Evaluating Relevant Vaccine Epitopes Displayed on HIV-Infected Cells

评估 HIV 感染细胞上显示的相关疫苗表位

• 批准号: 8071465
• 负责人: HING C. WONG
• 金额: $ 23.72万
• 依托单位: ALTOR BIOSCIENCE. LLC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-04 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8071465
• 关键词: AIDS/HIV problem; Acute; Address; Affinity; Antigen Presentation; Antigens; Antiviral Agents; Appearance; Attention; CD4 Positive T Lymphocytes; CD8B1 gene; Cell surface; Cells; Chronic; Collaborations; Complex; Consensus; Country; Development; Disease Progression; Epitopes; Event; Flow Cytometry; Fluorescence Microscopy; Generations; Goals; HIV; HIV Antigens; HIV Infections; HIV vaccine; HIV-1; Histocompatibility Antigens Class I; Human; Immune response; Immunologic Deficiency Syndromes; Immunotherapy; Individual; Infection; Kinetics; Knowledge; Laboratories; Life; Measures; Mediating; Methods; National Institute of Allergy and Infectious Disease; Patients; Peptides; Phase; Play; Proteins; Public Health; Reagent; Recording of previous events; Recurrence; Research; Resources; Role; Small Business Innovation Research Grant; Specificity; Staining method; Systemic infection; T cell response; T-Cell Receptor; T-Lymphocyte; Time; Tissues; Translating; Vaccination; Vaccines; Variant; Viral; Viral Load result; Viral Proteins; Viremia; Virus Diseases; antiretroviral therapy; base; neoplastic cell; novel; outcome forecast; pandemic disease; research and development; response; vaccine candidate; vaccine development

DESCRIPTION (provided by applicant): The HIV/AIDS pandemic continues to wreak havoc on global scale and has become one of the most destructive pandemics in recorded history. Despite the tremendous improvements in life-extending antiretroviral therapy, it is likely that the only way by which the HIV/AIDS pandemic can be halted is through the development of an effective HIV vaccine. Unfortunately, conventional vaccines against HIV have provided little or no protection, highlighting the need for a better understanding of HIV-specific immune responses and for novel HIV vaccine approaches. Studies have demonstrated the important role of CD8+ T cells in controlling HIV infections, yet there is no clear consensus as to which viral proteins are responsible for eliciting effective CD8+ T cell responses. Particularly, information is lacking on the timing, magnitude and relevance of T cell- specific epitopes displayed by the infected CD4+ T cells during the course of HIV infection, yet these parameters are of crucial importance when considering specific HIV proteins as components in vaccine-based approaches or as targets for immunotherapy. The goal of the proposed research is to develop new reagents and methods, which can be performed in an ordinary laboratory setting, to assess the HIV antigen presentation profile on infected cells and relate these parameters with the temporal events occurring early during the course of HIV infection. We have been developing novel T cell receptor (TCR)-based reagents and simple methods to more directly quantitate and visualize peptide antigen presentation on diseased cells and tissues, including HIV-infected cells. We have shown that soluble single-chain TCR (scTCR) reagents can be used to evaluate endogenous antigen presentation on tumor cells and recently have extended these studies to generate high- affinity soluble scTCR reagents that are capable of recognizing HIV peptide epitopes as well as their known respective epitope variants. These reagents were found to be capable of recognizing HIV peptide/HLA complexes displayed on HIV-infected CD4 T cells by flow cytometry, verifying the feasibility of this approach for evaluating the HIV antigen presentation profile. Under this proposal, we intend to expand the reagent portfolio of HIV antigen recognition specificities and further optimize methods for analyzing antigen presentation levels and kinetics in HIV-infected T cells. The following specific aims will be conducted to achieve the goals of this project: 1) Generate and characterize a panel of soluble scTCR reagents specific for at least 20 different well-characterized HIV peptide/HLA complexes and 2) utilize these reagents to quantitate HIV peptide antigen presentation by HIV-infected cells. The results of these studies will help establish which specific HIV epitopes may play a role in generating protective CD8 T cell responses early in infection and thus should aid in the selection of the most relevant HIV targets for preventative vaccines, an ultimate goal of this project. In parallel, we will rapidly commercialize the HIV-specific TCR reagents as part of our existing research reagent portfolio to allow their use beyond the studies contemplated in this proposal. PUBLIC HEALTH RELEVANCE: Current information is lacking on the timing, magnitude and relevance of HIV antigens displayed by patient's T cells during the course of viral infection, yet these parameters are of crucial importance when considering specific HIV proteins as components in vaccine-based approaches. The goal of the proposed research is to develop approaches to assess the HIV antigen presentation profile on infected cells and relate these parameters with the temporal events occurring early during the course of HIV infection. Ultimately, these studies will help establish which specific HIV antigens play a role in generating protective CD8+ T cell responses early in infection and thus should aid in the selection of the most relevant HIV targets for preventative vaccines.

