A Rational Approach for HIV Vaccine T Cell Epitope Selection

HIV 疫苗 T 细胞表位选择的合理方法

• 批准号: 8892071
• 负责人: Paul A. Goepfert
• 金额: $ 46.26万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8892071
• 关键词: Acute; Address; Affinity; Alleles; Antigens; Automobile Driving; Back; Benchmarking; Binding; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Clinical Markers; Cytotoxic T-Lymphocytes; Data; Detection; Disease Progression; Effectiveness; Epidemic; Epitopes; Evaluable Disease; Evaluation; Future; Generations; Genetic Variation; HIV; HIV Infections; HIV Vaccine Trials Network; HIV vaccine; HIV-1; Health; Immune; Immune response; Immunologics; Individual; Infection; Infection Control; Lead; Lifting; Methods; Mutate; Mutation; Pathway interactions; Patients; Peptides; Persons; Population; Relative (related person); Sampling; Shapes; Structure; T cell response; T-Cell Receptor; T-Lymphocyte Epitopes; TCR Activation; Testing; Time; Vaccination; Vaccine Antigen; Vaccine Clinical Trial; Vaccine Design; Vaccines; Viral; Viral Load result; Virus; base; cost; design; efficacy trial; fitness; immunogenic; immunogenicity; improved; in vivo; insight; killings; pathogen; pressure; response; sound; stem; vaccine development; vaccine trial

DESCRIPTION (provided by applicant): The high mutation rates inherent to HIV have created sufficient sequence diversity to pose a formidable challenge in designing a universal HIV vaccine. Over the years since the start of the HIV epidemic, the virus has successfully utilized many viral and host pathways to avoid immune recognition. One of the best-characterized and most frequent viral adaptations is escape from cytotoxic T lymphocyte (CTL). This evasion method generates adapted epitopes (AE) many of which are not expected to be immunogenic since these are by-products of the CTL escape. These HLA-I restricted adaptations or sequence mutations in CTL epitopes appear to accumulate in a viral population and amplify over time if there is no pressure to revert; however, many revert rapidly due to viral fitness constraints when transmitted to new hosts who cannot target the specific epitope. The make up of a virus in a population is therefore in constant flux depending on the HLA-I alleles in that population driving escape and viral fitness constraints that force reversions back to its non- adapted state. Our preliminary data shows that a large proportion of CTL epitopes in a transmitted founder virus (TFV or virus that established infection in a new host) are already mutated with respect to that person's HLA-I (i.e. AE) making it unlikely that an effective and broad CD8 T-cell response will be elicited. In addition, we also have nascent data demonstrating a direct correlation between number of adapted epitopes (AE) transmitted during acute infection and set point viral load. Taken together, these observations highlight a truly concerning scenario pertinent directly to HIV vaccine design since all current HIV vaccines encode a large number of AE. To address this problem, we will first identify HIV specific CTL epitopes that would strongly merit inclusion n future candidate HIV immunogens. We hypothesize that a majority of these will be the non-adapted epitopes (NAE) which a) will effectively kill HIV infected cells; b) undergo CTL escape (to become AE); c) the escape inflicting a significant fitness cost to the virus; and d) the NAE reverts to AE when the immune pressure is lifted. These features and additional functional attributes proposed for evaluation in aim 1 will help delineate a signature for "optimal CTL epitopes". Aim 2 will determine whether vaccines, used in prior efficacy studies, were enriched in AE thereby negating any effect on clinical markers of disease progression in vaccinees who became infected. We will also evaluate the immunogenicity of NAE and their AE counterparts in a candidate mosaic vaccine clinical trial. Finally, in aim 3 we gain mechanistic insights into how optimal CTL responses are generated by determining whether the structure of HLA-I bound peptides predicts the quality of the immune response. In summary, this proposal will define important non-adapted and adapted HIV epitopes in context of acute infection and vaccination. The information obtained will be immensely useful both for the design and generation of an evaluable benchmark for gauging the efficacy of future candidate HIV-1 vaccines.

描述（由申请人提供）：HIV 固有的高突变率已经产生了足够的序列多样性，对设计通用 HIV 疫苗构成了巨大的挑战。自艾滋病毒流行以来的多年来，该病毒已成功利用许多病毒和宿主途径来避免免疫识别。最具特征和最常见的病毒适应之一是逃离细胞毒性 T 淋巴细胞 (CTL)。这种逃避方法会产生适应表位 (AE)，其中许多表位预计不具有免疫原性，因为它们是 CTL 逃逸的副产品。这些 HLA-I 限制性适应或 CTL 表位的序列突变似乎会在病毒群体中积累，并且如果没有恢复压力的话，会随着时间的推移而放大；然而，当传播到无法针对特定表位的新宿主时，由于病毒适应性限制，许多病毒会迅速恢复。因此，群体中病毒的组成不断变化，这取决于该群体中驱动逃逸的 HLA-I 等位基因和迫使回复到其非适应状态的病毒适应度限制。我们的初步数据表明，传播的创始人病毒（TFV 或在新宿主中建立感染的病毒）中的很大一部分 CTL 表位已经相对于该人的 HLA-I（即 AE）发生突变，因此不太可能有效且有效的治疗方法。将引发广泛的 CD8 T 细胞反应。此外，我们还有新的数据证明急性感染期间传播的适应表位（AE）数量与设定点病毒载量之间存在直接相关性。总而言之，这些观察结果突显了与 HIV 疫苗设计直接相关的真正令人担忧的情况，因为所有当前的 HIV 疫苗都编码大量 AE。为了解决这个问题，我们将首先确定 HIV 特异性 CTL 表位，这些表位非常值得纳入未来的候选 HIV 免疫原中。我们假设其中大部分将是非适应表位 (NAE)，其 a) 将有效杀死 HIV 感染细胞； b) 经历CTL逃逸（成为AE）； c) 逃逸对病毒造成巨大的适应性成本； d) 当免疫压力解除时，NAE 恢复为 AE。目标 1 中提出用于评估的这些特征和附加功能属性将有助于描绘“最佳 CTL 表位”的签名。目标 2 将确定先前功效研究中使用的疫苗是否富含 AE，从而消除对受感染疫苗接种者疾病进展临床标志物的任何影响。我们还将在候选嵌合疫苗临床试验中评估 NAE 及其 AE 对应物的免疫原性。最后，在目标 3 中，我们通过确定 HLA-I 结合肽的结构是否预测免疫反应的质量，获得了如何产生最佳 CTL 反应的机制见解。总之，该提案将定义急性感染和疫苗接种背景下重要的非适应和适应的 HIV 表位。获得的信息对于设计和生成可评估的基准来衡量未来候选 HIV-1 疫苗的功效将非常有用。