Mimic Peptides of HIV-1 Epitopes as Vaccines

描述（由申请人提供）：尽管目前已有基于强效药物组合的积极治疗方案，但 HIV-1 感染的发病率仍在持续上升，目前在许多发展中国家呈流行​​病。 这些方案在降低病毒载量方面非常成功，甚至降低到不可检测的水平，但它们并不能消除病毒感染的静态储存库。因此，治疗必须是终生的、昂贵的并且伴随着显着的毒副作用。这种情况需要考虑替代策略，生物医学研究界仍然达成共识，即免疫治疗疫苗最终将提供最有效、负担得起的长期方法来阻止艾滋病毒/艾滋病的传播。 迄今为止的集体经验是，艾滋病毒具有免疫原性；它会在大多数感染者中激发免疫反应，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、病毒体蛋白或其肽片段进行免疫；到目前为止，还没有一个被证明是成功的。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，以创建优化的、高免疫原性的肽类似物，激发强大的 T 细胞介导的免疫，消除体内病毒感染的细胞。 MSI 开发了这项技术，并提供了概念验证，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库，以鉴定能够更有效地刺激针对天然肽序列的免疫反应的高免疫原性肽组。具体目标是 1) 鉴定针对保守 HIV 蛋白的几个 HLA-A2 限制性表位的优化模拟肽； 2）评估其在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，该肽序列信息将被纳入基于病毒载体中的多种肽、融合蛋白或DNA序列的治疗性/预防性多表位疫苗制剂中。

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.