Engineering Primary T cells for Resistance to HIV-1

改造原代 T 细胞以抵抗 HIV-1

• 批准号: 7761390
• 负责人: ELENA E PEREZ
• 金额: $ 8.65万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 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 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7761390
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adoptive Immunotherapy; Adoptive Transfer; Allergy and Immunology; Amino Acid Sequence; Antiviral Agents; Antiviral Therapy; Autologous; Binding; Binding Proteins; CCR5 gene; CD4 Positive T Lymphocytes; CXCR4 gene; Cell Line; Cells; Cellular biology; Characteristics; Chemokine (C-C Motif) Receptor 5; Childhood; Clinical; Clinical Trials; Code; DP178; Development; Disadvantaged; Down-Regulation; Drug Delivery Systems; Endopeptidases; Engineering; Enzymes; Epitopes; Evaluation; Family; Fellowship; Freezing; Future; Fuzeon; Generations; Genes; Goals; Grant; HIV; HIV Entry Inhibitors; HIV Fusion Inhibitors; HIV Infections; HIV vaccine; HIV-1; Helper-Inducer T-Lymphocyte; Highly Active Antiretroviral Therapy; Immune; Immunologics; Immunology; Immunotherapy; In Vitro; Infection; Infection prevention; Investigation; Lentivirus Vector; Life Cycle Stages; Membrane; Mentors; Mind; Molecular Conformation; Numbers; Patients; Pediatric Hospitals; Pennsylvania; Peptide Hydrolases; Phase; Phase I Clinical Trials; Phenotype; Philadelphia; Principal Investigator; Program Development; RNA Interference; RNA-Directed DNA Polymerase; Range; Research; Research Institute; Research Personnel; Residencies; Resistance; Resistance development; Resources; Small Interfering RNA; Surface; System; T-Lymphocyte; Testing; Toxic effect; Training; Training Programs; Transgenes; Translational Research; Translations; United States Food and Drug Administration; Universities; Vertebral column; Viral; Viral Load result; Viral Pathogenesis; Virulent; Virus; Work; anticancer research; antiretroviral therapy; base; cancer immunotherapy; career; cellular transduction; design; genetic regulatory protein; immune function; immunogenic; immunogenicity; inhibitor/antagonist; peptide T20; programs; receptor; receptor expression; reconstitution; research study; rev Genes; skills; sound; therapeutic gene; therapy resistant; transmission process; vector; virology

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HIV-1耐药原代T细胞的产生，作为HIV-1潜在的转化免疫疗法。具体目的包括：1)用HIV-1融合抑制剂C34的膜结合形式改造原代T细胞，评估抗病毒效果和细胞免疫功能；2)制定在慢病毒骨干载体中比较和组合多靶点转基因的策略；3)研究由于与靶细胞上表达的融合抑制剂结合而暴露的HIV表位的免疫原性。一种自我失活的慢病毒载体系统将被用于递送编码HIV-1进入抑制剂膜结合形式的基因，并与针对HIV-1共受体CCR5、HIV基因Rev和Tat的小干扰rna结合。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，并将评估细胞的免疫功能。在原代T细胞中对膜结合进入抑制剂的初步研究是有希望的，我们假设与siRNA结合对抗病毒共受体和/或调节HIV基因将具有附加的抗病毒作用。本提案描述了一个5年的培训计划，以发展儿科过敏和免疫学（a /I）的学术生涯。首席研究员在费城儿童医院完成了儿科住院医师培训，并且是她在A/I奖学金的第三年。这项资助将允许研究者拓宽她的科学技能，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）的各种可用资源。Drs。Carl June和James Hoxie将指导Perez博士的科学事业发展。June博士是AFCRI转化研究项目的主任，并领导了T细胞生物学和癌症和HIV感染的过继免疫疗法的开创性转化研究。Hoxie博士在HIV病毒学、发病机制和病毒进入方面有着广泛的背景。