HIV-1 Resistance to Chemokine Receptor Antagonists

HIV-1 对趋化因子受体拮抗剂的耐药性

• 批准号: 8507126
• 负责人: Daniel R. Kuritzkes
• 金额: $ 41.78万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8507126
• 关键词: AIDS clinical trial group; Affinity; Binding; Biological Assay; CCR5 gene; CD4 Positive T Lymphocytes; CXCR4 gene; Cells; Clinical; Collaborations; Data; Databases; Dependence; Development; Drug usage; Enrollment; Funding; Genetic; Genetic Polymorphism; Genomics; Glycoproteins; HIV Envelope Protein gp120; HIV-1; Haplotypes; Housing; Incubated; Instruction; Kinetics; Label; Laboratories; Learning; Length; Light; Modeling; Molecular Biology; Mutation; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Plasma; Preventive; Property; Proteins; Protocols documentation; Regimen; Resistance; Resolution; Role; Sampling; Surface; System; Tropism; V3 Loop; Variant; Viral; Virus; Work; chemokine; chemokine receptor; cohort; fitness; genome wide association study; genome-wide; inhibitor/antagonist; interest; macrophage; novel; prevent; receptor; small molecule; stem; transmission process

Chemokine receptor antagonists constitute a novel class of HIV-1 inhibitors that bind to cellular proteins on the surface of CD4+ T-cells and macrophages that serve as co-receptors for HIV-1. Escape of HIV-1 from inhibition by CCR5 antagonists occurs by two mechanisms¿emergence of CXCR4-using viruses or emergence of viruses that remain R5 but have adapted to use CCR5 for entry despite the presence of inhibitory concentrations of CCR5 antagonists. Work completed during the current funding period has led to the characterization of vicriviroc (VCV)-resistant clinical isolates of HIV-1 subtype B and C. These viruses share a number of properties, including accumulation of mutations in the stems of the V3 loop, stimulation of replication by VCV (suggesting VCV dependence for engaging CCR5) and reduced entry kinetics compared to wild-type that are restored in the presence of VCV. Given the relatively small number of CCR5 antagonistresistant isolates studied to date, much remains to be learned about the mechanisms of escape from CCR5 antagonists. The shared features of viruses resistant to small-molecule CCR5 antagonists suggest that VCVresistant viruses can serve as an excellent model for CCR5 antagonist resistance. Specific aims for the extension period of this project are as follows: 1) To complete a detailed assessment of entry kinetics of vicriviroc-resistant HIV-1. The entry kinetics of VCV-resistant HIV-1 will be explored over a range of CCR5 and CD4 levels using Affinofile cells in the presence of various concentrations of VCV or TAK-779. 2)To determine affinity of CCR5 antagonist-resistant HIV-1 envelopes for CD4 and CCR5. The ability of monomeric gp120 or trimeric HIV-1 envelope glycoproteins resistant to the CCR5 antagonists to bind CCR5- expressing cells will be examined in collaboration with Dr. Navid Madani using established protocols. 3)To explore associations between HIV-1 co-receptor usage and host genetic factors. We will make use of an existing genome-wide SNP database and high-resolution HLA haplotyping on a subcohort of 716 treatmentnaive patients to explore the hypothesis that host genetic factors are associated with emergence of CXCR4- usino virLis.

趋化因子受体拮抗剂是一类新型的HIV-1抑制剂， 作为HIV-1共受体的CD 4 + T细胞和巨噬细胞的表面。HIV-1从 CCR 5拮抗剂的抑制作用通过两种机制发生：使用CXCR 4的病毒的出现或 出现了仍然是R5的病毒，但已经适应了使用CCR 5进入，尽管存在 CCR 5拮抗剂的抑制浓度。本供资期间完成的工作导致 HIV-1亚型B和C的vicriviroc（VCV）耐药临床分离株的表征。这些病毒 共有许多特性，包括V3环茎中突变的积累， 通过VCV复制（表明VCV依赖于参与CCR 5）和降低的进入动力学比较 在VCV存在下恢复的野生型。鉴于CCR 5拮抗剂耐药的数量相对较少 迄今为止研究的分离株中，关于从CCR 5逃逸的机制仍有许多有待了解的地方。 对手。对小分子CCR 5拮抗剂耐药的病毒的共同特征表明， 病毒可以作为CCR 5拮抗剂抗性的优良模型。具体目标 该项目的扩展期如下：1）完成进入动力学的详细评估， 抗vicrivirocHIV-1将在一系列CCR 5中探索抗VCV HIV-1的进入动力学。 在存在不同浓度VCV或TAK-779的情况下使用Affinofile细胞测定的CD 4水平。2）至 确定CCR 5拮抗剂抗性HIV-1包膜对CD 4和CCR 5的亲和力。的能力 单体gp 120或三聚体HIV-1包膜糖蛋白对CCR 5拮抗剂具有抗性，以结合CCR 5- 将与Navid Madani博士合作，使用已建立的方案检查表达细胞。3）至 探索HIV-1辅助受体使用与宿主遗传因素之间的关联。我们将利用一个 现有的全基因组SNP数据库和高分辨率HLA单体型分型对716例初治患者的亚队列研究 患者探索宿主遗传因素与CXCR 4 - 1的出现相关的假设。 乌西诺·弗里斯