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）：大约一半的 HIV 感染者会发生辅助受体转变，并且通过使用 CCR5 拮抗剂疗法会促进这种转变。拟议的工作使用一组独特的 CCR5/CXCR4 嵌合辅助受体和一组辅助受体转移 HIV-1 分离株来检查 HIV 进入所需的 CXCR4 关键域。该方法包括对 U87.CD4 细胞的准种 HIV-1 gp120 序列进行超密集序列分析，这些细胞被 env 扩增子感染，这些扩增子来自患者特异性病毒库中 CCR5 拮抗剂治疗期间选择的一组双重/混合分离株。目标 1. HIV-1 gp120 序列中占 VCVr 耐药性的比例是多少？VCV 和 VCVr 分离株的 HIV-1 gp120 序列有何不同？为此，在存在或不存在 VCV 的情况下，U87.CD4.R5.X4 细胞将被患者特异性病毒库感染，并对感染的细胞 DNA 进行超密集序列分析。目标 2. HIV-1 gp120 序列中利用 CXCR4 进入的比例是多少？gp120 序列与不能利用 CXCR4 的序列有何不同？为此，U87.CD4.R5和U87.CD4.X4细胞将被患者特异性病毒库感染，并对感染的细胞DNA进行超密集序列分析。目标 3. 用于感染的 CXCR4 的最小结构域是什么？利用 ECL3 或 ECL2 的 HIV-1 gp120 序列与不利用这些结构域的 HIV-1 gp120 序列有何不同？为此，表达嵌合CCR5/CXCR4辅助受体的U87.CD4细胞将被患者特异性病毒库感染，并对感染的细胞DNA进行超密集序列分析。 HIV 进入所需的 CXCR4 最小结构域的使用的分子细节将为指导更有效的抗病毒药物的开发提供关键信息。