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(申请人提供)：艾滋病毒/艾滋病大流行继续在全球范围内肆虐，并已成为有记录以来最具破坏性的大流行病之一。尽管延长生命的抗逆转录病毒疗法有了巨大的改进，但遏制艾滋病毒/艾滋病大流行的唯一途径很可能是开发有效的艾滋病毒疫苗。不幸的是，针对艾滋病毒的传统疫苗提供的保护很少或根本没有，这突显了更好地了解艾滋病毒特异性免疫反应和寻找新的艾滋病毒疫苗方法的必要性。研究已经证明了CD8+T细胞在控制HIV感染中的重要作用，但对于哪些病毒蛋白负责激发有效的CD8+T细胞反应还没有明确的共识。特别是，缺乏关于在HIV感染过程中被感染的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，但当考虑将特定的HIV蛋白作为基于疫苗的方法的组成部分或作为免疫治疗的靶点时，这些参数是至关重要的。拟议研究的目标是开发新的试剂和方法，可以在普通实验室环境下进行，以评估感染细胞上的艾滋病毒抗原提呈谱，并将这些参数与艾滋病毒感染过程中早期发生的时间事件联系起来。我们一直在开发基于T细胞受体(TCR)的新型试剂和简单的方法，以更直接地定量和可视化疾病细胞和组织(包括HIV感染细胞)上的多肽抗原递呈。我们已经证明了可溶性单链TCR(ScTCR)试剂可以用来评估肿瘤细胞上的内源性抗原提呈，最近我们扩展了这些研究，以产生能够识别HIV多肽表位及其已知的各自表位变体的高亲和力的可溶性scTCR试剂。通过流式细胞仪检测，这些试剂能够识别HIV感染的CD4T细胞上展示的HIV多肽/人类白细胞抗原复合体，验证了该方法用于评价HIV抗原提呈谱的可行性。根据这一建议，我们打算扩大HIV抗原识别特异性的试剂组合，并进一步优化分析HIV感染T细胞中抗原提呈水平和动力学的方法。为实现该项目的目标，将进行以下具体目标：1)产生和鉴定一组针对至少20种不同的、具有良好特性的HIV多肽/人类白细胞抗原复合体的可溶性单链TCR试剂，以及2)利用这些试剂对HIV感染细胞的HIV多肽抗原提呈进行定量。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，因此应该有助于为预防性疫苗选择最相关的HIV靶点，这是该项目的最终目标。同时，我们将迅速将HIV特异性TCR试剂商业化，作为我们现有研究试剂组合的一部分，以允许它们在本提案所考虑的研究之外的使用。 公共卫生相关性：目前缺乏关于患者T细胞在病毒感染过程中显示的艾滋病毒抗原的时间、大小和相关性的信息，但这些参数在考虑将特定的艾滋病毒蛋白作为基于疫苗的方法的组成部分时至关重要。这项拟议研究的目标是开发方法来评估感染细胞上的艾滋病毒抗原提呈谱，并将这些参数与艾滋病毒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细胞反应方面发挥作用，因此应该有助于为预防性疫苗选择最相关的HIV靶标。