HIV CORECEPTOR SHIFT

HIV受体转变

• 批准号: 8537609
• 负责人: Lee Ratner
• 金额: $ 21.43万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-15 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8537609
• 关键词: Antiviral Agents; Biological Assay; CCR5 gene; CD4 Antigens; CD4 Positive T Lymphocytes; CXCR4 gene; Cells; Code; Cytotoxic T-Lymphocytes; DNA; Data; Development; Disease; Exhibits; Frequencies; Goals; HIV; HIV Envelope Protein gp120; HIV Infections; HIV-1; Individual; Infection; Libraries; Mediating; Methodology; Molecular; Pathogenesis; Patients; Phylogenetic Analysis; Plasma; Process; Resistance; Resolution; Sequence Analysis; Structure; T cell response; Trees; Variant; Virus; Work; chemokine; env Gene Products; innovation; neutralizing antibody; pressure; public health relevance; receptor

DESCRIPTION (provided by applicant): Coreceptor shift occurs in approximately half of all HIV infected individuals, and is promoted by use of CCR5 antagonist therapy. The proposed work uses a unique panel of CCR5/CXCR4 chimeric coreceptors and a panel of coreceptor shift HIV-1 isolates to examine the critical domains of CXCR4 required for HIV entry. The methodology includes ultra dense sequence analysis of HIV-1 gp120 sequences of quasispecies from U87.CD4 cells infected with env amplicons from a panel of dual/mixed isolates selected during CCR5 antagonist therapy in patient-specific virus libraries. Aim 1. What proportion of HIV-1 gp120 sequences are responsible for VCVr resistance and how do HIV- 1 gp120 sequences of VCVs and VCVr isolates differ? For this purpose, U87.CD4.R5.X4 cells will be infected with patient-specific virus libraries in the presence or absence of VCV, and infected cell DNA subjected to ultra dense sequence analysis. Aim 2. What proportion of HIV-1 gp120 sequences utilize CXCR4 for entry and how to the gp120 sequences differ from those that can not utilize CXCR4? For this purpose, U87.CD4.R5 and U87.CD4.X4 cells will be infected with patient-specific virus libraries, and infected cell DNA subjected to ultra dense sequence analysis. Aim 3. What are the minimal domains of CXCR4 utilized for infection and how do HIV-1 gp120 sequences utilizing ECL3 or ECL2 differ from those that do not utilize these domains? For this purpose, U87.CD4 cells expressing chimeric CCR5/CXCR4 coreceptors will be infected with patient-specific virus libraries, and infected cell DNA subjected to ultra dense sequence analysis. Molecular details on the use of minimal domains of CXCR4 required for HIV entry will provide critical information to guide the development of more effective antiviral agents.

描述（由申请人提供）：在所有艾滋病毒感染的个体中，大约一半发生了共感受器的转移，并通过使用CCR5拮抗剂治疗来促进。拟议的工作使用CCR5/CXCR4嵌合聚糖的独特面板和一组Coleceptor Shift HIV-1分离株来检查HIV进入所需的CXCR4的关键域。该方法包括对来自U87.CD4细胞的HIV-1 GP120序列的超密集序列分析，这些细胞在患者特异性病毒库中从CCR5拮抗剂治疗期间选择了一组双/混合分离株的ENV扩增子。 AIM 1。HIV-1 GP120序列的哪些比例负责VCVR抗性？HIV-1 GP120 VCV和VCVR分离株的序列有何不同？为此，U87.CD4.R5.x4细胞将在存在或不存在VCV的情况下感染患者特异性病毒库，并感染经过超密集序列分析的细胞DNA。 AIM 2。HIV-1 GP120序列的哪些比例利用CXCR4进行进入，以及如何与无法使用CXCR4的GP120序列不同？为此，U87.CD4.R5和U87.cd4.x4细胞将感染患者特异性病毒文库，并感染经过超密集序列分析的细胞DNA。 AIM 3。用于感染的CXCR4的最小域是什么？利用ECL3或ECL2的HIV-1 GP120序列与不利用这些域的序列有何不同？为此，表达嵌合CCR5/CXCR4共肽的U87.CD4细胞将感染患者特异性病毒库，并感染经过超密集序列分析的细胞DNA。 关于使用HIV进入的最小CXCR4域使用的分子细节将提供关键信息，以指导更有效的抗病毒药物的发展。