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科普广泛的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的逃逸突变体的能力已经针对少数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体（即潜在感染序列）的能力。类似地，参与表位变体的广泛识别的机制尚未完全评估。该提案的目标是确定HIV GAG特异性T细胞识别频繁发生的序列变异的潜力，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11聚体Gag肽（包括Los Alamos国家实验室序列数据库中至少5%的Gag序列中存在的所有变体11聚体序列）检测病毒复制自发控制和未自发控制的受试者的免疫应答。通过评估在IFN-3/IL-2双色ELISpot测定中引发半数最大应答所需的肽浓度来确定对所有靶向表位及其变体具有特异性的CTL的功能亲合力，并将其与疾病进展以及CTL识别大比例天然存在的变体的能力相关联。此外，将在治疗中断前在接受抗逆转录病毒治疗的受试者中确定GAG特异性CTL的功能亲合力，并将其与治疗停止后的病毒载量设定点相关联，以测试与低亲合力应答相比，高亲合力应答是否预测治疗中断的上级结果。总之，本申请将提供将GAG特异性CTL的功能亲合力与HIV疾病的结果相关联的关键数据，并通过增加对病毒变体的识别来提供对这种益处的潜在机制解释。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科普病毒序列变异性。 公共卫生关系：本申请旨在通过评估HIV特异性T细胞的两种定义不清的功能来定义对HIV感染的免疫保护的相关性。由于HIV的极端变异性，T细胞科普HIV抗原多样性的能力以及它们对甚至低浓度的HIV抗原的亲和力是疫苗设计中要考虑的重要参数。在本提案中，将在具有和不具有HIV复制自发控制的受试者中以及在经历抗逆转录病毒治疗中断的个体中评估这两种功能，以解决高度亲合力的HIV特异性T细胞在该病原体的免疫控制中的作用。