HIV Macromolecular Interactions and Impact on Viral Evolution of Drug Resistance

HIV大分子相互作用及其对病毒耐药性进化的影响

• 批准号: 8537483
• 负责人: ARTHUR J. OLSON
• 金额: $ 387.13万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8537483
• 关键词: Address; Anti-HIV Agents; Behavior; Binding Sites; Biochemistry; Biological; Chemicals; Chromatin; Complex; Computational Biology; Computing Methodologies; Crystallization; Crystallography; DNA Integration; DNA biosynthesis; Data; Drug Design; Drug Targeting; Drug resistance; Environment; Enzymes; Evolution; Gagging; Goals; HIV; HIV Integrase; HIV Protease; HIV-1; Human; Kinetics; Knowledge; Life Cycle Stages; Link; Membrane; Methodology; Methods; Modeling; Molecular Biology; Molecular Structure; Mutation; Nucleic Acids; Peptide Hydrolases; Play; Polyproteins; Predisposition; Process; Property; Proteins; RNA; RNA-Directed DNA Polymerase; Research Personnel; Resistance; Ribonuclease H; Role; Serial Passage; Site; Structural Models; Structure; Synthesis Chemistry; System; Testing; Therapeutic; Thermodynamics; Transfer RNA; Viral; Viral Physiology; Virion; base; chemical synthesis; combat; fitness; flexibility; gag Gene Products; improved; inhibitor/antagonist; insight; knowledge base; macromolecule; mutant; novel; pol Gene Products; protein complex; resistance mutation; screening; small molecule; therapeutic target; virology; virtual

DESCRIPTION (provided by applicant): We have formed the HIVE Center to characterize at the atomic level the structural and dynamic relationships between interacting macromolecules in the HIV life cycle. We will focus on interactions of the major HIV enzymes with their partners and effectors since they encompass key processes in the viral life cycle and as existing drug targets provide a rich base of structural, biological and evolutionary data that will serve to infom our goals. We will explore resistance evolution in HIV as an opportune platform upon which to characterize the dynamic relationships between interacting macromolecular structures at the atomic level. The HIVE Center comprises a group of investigators with considerable expertise in HIV crystallography, virology, molecular biology, synthetic chemistry and computational biology. We will study the mechanistic implications of viral macromolecular interactions and dynamics and its broader impacts of the evolution of drug resistance. The goals of this center are to answer the following fundamental questions with our studies: 1. How do structures of the HIV polyprotein precursors direct assembly, maturation, and replication? 2. What novel HIV-Host interactions drive DNA replication and integration? 3. How does dynamics impact viral fitness and how can it be exploited for therapeutic targeting? 4. What are the structural and dynamic consequences of resistance mutations in the HIV life cycle, and how? In order to carry out these studies we will develop, improve and apply the following Technical Methods for: 1. Efficient expression, crystallization, and atomic level structure determination of HIV polyprotein and nucleic acid complexes. 2. Determination and characterization of novel binding sites and their impact on the dynamic and evolutionary properties of HIV protein complexes. 3. Computational methods to characterize the interactions, dynamics and evolution of HIV protein complexes at multiple spatial and temporal scales. Our approach is significant both for the promise of new structural insights into the interdependence of viral mechanisms, but also for the direct potential for new drug design methodologies and therapeutic strategies.

描述（由申请人提供）：我们成立了 HIVE 中心，以在原子水平上表征 HIV 生命周期中相互作用的大分子之间的结构和动态关系。我们将重点关注主要 HIV 酶与其伴侣和效应子的相互作用，因为它们涵盖了病毒生命周期中的关键过程，并且现有药物靶点提供了丰富的结构、生物学和进化数据基础，这些数据将有助于实现我们的目标。我们将探索艾滋病毒的耐药性进化，将其作为一个合适的平台，在原子水平上表征相互作用的大分子结构之间的动态关系。 HIVE 中心由一群在 HIV 晶体学、病毒学、分子生物学、合成化学和计算生物学方面拥有丰富专业知识的研究人员组成。我们将研究病毒大分子相互作用和动力学的机制意义及其对耐药性进化的更广泛影响。该中心的目标是通过我们的研究回答以下基本问题： 1. HIV 多蛋白前体的结构如何指导组装、成熟和复制？ 2. 哪些新的 HIV-宿主相互作用驱动 DNA 复制和整合？ 3. 动力学如何影响病毒适应性以及如何将其用于治疗靶向？ 4. HIV 生命周期中耐药突变的结构和动态后果是什么？如何产生？为了开展这些研究，我们将开发、改进和应用以下技术方法： 1. HIV多蛋白和核酸复合物的高效表达、结晶和原子水平结构测定。 2. 新结合位点的确定和表征及其对 HIV 蛋白复合物动态和进化特性的影响。 3. 表征 HIV 蛋白复合物在多个空间和时间尺度上的相互作用、动态和进化的计算方法。我们的方法不仅对于病毒机制相互依赖性的新结构见解的承诺，而且对于新药物设计方法和治疗策略的直接潜力也具有重要意义。