Engineering Primary T cells for Resistance to HIV-1

改造原代 T 细胞以抵抗 HIV-1

• 批准号: 6843528
• 负责人: ELENA E PEREZ
• 金额: $ 11.63万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6843528
• 关键词: AIDS therapy; CD antigens; Lentivirus; RNA interference; T cell receptor; T lymphocyte; binding sites; biotechnology; cellular immunity; gene delivery system; gene therapy; genetic manipulation; helper T lymphocyte; human subject; human tissue; immune response; laboratory mouse; lymphocyte proliferation; membrane proteins; phenotype; protein engineering; small interfering RNA; therapy design /development; transfection /expression vector; vaccine development; virulence

DESCRIPTION (provided by applicant): This research application focuses on the generation of HIV-1 resistant primary T cells as potential translational immunotherapies for HIV-1. The specific aims include: 1) engineering primary T cells with a membrane bound form of the HIV-1 fusion inhibitor C34, evaluation of antiviral effects and cellular immune function, 2) development of strategies to compare and combine multi-target transgenes in a lentiviral backbone vector and 3) investigation of the immunogenicity of HIV epitopes exposed as a result of binding to the fusion inhibitor expressed on the target cell. A self-inactivating lentiviral vector system will be used to deliver genes coding for membrane bound forms of an HIV-1 entry inhibitor alone, and in combination with small interfering RNAs against HIV-1 co-receptor CCR5, and HIV genes Rev and Tat. Transduced primary T cells will be challenged with a variety of HIV-1 viruses including primary isolates, and cells will be evaluated for immunologic function. Preliminary studies in primary T cells are promising for the membrane bound entry inhibitor, and we hypothesize that combinations with siRNA against viral co-receptor and/or regulatory HIV genes will have an additive anti-viral effect. This proposal describes a 5-year training program for the development of an academic career in Pediatric Allergy and Immunology (A/I). The principal investigator has completed Pediatric residency training at the Children's Hospital of Philadelphia, and is in her third year of A/I Fellowship. This grant will allow the investigator to broaden her scientific skills while benefiting from the diverse resources available at the University of Pennsylvania (UPENN) within the Department of Immunology, the Center for AIDS Research (CFAR), and the Abramson Family Cancer Research Institute (AFCRI). Drs. Carl June and James Hoxie will mentor Dr. Perez's scientific career development. Dr. June is the Director of the Translational Research Program of the AFCRI, and has led pioneering translational research in T cell biology and adoptive immunotherapy of cancer and HIV infection. Dr. Hoxie, Director of the UPENN CFAR, has an extensive background in HIV virology, pathogenesis and viral entry.

描述（由申请人提供）：本研究申请的重点是产生 HIV-1 抗性原代 T 细胞，作为 HIV-1 的潜在转化免疫疗法。具体目标包括：1) 用膜结合形式的 HIV-1 融合抑制剂 C34 改造原代 T 细胞，评估抗病毒作用和细胞免疫功能，2) 制定比较和组合慢病毒主干载体中多靶点转基因的策略，以及 3) 研究由于与表达的融合抑制剂结合而暴露的 HIV 表位的免疫原性。 目标细胞。自失活慢病毒载体系统将用于单独递送编码HIV-1进入抑制剂膜结合形式的基因，并与针对HIV-1共同受体CCR5的小干扰RNA以及HIV基因Rev和Tat组合。转导的原代 T 细胞将受到多种 HIV-1 病毒（包括原代分离株）的攻击，并且将评估细胞的免疫功能。原代 T 细胞的初步研究对膜结合进入抑制剂很有希望，我们假设与针对病毒共受体和/或调节性 HIV 基因的 siRNA 组合将具有附加的抗病毒作用。该提案描述了一项为期 5 年的儿童过敏和免疫学 (A/I) 学术职业发展培训计划。首席研究员已在费城儿童医院完成儿科住院医师培训，目前已是 A/I 奖学金的第三年。这笔赠款将使研究人员能够扩大她的科学技能，同时受益于宾夕法尼亚大学 (UPENN) 免疫学系、艾滋病研究中心 (CFAR) 和艾布拉姆森家庭癌症研究所 (AFCRI) 的各种资源。博士。卡尔·琼 (Carl June) 和詹姆斯·霍克西 (James Hoxie) 将指导佩雷斯博士的科学职业发展。 June 博士是 AFCRI 转化研究项目的主任，领导了 T 细胞生物学以及癌症和 HIV 感染的过继免疫治疗领域的开创性转化研究。 Hoxie 博士是 UPENN CFAR 主任，在 HIV 病毒学、发病机制和病毒进入方面拥有广泛的背景。