Engineering Primary T cells for Resistance to HIV-1

改造原代 T 细胞以抵抗 HIV-1

• 批准号: 7058743
• 负责人: ELENA E PEREZ
• 金额: $ 12.71万
• 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/7058743
• 关键词: AIDS therapy; CD antigens; Lentivirus; T cell receptor; T lymphocyte; binding sites; biotechnology; cellular immunity; gene delivery system; gene therapy; genetic manipulation; helper T lymphocyte; human subject; 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。具体目的包括：1）具有HIV-1融合抑制剂C34的膜结合形式的工程原始T细胞，评估抗病毒药物和细胞免疫功能，2）开发与宽带骨架载体中的多态转基因进行比较和结合多键型转基因的策略，并将其构成HIV的构成构成的融合构成的融合构成的融合构成的融合构成的构成构成型的融合。目标细胞。仅使用HIV-1输入抑制剂的膜结合形式编码的基因，并与对HIV-1共受体CCR5和HIV基因REV和TAT结合使用，将使用自动灭病毒载体系统进行编码的基因。转导的原代T细胞将受到包括原发性分离株在内的多种HIV-1病毒的挑战，并将评估细胞以获得免疫功能。对于原代T细胞的初步研究对于膜结束抑制剂来说是有希望的，我们假设与病毒共受体和/或调节性HIV基因的siRNA组合将具有添加剂抗病毒效应。该建议描述了一项为期5年的培训计划，以开发儿科过敏和免疫学（A/I）的学术生涯。首席调查员已经在费城儿童医院完成了儿科住院医师培训，并在A/I奖学金的第三年。该赠款将使研究人员能够扩大她的科学技能，同时从免疫学系，艾滋病研究中心（CFAR）和艾布拉姆森家庭癌症研究所（AFCRI）的宾夕法尼亚大学（UPENN）中获得的各种资源受益。博士。卡尔·六月（Carl June）和詹姆斯·霍西（James Hoxie）将指导佩雷斯（Perez）博士的科学职业发展。 June博士是AFCRI转化研究计划的主任，并领导了T细胞生物学和癌症和艾滋病毒感染的收养免疫疗法的开创性转化研究。 UPENN CFAR主任Hoxie博士在HIV病毒学，发病机理和病毒进入方面具有广泛的背景。