Breadth and Functional Assessment of "Toggle"-Peptide-specific T Cell Responses

“切换”肽特异性 T 细胞反应的广度和功能评估

• 批准号: 7426244
• 负责人: CHRISTIAN BRANDER
• 金额: $ 47.94万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7426244
• 关键词: Amino Acid Sequence; Amino Acid Substitution; Amino Acids; Antigens; Arginine; Autologous; Base Sequence; CD4 Positive T Lymphocytes; Cell physiology; Characteristics; Class; Consensus; Data; Databases; Detection; Development; Epitopes; Experimental Designs; Frequencies; Future; Gagging; HIV; HIV Infections; HIV vaccine; Helper-Inducer T-Lymphocyte; Immune; Immune Targeting; Immune response; In Vitro; Individual; Lysine; Minor; Nature; Nucleotides; Numbers; Outcome; Pattern; Peptide Library; Peptide Sequence Determination; Peptides; Population; Positioning Attribute; Property; Proteins; Sequence Analysis; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Vaccine Design; Vaccines; Valine; Variant; Viral; Viral Proteins; Virus; Work; base; cohort; concept; coping; cost; cross reactivity; cytotoxic; design; disorder control; immunogenicity; improved; pol genes; reagent testing; response

HIV sequence diversity is a major hurdle for the development of an HIV vaccine and severely impacts the ability to detect ex vivo immune responses in HIV infected individuals. Different approaches have been suggested to cope with this issue, but have not always been effective in overcoming the discrepancy between infecting viral sequence and in vitro antigen test sets. As a consequence, most immune analyses to date provide limited information on the immunogenicity of sequence variants that could represent valuable candidates for HIV vaccine design. In addition, most past efforts defining immune correlates of controlled HIV infection have been similarly limited in their inclusion of sequence diversity, questioning whether all of the phenotypic and functional characteristics of reportedly protective responses would extend to variant sequences. The use of "toggled" peptides, representing essentially small peptide libraries with limited diversity, has the potential to overcome a number of these problems, providing important guidance for antigen selection and sequence variant inclusion in future vaccine immunogens. Aside from detecting significantly more and stronger HIV-specific immune responses, sequence variants that are present in the toggled peptides may induce quantitatively and qualitatively different immune responses, for both CD4 as well as CDS T cells, providing the basis to more comprehensively define potential immune correlates of controlled HIV infection. Based on extensive preliminary data showing the superiority of toggled peptides to elicit T cell responses compared to different single sequence (e.g. consensus) test reagents, the present application aims in a first step to define the level of sequence diversity coverage that provides optimal detection of HIV-specific responses in a cohort of HIV clade B infected individuals with varying disease control. Subsequently, toggled peptides are investigated for their ability to stimulate recall responses with different functional and phenotypic patterns, identifying sequence variants with improved immunogenicity and associated with polyfunctional responses. The frequency of these sequence variants in the HIV database and the preferential detection of specific polyfunctional response patterns in HIV controllers will be investigated to support rational sequence variant selection for inclusion in vaccine candidates. Overall, the proposed studies will provide urgently needed information on the impact of sequence diversity on the functional properties of virus-specific CD4 and CDS T cells, and together with an assessment of the potential for T cell responses to cross-react between different viral isolates or clades, the analyses will support the further design of HIV vaccines immunogens that can induce broad, strong and self-renewing T cell responses with wide cross-reactivity potential.

艾滋病毒序列多样性是开发艾滋病毒疫苗的主要障碍，并严重影响 能够检测受HIV感染个体的体内免疫反应。不同的方法已经 建议应对这个问题，但并非总是有效克服差异 在感染病毒序列和体外抗原测试集之间。结果，大多数免疫分析 迄今为止提供有关序列变体免疫原性的有限信息，这些信息可能代表有价值 HIV疫苗设计的候选人。此外，过去的大多数定义受控免疫相关性的努力 艾滋病毒感染在包含序列多样性时也受到同样的限制，质疑是否所有 据报道，保护性反应的表型和功能特征将扩展到变体 序列。使用“切换”的肽，代表具有有限的基本小肽库 多样性有可能克服许多此类问题，为 抗原的选择和序列变体包含在未来的疫苗免疫原中。 除了检测到更多和更强的HIV特异性免疫反应外，序列变体 在切换的肽中存在可能诱导定量和质量不同的免疫反应， 对于CD4和CDS T细胞，为更全面地定义潜在免疫的基础 受控HIV感染的相关性。基于广泛的初步数据，显示了 与不同的单个序列（例如共识）测试相比，将肽切换为引起T细胞反应 试剂，本应用程序的目标是确定序列多样性覆盖范围的第一步 在HIV进化枝B感染的人群中，提供了最佳检测HIV特异性反应 不同的疾病控制。随后，研究了切换的肽的刺激能力 具有不同功能和表型模式的响应，鉴定有改进的序列变体 免疫原性，与多功能反应有关。这些序列变体的频率 HIV数据库和HIV中特定多功能响应模式的优先检测 将研究控制器以支持有理序列变体选择，以纳入疫苗 候选人。 总体而言，拟议的研究将迫切需要有关序列多样性影响的信息 关于病毒特异性CD4和CDS T细胞的功能特性，以及评估 T细胞对不同病毒分离株或进化枝之间交叉反应的反应的潜力，分析将 支持可以诱导广泛，坚固和自我更新的艾滋病毒疫苗免疫原子的进一步设计 具有广泛交叉反应潜力的细胞反应。