Role of CTL avidity in epitope variant recognition and immune control of HIV

CTL亲合力在HIV表位变异识别和免疫控制中的作用

• 批准号: 7494844
• 负责人: Nicole Frahm
• 金额: $ 26.4万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-11 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7494844
• 关键词: Address; Affinity; Aftercare; Alleles; Amino Acids; Animal Model; Anti-Retroviral Agents; Antigenic Diversity; Antigens; Appearance; Avidity; Biological Assay; CD4 Lymphocyte Count; CD8B1 gene; Classification; Color; Cytotoxic T-Lymphocytes; Data; Databases; Disease; Disease Progression; Effectiveness; Epitopes; Escape Mutant; Evaluation; Fibrinogen; Gagging; Goals; HIV; HIV Antigens; HIV Infections; Immune; Immune response; Immunity; Individual; Infection Control; Interruption; Laboratories; Link; Mediating; Mus; Mutation; Outcome; Peptides; Play; Population; Prognostic Marker; Progressive Disease; Relative (related person); Role; SIV; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Time; Translating; Treatment outcome; Vaccine Design; Vaccines; Variant; Viral; Viral Load result; Viral Proteins; Viremia; Virus; Virus Diseases; Withholding Treatment; base; coping; cross reactivity; cytokine; design; in vivo; outcome forecast; pathogen; pressure; prevent; prophylactic; public health relevance; response; tumor; vaccine delivery

DESCRIPTION (provided by applicant): HIV-specific cytotoxic T lymphocyte (CTL) responses have been implicated in viral control, but precise correlates of immune protection remain to be defined. One parameter likely to be associated with viral control is the potential of CTLs to cope with the extensive viral sequence variation. The ability of HIV- specific CTLs to recognize epitope variants arising in vivo as potential escape mutants has been studied for a few, highly selected epitopes. However, a more systematic approach of assessing the capacity of CTLs to recognize frequently occurring sequence variants (i.e. potentially infecting sequences) has not been undertaken. Similarly, the mechanisms involved in broad recognition of epitope variants have not completely been assessed. The goal of this proposal is to determine the potential of HIV Gag-specific T cells to recognize frequently occurring sequence variants, and to link variant recognition with the functional avidity of these responses. To this end, immune responses in subjects with and without spontaneous control of viral replication will be tested using 11mer Gag peptides overlapping by 10 amino acids, including all variant 11mer sequences that are present in at least 5% of all Gag sequences available at the Los Alamos National Laboratory Sequence database. The functional avidity of CTLs specific for all targeted epitopes and their variants will be determined by assessing the peptide concentration needed to elicit half-maximal responses in IFN-3/IL-2 dual color ELISpot assays, and correlated with disease progression as well as the CTLs' ability to recognize large proportions of naturally occurring variants. Furthermore, the functional avidity of Gag-specific CTLs will be determined in subjects on antiretroviral treatment prior to treatment interruptions and associated to the viral load set-point after cessation of treatment to test if high-avidity responses are predictive of superior outcome of treatment interruptions compared to low-avidity responses. In summary, this application will provide critical data correlating the functional avidity of Gag-specific CTL with outcome of HIV disease and offering a potential mechanistic explanation for this benefit through the increased recognition of viral variants. These data will be vital for immunogen design, since a broadly applicable prophylactic vaccine will need to cope effectively with viral sequence variability. PUBLIC HEALTH RELEVANCE: The present application aims to define correlates of immune protection to HIV infection by assessing two poorly defined functions of HIV-specific T cells. Due to the extreme variability of HIV, the ability of T cells to cope with HIV antigenic diversity as well as their affinity for even low concentrations of HIV antigen are important parameters to be considered in vaccine design. In this proposal, both of these functions will be assessed in subjects with and without spontaneous control of HIV replication and in individuals undergoing antiretroviral treatment interruptions to address the role of highly avid HIV- specific T cells in the immune control of this pathogen.

描述（由申请人提供）：HIV 特异性细胞毒性 T 淋巴细胞（CTL）反应与病毒控制有关，但免疫保护的精确相关性仍有待确定。可能与病毒控制相关的一个参数是 CTL 应对广泛病毒序列变异的潜力。 HIV特异性CTL识别体内产生的表位变体作为潜在逃逸突变体的能力已经针对一些高度选择的表位进行了研究。然而，尚未采用更系统的方法来评估 CTL 识别频繁出现的序列变异（即潜在感染序列）的能力。同样，广泛识别表位变体所涉及的机制尚未完全评估。该提案的目标是确定 HIV Gag 特异性 T 细胞识别频繁出现的序列变异的潜力，并将变异识别与这些反应的功能亲合力联系起来。为此，将使用重叠 10 个氨基酸的 11mer Gag 肽来测试有或没有病毒复制自发控制的受试者的免疫反应，包括在 Los 可用的所有 Gag 序列中至少 5% 中存在的所有变体 11mer 序列。阿拉莫斯国家实验室序列数据库。对所有目标表位及其变体具有特异性的 CTL 的功能亲和力将通过评估在 IFN-3/IL-2 双色 ELISpot 测定中引发半最大反应所需的肽浓度来确定，并与疾病进展以及疾病进展相关。 CTL 能够识别大量自然发生的变异。此外，将在治疗中断之前在接受抗逆转录病毒治疗的受试者中确定Gag特异性CTL的功能亲和力，并将其与停止治疗后的病毒载量设定点相关联，以测试高亲和力反应是否可以预测治疗中断的优异结果与低亲和力反应相比。总之，该应用将提供将 Gag 特异性 CTL 的功能亲和力与 HIV 疾病的结果相关联的关键数据，并通过增加对病毒变异的识别来为这种益处提供潜在的机制解释。这些数据对于免疫原设计至关重要，因为广泛适用的预防性疫苗需要有效应对病毒序列变异性。 公共健康相关性：本申请旨在通过评估 HIV 特异性 T 细胞的两种定义不明确的功能来定义免疫保护与 HIV 感染的相关性。由于 HIV 的极端变异性，T 细胞应对 HIV 抗原多样性的能力以及它们对低浓度 HIV 抗原的亲和力是疫苗设计中需要考虑的重要参数。在该提案中，将在有或没有自发控制 HIV 复制的受试者以及正在接受抗逆转录病毒治疗中断的个体中评估这两种功能，以解决高度活跃的 HIV 特异性 T 细胞在这种病原体的免疫控制中的作用。