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）：辅助受体转换发生在大约一半的HIV感染个体中，并且通过使用CCR 5拮抗剂治疗而促进。拟议的工作使用了一个独特的面板CCR 5/CXCR 4嵌合辅助受体和辅助受体转移HIV-1分离物的面板检查HIV进入所需的CXCR 4的关键结构域。该方法包括对来自U87.CD4细胞的准种的HIV-1 gp 120序列进行超密集序列分析，所述U87.CD4细胞感染来自患者特异性病毒文库中CCR 5拮抗剂治疗期间选择的一组双重/混合分离株的env扩增子。目标1. HIV-1 gp 120序列中有多大比例导致VCVr耐药？VCV和VCVr分离株的HIV- 1 gp 120序列有何不同？为此，在存在或不存在VCV的情况下，用患者特异性病毒文库感染U87.CD4.R5.X4细胞，并对感染的细胞DNA进行超密集序列分析。目标2. HIV-1 gp 120序列中利用CXCR 4进入的比例是多少？gp 120序列与不能利用CXCR 4的序列有何不同？为此，将用患者特异性病毒文库感染U87.CD4.R5和U87.CD4.X4细胞，并对感染的细胞DNA进行超密集序列分析。目标3. CXCR 4用于感染的最小结构域是什么？利用ECL 3或ECL 2的HIV-1 gp 120序列与不利用这些结构域的HIV-1 gp 120序列有何不同？为此，将表达嵌合CCR 5/CXCR 4共受体的U87.CD4细胞用患者特异性病毒文库感染，并将感染的细胞DNA进行超密集序列分析。 关于HIV进入所需的CXCR 4最小结构域的分子细节将为指导开发更有效的抗病毒剂提供关键信息。