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在鉴定免疫显性应答，以确定可能包含在HIV-1疫苗中的合适免疫原。然而，孤立地关注这种方法有其缺点。主要的问题是HIV-1的巨大序列变异性决定了其他表位的鉴定。鉴于最近默克疫苗试验或步骤研究的失败，这个问题尤其尖锐，因为该疫苗诱导的CD 8 T淋巴细胞（CD 8-TL）应答的有限宽度可能导致其缺乏疗效。在尝试鉴定新靶点以增加基于CD 8-TL的疫苗的广度时，当前的提议旨在研究一类独特的表位。隐藏表位（CE）是从替代阅读框（ARF）翻译的，而不是用于合成功能蛋白的主要阅读框。我们的数据表明，CE通常是针对原发性和慢性HIV-1感染。这一发现是当前提案目标1的合理性，该提案将使用跨越HIV-1蛋白质组ARF的重叠肽全面表征CE。这将产生关于经常被靶向的隐藏表位的有价值的信息，以及它们是否与慢性HIV感染（CHI）背景下的病毒控制相关。当前提案的目标2将确定这些CE应答在原发性HIV感染（PHI）背景下的生物学意义。该属性将通过CE逃避免疫压力并在突变病毒传播给非HLA-I匹配的受体时恢复为野生型的倾向来测量。如果我们的假设被证明是正确的，疫苗领域可以开始设计诱导CE应答的载体，从而显著增加CD 8-TL靶标的数量，而不必增加插入物的大小。最后，在目标3中，我们假设相对低效的蛋白质生产可能因此允许增加CE响应。对两种不同HIV-1疫苗接种者的PBMC样本进行分析，在临床试验中进行测试，使我们有独特的机会来测试这一假设，如申请中所详述。综上所述，该提议不仅将确定CE应答的生物学意义，而且还将确定这些应答是否是使用当前的重组HIV-1疫苗诱导的。这些信息将对未来的HIV-1疫苗设计非常有帮助。该提案旨在了解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。这些信息将与HIV-1疫苗的设计高度相关并直接适用。