Analysis of Variant Epitope Specific CD8 T-Cells to Optimize HIV Vaccine Design

分析变异表位特异性 CD8 T 细胞以优化 HIV 疫苗设计

• 批准号: 8546018
• 负责人: Paul A. Goepfert
• 金额: $ 63.62万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-21 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8546018
• 关键词: Address; Adenoviruses; Alleles; Antibodies; Antigens; Autologous; Avidity; Biological Assay; CD4 Lymphocyte Count; CD8B1 gene; Characteristics; Chronic; Clinical Trials; Consensus; Data; Development; Epidemic; Epitopes; Evolution; Frequencies; Future; Gagging; Genes; Genetic Polymorphism; HIV; HIV Infections; HIV Vaccine Trials Network; HIV vaccine; HIV-1; Human; Immune response; Immune system; Individual; Infection prevention; Interferons; Link; Macaca mulatta; Measures; Mutate; Mutation; Participant; Patients; Peptides; Peripheral Blood Mononuclear Cell; Plasma; Polymorphism Analysis; Population; Preventive; Proteome; Recombinants; Regimen; Relative (related person); Research; Resources; Sampling; Site; T cell response; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Vaccinated; Vaccination; Vaccine Clinical Trial; Vaccine Design; Vaccines; Variant; Viral; Viral Load result; Virus; Virus Diseases; antiretroviral therapy; base; cohort; design; efficacy testing; immunogenic; immunogenicity; mutant; pathogen; phase 1 study; response; therapy development; transmission process; vaccine candidate; vaccine development; vaccine efficacy

DESCRIPTION (provided by applicant): A significant hurdle in the field of HIV vaccine design is the enormous diversity of the circulating virus. Mutations occur within an infected subject and are then transmitted to the next host making the task of generating a single vaccine that prevents infection from an ever-evolving virus more challenging. In this application, we seek to have a better understanding of the mutations occurring in the virus that are then transmitted to another individual and whether or not these mutations should be targeted by a vaccine. We hypothesize that some mutations that occur and persist in the viral sequence of HIV may be able to elicit an effective immune response and that designing vaccines to recognize virus encoding these mutations will be beneficial. To prove this hypothesis, we seek to evaluate the frequency and quality of CD8 T cell responses to mutated and non-mutated sequences in chronically HIV infected subjects. These data will be compared with the level of viral control at a population level to determine the contribution of immune responses targeting mutated virus to viral replication. A score for each epitope will be calculated based a number of characteristics with high scoring epitopes being ideal for vaccine inclusion. In the second aim, we will sequence the virus in primary HIV infection to determine the frequency of mutated and non-mutated sequences encoded by the single infecting viral strain. We will then examine the frequency and quality of CD8 T cells targeting the mutated or nonmutated sequences. We expect to find that targeting some mutated sequences will be beneficial while other sequences will elicit poor quality or no response at all. These results will inform the design of future vaccines by defining specific viral sequences to target or exclude. Finally, in the last aim, we will evaluate the capacity of a mosaic vaccine to elicit immune responses that recognize mutated virus. Mosaic vaccines are designed to have viral sequences that encode non-mutated and common mutants to increase the number of immune responses elicited in the vaccinee. We will enumerate the frequency and determine the quality of the responses generated as a result of this vaccine construct. Taken together, this proposal will determine the biologic significance of immune responses recognizing mutated virus in context of HIV infection and vaccination. Such information will be extremely pertinent for future HIV-1 vaccine design and efficacy testing.

描述（由申请人提供）：HIV疫苗设计领域的一个重大障碍是流行病毒的巨大多样性。突变发生在受感染的受试者体内，然后传播到下一个宿主，使得产生单一疫苗以防止不断进化的病毒感染的任务更具挑战性。在本申请中，我们试图更好地了解病毒中发生的突变，然后将其传播给另一个个体，以及这些突变是否应该被疫苗靶向。我们假设，在HIV病毒序列中发生并持续存在的一些突变可能能够引发有效的免疫应答，并且设计识别编码这些突变的病毒的疫苗将是有益的。为了证明这一假设，我们试图评估慢性HIV感染受试者中CD 8 T细胞对突变和非突变序列应答的频率和质量。这些数据将与病毒对照水平进行比较， 群体水平，以确定靶向突变病毒的免疫应答对病毒复制的贡献。每个表位的评分将基于多个特征计算，其中高评分表位对于疫苗包含是理想的。在第二个目标中，我们将对原发性HIV感染中的病毒进行测序，以确定由单个感染病毒株编码的突变和非突变序列的频率。然后，我们将检查针对突变或非突变序列的CD 8 T细胞的频率和质量。我们期望发现靶向一些突变序列将是有益的，而其他序列将引起质量差或根本没有反应。这些结果将通过定义靶向或排除的特定病毒序列为未来疫苗的设计提供信息。最后，在最后一个目标中，我们将评估镶嵌疫苗引发识别突变病毒的免疫应答的能力。嵌合疫苗被设计为具有编码非突变和常见突变体的病毒序列，以增加在疫苗接种者中引发的免疫应答的数量。我们将列举频率，并确定作为该疫苗构建体的结果产生的应答的质量。总之，这一提议将确定在HIV感染和疫苗接种的背景下识别突变病毒的免疫应答的生物学意义。这些信息将对未来的HIV-1疫苗设计和有效性测试非常相关。