以及 解释)数据、免疫学(T细胞亚群)、病毒学(艾滋病毒RNA)和治疗(序贯治疗 来自南加州的三个临床地点)和一项针对高度晚期患者的“抢救”试验 (抗逆转录病毒治疗中的选择-最佳，子研究)，以及(2)识别和表征(聚合酶链式反应) 来自临床试验的样本的扩增和测序)(OPTIMA亚研究，药物依从性 感染艾滋病毒的退伍军人)可能含有适合项目4研究的突变。