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，但仍有确切的免疫保护相关性。一个可能与病毒控制有关的参数是CTL的潜力，以应对广泛的病毒序列变化。已经研究了一些高度选择的表位的HIV特异性CTL识别体内作为潜在逃生突变体的表位变体的能力。但是，尚未采用一种更系统的方法来评估CTL识别经常发生的序列变体（即潜在感染序列）的能力的方法。同样，尚未完全评估参与广泛识别表位变体的机制。该提案的目的是确定HIV GAG特异性T细胞识别经常发生的序列变体的潜力，并将变体识别与这些响应的功能亲和力联系起来。为此，将使用11mer GAG肽与10个氨基酸重叠的11mer GAG肽对具有和不自发控制的受试者的免疫反应进行测试，其中包括所有在Los Alamos国家实验室序列数据库中至少存在所有可用的GAG序列中的所有变体11Mer序列。 CTLS对所有靶向表位及其变体的功能性持续性将通过评估在IFN-3/IL-2双色ELISPOT分析中评估肽浓度所需的肽浓度，并与疾病进度以及CTL识别自然差异的大分子的能力相关。此外，在治疗中断之前，将在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，并在停止治疗后与病毒载荷设定点相关，以测试与高配款相比，是否可以预测高避免性反应是否可以预测治疗中断的卓越结果。总而言之，该应用将提供关键的数据，将GAG特异性CTL与HIV疾病的结果相关联，并通过增加病毒变体的识别来为这种益处提供潜在的机械解释。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地应对病毒序列的可变性。 公共卫生相关性：目前的应用旨在通过评估HIV特异性T细胞的两个定义较差的功能来定义与HIV感染的免疫保护相关性。由于艾滋病毒的极大差异，T细胞应对HIV抗原多样性的能力及其对低浓度的HIV抗原的亲和力在疫苗设计中是要考虑的重要参数。在此提案中，这两个功能都将在具有和没有自发控制HIV复制的受试者以及接受抗逆转录病毒治疗中断的个体中评估，以解决高度狂热的HIV-特定T细胞在该病原体的免疫控制中的作用。