Mimic Peptides of HIV-1 Epitopes as Vaccines

描述(由申请人提供)：尽管基于现有的强大药物组合的积极治疗方案，艾滋病毒-1感染的发病率继续上升，它现在在许多发展中国家流行。这些方案在减少病毒载量方面非常成功，甚至降低到无法检测到的水平，但它们不能消除病毒感染的静止蓄水池。因此，治疗必须是终生的，费用高昂，并伴随着显著的毒副作用。这种情况需要考虑替代战略，生物医学研究界的共识仍然是，免疫治疗性疫苗最终将提供最有效、最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；它在大多数感染者中引发免疫反应，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、病毒粒子蛋白或它们的多肽片段进行免疫；到目前为止，还没有一项被证明是成功的。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细胞表位的多肽序列，以创建优化的、高免疫原性的多肽类似物，从而激发强大的T细胞介导的免疫，从而消除体内受病毒感染的细胞。 MSI已经开发了这项技术，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文库，以确定在刺激针对天然肽序列的免疫反应方面更有效的高免疫原性多肽组。其具体目的是：1)针对HIV保守蛋白的几个HLA-A2限制性表位寻找优化的模拟多肽；2)评价它们在人类白细胞抗原A2转基因小鼠中的免疫原性；3)探索进一步提高免疫原性的策略。最终，这些肽序列信息将被整合到基于病毒载体中的多肽、融合蛋白或DNA序列的治疗性/预防性多表位疫苗配方中。

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.