HIV Interactions In Viral Evolution

病毒进化中的艾滋病毒相互作用

• 批准号: 9769769
• 负责人: Stefan G Sarafianos
• 金额: $ 531.78万
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769769
• 关键词: AIDS/HIV problem; Address; Antiviral resistance; Automobile Driving; Biochemical; Biological; Biological Process; Biophysics; Capsid; Chemicals; Chemistry; Complex; Computational Biology; Drug resistance; Event; Evolution; Genetic Structures; Goals; HIV; HIV drug resistance; Integrase; Lead; Life Cycle Stages; Mutation; Polyproteins; Proteins; RNA-Directed DNA Polymerase; Research; Research Personnel; Reverse Transcription; Role; Shapes; Structural Models; Structural Protein; Structure; Synthesis Chemistry; System; Viral; Viral Physiology; Virus; Virus Integration; base; design; experience; fitness; insight; macromolecule; new therapeutic target; novel; pleiotropism; pol Gene Products; predictive modeling; programs; protein structure; resistance mutation; small molecule; targeted treatment; virology

The HIV Interaction in Viral Evolution (HIVE) Center came together a little more than four years ago to understand, at the atomic, biophysical and evolutionary level, the system interdependency of interacting HIV macromolecules and their assemblies which shape the HIV life cycle. To accomplish this goal the proposed program will continue to explore the structural and biophysical interactions of HIV Gag and Gag-Pol polyproteins, capsid, reverse transcriptase, and integrase and their evolutionary relationships. The Center's research focus will also extend to cellular factors that inform the structural and macromolecular dynamics of events in reverse transcription, assembly, and integration. This will include studies on how APOBEC3 proteins suppress reverse transcription, and the role of LEDGF in guiding viral integration and its contribution to latency in conjunction with CPSF6. Studies on HIV drug resistance will tie together a genetic and structural perspective, based on mutational correlations that are due to constraints on protein structural stability and function and which ultimately shape fitness. The depth of the computational strength of the program is centered on expanding structural, biophysical, and viral sequencing findings for developing predictive structural models and small molecule probes targeting viral function. The strength of the Center's biological and computational research will provide insights into the interrelationships of viral and host mechanisms, enabling discovery of new drug targets and therapeutic strategies that may ultimately lead to a cure. The HIVE Center comprises a group of highly collaborative investigators with deep experience in HIV research and well established expertise in structural, biophysical, biochemical, and computational biology, as well as synthetic chemistry, and virology. They will study the mechanistic implications of viral and viral-host macromolecular interactions along with the dynamics and the impacts of the evolution of drug resistance to address relevant biological questions with the following Specific Aims: AIM1: Defining HIV polyproteins and their components in retroviral assembly and maturation AIM 2: Determining HIV-host interactions driving virus reverse transcription and integration AIM 3: Understanding evolution of antiviral resistance mutations and their biological and biophysical implications through studies AIM 4: Developing and characterizing novel small molecule probes to understand biological function

HIV病毒进化中的相互作用（HIVE）中心在四年多前聚集在一起， 在原子、生物物理和进化水平上，理解相互作用的艾滋病毒的系统相互依赖性 大分子和它们的组合体塑造了艾滋病毒的生命周期。为了实现这一目标， 该计划将继续探索HIV Gag和Gag-Pol多聚蛋白的结构和生物物理相互作用， 衣壳，逆转录酶和整合酶及其进化关系。中心的研究重点 也将延伸到细胞因子，这些细胞因子反向告知事件的结构和大分子动力学 转录、组装和整合。这将包括关于APOBEC 3蛋白如何抑制逆转录病毒的研究。 转录，以及LEDGF在引导病毒整合中的作用及其对潜伏期的贡献， CPSF 6。对艾滋病毒耐药性的研究将结合遗传和结构的观点，基于突变， 由于蛋白质结构稳定性和功能的限制， 健身该计划的计算强度的深度集中在扩展结构，生物物理， 和病毒测序结果，用于开发预测结构模型和小分子探针靶向 病毒功能该中心的生物和计算研究的实力将提供深入了解 病毒和宿主机制的相互关系，使发现新的药物靶点和治疗 这些策略最终可能会导致治愈。蜂巢中心由一群高度合作的 研究人员在艾滋病毒研究方面有着丰富的经验，在结构、生物物理、 生物化学、计算生物学、合成化学和病毒学。他们将研究 病毒和病毒-宿主大分子相互作用的机制影响，沿着动力学和 耐药性演变的影响，以解决相关的生物学问题，具体如下 目的： AIM 1：定义HIV多聚蛋白及其在逆转录病毒装配和成熟中的组分 目的2：确定驱动病毒逆转录和整合的HIV-宿主相互作用 目的3：了解抗病毒耐药突变的演变及其生物学和生物物理学 研究的影响 目的4：开发和表征新型小分子探针以了解生物学功能