CHARACTERIZATION OF CYTOTOXIC RESPONSES TO HIV ANTIGENS

HIV 抗原细胞毒性反应的特征

• 批准号: 3791181
• 负责人: ROBERT T SCHOOLEY
• 金额: --
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3791181
• 关键词: AIDS; AIDS vaccines; B lymphocyte; Bacillus Calmette Guerin vaccine; Epstein Barr virus; Escherichia coli; T lymphocyte; affinity chromatography; antibody neutralization test; antiviral antibody; beta galactosidase; cell line; cell mediated cytotoxicity; cell transformation; delayed hypersensitivity; genetic manipulation; human immunodeficiency virus; human tissue; leukocyte activation /transformation; mitogens; molecular cloning; monocyte; neutralizing antibody; recombinant DNA; viral vaccines; virus antigen; virus protein

The acquired immunodeficiency syndrome (AIDS) induced by the human immunodeficiency virus (HIV), a pathogenic human retrovirus has reached epidemic proportions worldwide, and the need for immunoprophylaxis to stem the spread of this disease is paramount. Rational design of a vaccine requires a thorough understanding of the immunobiology of HIV infection. While it is not yet known exactly what constitutes protective immunity, or what parameters determine clinical progression of disease, a variety of HIV-specific immune responses have been identified. These include neutralizing antibodies, antibody-dependent cellular cytotoxicity (ADCC), cellular proliferative responses, and cytotoxic T cell (CTL) responses. We propose to systemically investigate the immunogenic epitopes involved in generation of these HIV-specific immune responses, in order that the most important immunogenic epitiopes can be incorporated into a subunit vaccine. Recombinant DNA expression technology will be used by collaborators at the Whitehead Institute to create a library of overlapping clones of HIV proteins in E. coli. E coli lysates or immunoaffinity-column purified fusion protein will then be used as a source of cloned antigen for presentation to HIV- specific CTL. Three different autologous target cell approaches will be used for presentation of antigen. These include a) EBV immortalized B cells b) PHA blasts or c) monocyte/macrophages. The effector CTL to be used will be obtained from HIV seropositive subjects and consist of a) bulk HIV-specific CTL b) peripheral blood mononuclear cells prestimulated with HIV antigens in vitro c) HIV-specific cloned T cells. Immunogenic epitopes will then be used to elute reactive antibodies from serum of HIV seropositive subjects, and these antibodies tested for their ability to mediate ADCC and neutralization. The information provided by these studies will then be used in design of a BCG-HIV recombinant vaccine. Candidate vaccines found promising in animal studies will then be tested in clinical trails in humans.

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