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: 9302653
• 负责人: Paul A. Goepfert
• 金额: $ 46.38万
• 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 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9302653
• 关键词: Acute; Address; Affinity; Alleles; Antigens; Automobile Driving; Back; Benchmarking; Binding; CD4 Positive T Lymphocytes; CD8-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; HIV-1 vaccine; Immune; Immune response; Immunologics; Impairment; Individual; Infection; Intuition; Lead; Lifting; Methods; Mosaicism; Mutate; Mutation; Pathway interactions; Patients; Peptides; Persons; Population; 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 study; efficacy trial; fitness; immunogenic; immunogenicity; improved; in vivo; insight; killings; pathogen; pressure; progression marker; prospective; public health relevance; response; sound; stem; vaccine development; vaccine trial; viral fitness

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）：艾滋病毒固有的高突变率创造了足够的序列多样性，在设计通用HIV疫苗时构成了巨大的挑战。自HIV流行病开始以来，该病毒已成功地利用了许多病毒和宿主途径来避免免疫识别。特征最常见和最常见的病毒适应之一是逃避细胞毒性T淋巴细胞（CTL）。这种逃避方法会产生适应的表位（AE），其中许多不预期是免疫原性的，因为这些是CTL逃生的副产物。这些HLA-I限制了CTL表位中的适应或序列突变似乎在病毒种群中积聚，并且如果没有恢复压力的压力，随着时间的推移会随着时间的流逝而放大。但是，由于传播给无法针对特定表位的新宿主时，许多人由于病毒适应性的限制而迅速恢复。因此，人群中病毒的组成持续不断变化，具体取决于HLA-I等位基因，该人群驱动逃生和病毒适应性约束，这些限制将其恢复到其非适应状态。我们的初步数据表明，在传播的创建者病毒（在新宿主中建立感染的TFV或病毒）中的CTL表位很大一部分已经相对于该人的HLA-I（即AE）而突变，从而使有效的和广泛的CD8 T-Cell反应不太可能被提出。此外，我们还具有新生的数据，证明了在急性感染和设定点病毒载荷过程中传播的适应性表位（AE）之间的直接相关性。综上所述，这些观察结果突出了与HIV疫苗设计有关的真正方案，因为所有当前的HIV疫苗都编码了大量AE。为了解决这个问题，我们将首先确定艾滋病毒特定的CTL表位，这些表位将非常值得纳入未来的候选HIV免疫原。我们假设其中大多数将是非适应性表位（NAE），a）将有效地杀死受HIV感染的细胞； b）进行CTL逃生（成为AE）； c）逃避对病毒的巨大健身成本； d）当免疫压力升高时，NAE恢复为AE。这些功能和AIM 1评估提出的其他功能属性将有助于描绘“最佳CTL表位”的签名。 AIM 2将确定在先前的疗效研究中使用的疫苗是否富含AE，从而否定了被感染的疫苗疾病进展的任何影响。我们还将评估NAE及其AE对应物在候选镶嵌疫苗临床试验中的免疫原性。最后，在AIM 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来获得最佳CTL响应的机械见解。总而言之，该提案将在急性感染和疫苗接种的背景下定义重要的非适应性和适应的HIV表位。获得的信息将非常适合设计和生成可评估的基准测试，以测量未来候选HIV-1疫苗的功效。