描述（由申请人提供）：艾滋病毒/艾滋病大流行继续对全球规模造成严重破坏，并已成为记录史上最具破坏性的大流行之一。尽管延长生命的抗逆转录病毒疗法的改善，但唯一可以通过开发有效的HIV疫苗来制止HIV/AIDS大流行的唯一途径。不幸的是，针对艾滋病毒的常规疫苗几乎没有或根本没有保护，强调需要更好地了解艾滋病毒特异性免疫反应和新型的HIV疫苗方法。研究表明，CD8+ T细胞在控制HIV感染中的重要作用，但是对于哪些病毒蛋白负责引起有效的CD8+ T细胞反应，尚无明确的共识。尤其是，缺乏有关在HIV感染过程中感染CD4+ T细胞显示的T细胞特异性表位的时间，大小和相关性的信息，但是当将特定的HIV蛋白作为疫苗基于疫苗的特定成分作为基于疫苗的方法或作为免疫疗法靶标的组成时，这些参数至关重要。拟议的研究的目的是开发可以在普通实验室环境中执行的新试剂和方法，以评估感染细胞上的HIV抗原表现谱，并将这些参数与HIV感染过程中的时间事件相关联。我们一直在开发新型T细胞受体（TCR）的试剂和简单的方法，以更直接定量和可视化患病细胞和组织（包括HIV感染的细胞）上的肽抗原呈递。我们已经表明，可溶性的单链TCR（SCTCR）试剂​​可用于评估肿瘤细胞上的内源性抗原呈递，最近扩展了这些研究以产生能够识别HIV HIV肽表位的高亲和力可溶性SCTCR试剂，并具有其已知的表育息肉变种。发现这些试剂能够识别通过流式细胞仪在HIV感染的CD4 T细胞上显示的HIV肽/HLA复合物，从而验证了这种方法评估HIV抗原呈递概况的可行性。根据该提案，我们打算扩大HIV抗原识别特异性的试剂组合，并进一步优化用于分析HIV感染的T细胞中抗原表现水平和动力学的方法。将实现以下特定目标以实现该项目的目标：1）生成和表征一组可溶性SCTCR试剂，至少针对20种不同特征良好的HIV肽/HLA复合物和2）利用这些试剂来量化HIV感染的HIV肽抗原通过HIV感染的细胞来量化HIV肽抗原的表现。这些研究的结果将有助于确定哪些特定的HIV表位可能在感染早期产生保护性CD8 T细胞反应中发挥作用，因此应有助于选择最相关的HIV靶标预防疫苗，这是该项目的最终目标。同时，作为现有研究试剂组合的一部分，我们将迅速将HIV特异性TCR试剂商业化，以允许其使用本提案中的研究。 公共卫生相关性：目前缺乏有关患者T细胞在病毒感染过程中表现出的HIV抗原的时间，大小和相关性的信息，但是当将特定的HIV蛋白视为基于疫苗的方法中的特定成分时，这些参数至关重要。拟议的研究的目的是开发评估感染细胞上HIV抗原表现谱的方法，并将这些参数与HIV感染过程中早期发生的时间事件联系起来。最终，这些研究将有助于确定哪些特定的HIV抗原在感染早期产生保护性CD8+ T细胞反应中起作用，因此应有助于选择最相关的预防疫苗艾滋病毒靶标。