HIV-1 Cryptic Epitopes: Implications for Vaccine Design

HIV-1 隐性表位：对疫苗设计的影响

• 批准号: 8131729
• 负责人: Paul A. Goepfert
• 金额: $ 50.19万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-11 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8131729
• 关键词: Abbreviations; Accounting; Acquired Immunodeficiency Syndrome; Adenoviruses; Anti-Retroviral Agents; Antibodies; Antigens; Area; Biological; CD8-Positive T-Lymphocytes; Characteristics; Chronic; Clinical Trials; Cytotoxic T-Lymphocytes; Data; Dependence; Disadvantaged; Disease; Disease Progression; Epitopes; Failure; Flow Cytometry; Frequencies; Future; Genetic Transcription; Genetic Translation; HIV Infections; HIV-1; HLA Antigens; Immune; Immune Targeting; Immune response; Infection; Interferon Type II; Interferons; Light; Link; Measures; Modified Vaccinia Virus Ankara; Mutate; Mutation; Open Reading Frames; Patients; Peptides; Peripheral Blood Mononuclear Cell; Plasma; Process; Production; Protein Biosynthesis; Proteins; Proteome; Reading Frames; Recombinants; Ribosomal Frameshifting; Sampling; Specificity; Structural Protein; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Translating; Translations; Vaccination; Vaccine Clinical Trial; Vaccine Design; Vaccines; Viral; Viral Load result; Virus; base; cohort; combat; design; fitness; genetic regulatory protein; healthy volunteer; improved; novel; pol Gene Products; pressure; research clinical testing; response; transmission process; vaccinology; vector-induced

DESCRIPTION (provided by applicant): The field of HIV-1 vaccinology has primarily focused on identifying the immunodominant responses to determine suitable immunogens that might be included in an HIV-1 vaccine. However, focusing on this approach in isolation has disadvantages. The main problem is that the enormous sequence variability of HIV-1 dictates that other epitopes be identified. This issue is especially poignant in light of the recent failure of the Merck vaccine trial or Step Study, as the limited breadth of CD8 T lymphocyte (CD8-TL) response induced by this vaccine likely contributed to its lack of efficacy. In an attempt to identify novel targets to increase the breadth of a CD8-TL based vaccine, the current proposal aims to study a unique class of epitopes. Cryptic epitopes (CE) are translated from alternate reading frames (ARF) and not the main reading frame used to synthesize the functional proteins. We show data that CE are commonly targeted in primary and chronic HIV-1 infection. This finding is justification for aim 1 of the current proposal which will characterize CE comprehensively using overlapping peptides spanning the ARF of the HIV-1 proteome. This will yield valuable information about cryptic epitopes that are frequently targeted and whether they correlate with viral control in the setting of chronic HIV infection (CHI). Aim 2 of the current proposal will determine the biological significance of these CE responses in the setting of primary HIV infection (PHI). This attribute will be measured by the propensity of the CE to escape immune pressure and to revert to wild type when the mutated virus is transmitted to a non-HLA-I matched recipient. If our hypothesis were proven to be correct, the vaccine field can begin to design vectors that induce CE responses, thereby significantly increasing the number of CD8-TL targets without necessarily increasing the size of the insert. Lastly, in aim 3 we hypothesize that relatively inefficient protein production may thereby allow for increased CE responses. Analysis of the PBMC samples from recipients of two different HIV-1 vaccines, being tested in clinical trials, allows us the unique opportunity to test this hypothesis as is detailed in the application. Taken together, this proposal will not only determine the biologic significance of CE responses but also determine if these responses are induced using the current recombinant HIV-1 vaccines. Such information will be extremely helpful for future HIV-1 vaccine design. This proposal aims to understand the full breadth and functional features of cytotoxic T lymphocytes that may be induced during both HIV-1 infection and HIV-1 vaccination. This information will be highly relevant and directly applicable to the design of an HIV-1 vaccine.

描述（由申请人提供）：HIV-1疫苗学领域主要集中于识别免疫剂反应，以确定可能包含在HIV-1疫苗中的合适免疫原子。但是，专注于这种孤立的方法是缺点。主要问题是HIV-1的巨大序列可变性决定了其他表位。鉴于默克疫苗试验或步骤研究的最近失败，由于这种疫苗引起的CD8 T淋巴细胞（CD8-TL）反应的有限广度可能导致其缺乏功效，因此这个问题尤其令人发指。为了确定新的目标以增加基于CD8-TL的疫苗的广度，目前的提案旨在研究独特的表位。神秘的表位（CE）是从替代读取框（ARF）转换的，而不是用于合成功能蛋白的主要阅读框。我们显示的数据表明，CE通常针对原发性和慢性HIV-1感染。这一发现是针对当前建议的目标1的理由，它将使用跨越HIV-1蛋白质组ARF的重叠肽对CE进行全面表征。这将产生有关经常靶向的神秘表位的有价值的信息，以及它们是否与慢性HIV感染（CHI）的病毒控制相关。当前建议的目标2将确定原发性HIV感染（PHI）中这些CE反应的生物学意义。该属性将通过CE的倾向来避免免疫压力，并在将突变的病毒传播到非HLA-I匹配的受体时恢复为野生型。如果我们的假设被证明是正确的，那么疫苗场就可以开始设计诱导CE反应的向量，从而显着增加CD8-TL靶标的数量，而不必增加插入片段的大小。最后，在AIM 3中，我们假设相对低效的蛋白质产生可能会增加CE反应。在临床试验中测试的两种不同HIV-1疫苗的受体的PBMC样品分析，使我们有一个独特的机会来检验该假设，如应用程序中所述。综上所述，该建议不仅将确定CE反应的生物学意义，而且还可以确定使用当前的重组HIV-1疫苗诱导这些反应。此类信息将对未来的HIV-1疫苗设计非常有帮助。该建议旨在了解在HIV-1感染和HIV-1疫苗接种过程中可能诱导的细胞毒性T淋巴细胞的全部广度和功能特征。该信息将高度相关，直接适用于HIV-1疫苗的设计。