Mimic Peptides of HIV-1 Epitopes as Vaccines

HIV-1 表位模拟肽作为疫苗

• 批准号: 6799813
• 负责人: DARCY B WILSON
• 金额: $ 74.65万
• 依托单位: MIXTURE SCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6799813
• 关键词: AIDS vaccines; MHC class I antigen; biomimetics; biotechnology; cellular immunity; clinical research; cytotoxic T lymphocyte; gag protein; genetically modified animals; human immunodeficiency virus 1; human subject; laboratory mouse; microorganism immunology; patient oriented research; synthetic peptide; synthetic vaccines; vaccine development; vaccine evaluation; virion; virus antigen; virus protein

DESCRIPTION (provided by applicant): Despite aggressive treatment protocols based on powerful drug combinations currently available, the incidence of HIV-1 infection continues to rise and it is now pandemic in many of the developing nations. These protocols are highly successful at reducing viral loads, even to undetectable levels, but they do not eliminate quiescent reservoirs of viral infection. Thus, treatments must be lifelong, are costly, and are accompanied by significant toxic side effects. This situation requires consideration of alternative strategies and it remains a consensus in the biomedical research community that an immunotherapeutic vaccine will eventually provide the most effective, affordable long-term approach to halting the spread of HIV/AIDS. The collective experience to date is that HIV is immunogenic; it provokes an immune response in most infected individuals, but this immune response must be considered to be ineffective. Current vaccine trials consist of immunization with attenuated native virus, virion proteins or their peptide fragments; so far none have proven to be successful. Stronger immunogens are required. One approach not yet tried involves alterations of the peptide sequence of native viral T cell epitopes to create optimized, highly immunogenic peptide analogues that provoke strong T cell mediated immunity that eliminates viral infected cells in the body. MSI has developed the technology and provided proof-of-concept for screening combinatorial peptide libraries with T cell lines and clones having a clinically relevant specificity to identify panels of highly immunogenic peptides that are more effective in stimulating immune responses against the native peptide sequence. The specific Aims are 1) to identify optimized mimic peptides for several HLA-A2 restricted epitopes of conserved HIV proteins; 2) assess their immunogenicity in HLA-A2 transgenic mice; and 3) explore strategies for further enhancement of immunogenicity. Ultimately, this peptide sequence information will be incorporated into a therapeutic/ prophylactic multi-epitope vaccine formulation based on multiple peptides, fusion proteins or DNA sequences in viral vectors.

描述（由申请人提供）：尽管目前有基于强效药物组合的积极治疗方案，但HIV-1感染的发病率继续上升，目前在许多发展中国家流行。 这些方案在降低病毒载量方面非常成功，甚至降低到无法检测的水平，但它们不能消除病毒感染的静止储库。因此，治疗必须是终身的，是昂贵的，并伴随着显着的毒副作用。这种情况需要考虑替代战略，生物医学研究界仍然一致认为，免疫疫苗最终将为制止艾滋病毒/艾滋病的蔓延提供最有效、负担得起的长期办法。 迄今为止的集体经验是，艾滋病毒是免疫原性的;它在大多数感染者中引起免疫反应，但这种免疫反应必须被认为是无效的。目前的疫苗试验包括用减毒的天然病毒、病毒粒子蛋白或其肽片段免疫;迄今为止没有一种被证明是成功的。需要更强的免疫原。一种尚未尝试的方法涉及改变天然病毒T细胞表位的肽序列以产生优化的、高度免疫原性的肽类似物，其激发强T细胞介导的免疫力，从而消除体内的病毒感染细胞。 MSI开发了该技术，并提供了用于筛选具有临床相关特异性的T细胞系和克隆的组合肽文库的概念验证，以鉴定在刺激针对天然肽序列的免疫应答中更有效的高免疫原性肽组。本研究的主要目的是：1）鉴定HIV保守蛋白HLA-A2限制性表位的模拟肽; 2）评价其在HLA-A2转基因小鼠中的免疫原性; 3）探索进一步增强免疫原性的策略。最终，该肽序列信息将被并入基于病毒载体中的多个肽、融合蛋白或DNA序列的治疗性/预防性多表位疫苗制剂中。