CC Chemokine Secretion to Protect Antigen-Specific CD4 T Cells from HIV

CC 趋化因子分泌保护抗原特异性 CD4 T 细胞免受 HIV 感染

• 批准号: 7761148
• 负责人: Catarina E Hioe
• 金额: $ 42.26万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-12 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7761148
• 关键词: Accounting; Acquired Immunodeficiency Syndrome; Address; Adenoviruses; Affinity; Alleles; Amino Acid Substitution; Antibodies; Antigens; Avidity; B-Lymphocytes; Binding; CCR5 gene; CD4 Positive T Lymphocytes; CD8B1 gene; Candida; Cells; Chronic; Clinical; Complex; Cytomegalovirus; Data; Dendritic Cells; Development; Dose; Ducks; Epitopes; Failure; Fibrinogen; Flow Cytometry; Fungal Antigens; HIV; HIV Antigens; HIV Envelope Protein gp120; HIV Infections; HIV vaccine; HIV-1; HIV-1 vaccine; Helper-Inducer T-Lymphocyte; Human; Immune; Immune response; Immunity; In Vitro; Individual; Infection; Interferons; Interleukin-2; Investigation; Ionomycin; Ligands; MHC Interaction; Mediating; Monitor; Mumps; Mus; Natural Killer Cells; Pattern; Peptide/MHC Complex; Peptides; Peripheral; Physiologic pulse; Predisposition; Production; RANTES; Recombinants; Relative (related person); Resistance; Small Inducible Cytokine A3; Staphylococcal Enterotoxin B; Study Subject; Superantigens; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; Testing; Tetanus; Th1 Cells; Th2 Cells; Vaccination; Vaccine Adjuvant; Vaccines; Viral load measurement; Virus; base; beta-Chemokines; chemokine; combat; cytokine; design; flu; in vivo; influenzavirus; mRNA Differential Displays; pandemic disease; pathogen; preclinical study; prophylactic; response; tool; vaccine candidate; vector; viral resistance

DESCRIPTION (provided by applicant): CD4 T cells are an essential component of the immune responses against HIV and other viruses, but CD4 T cells are the prime targets for HIV infection. Hence, there are concerns that HIV vaccines which stimulate and expand CD4 T cells may supply more target cells for the virus and increase the host susceptibility to HIV infection. Nevertheless, in the course of HIV infection, not all antigen-specific CD4 T cells succumb to HIV and become infected. Antigen stimulation of CD4 T cells specific for certain HIV epitopes have been shown to render these cells more resistant to CCR5-tropic HIV and this resistance is associated with production of CCR5 ligands, i.e. CC chemokines MIP-1a, MIP-1¿, and RANTES by the cells. While CC chemokine expression has been associated with Th1 responses, not all Th1 cells secrete these chemokines in response to their specific antigens. CD4 Th1 cells invariably display differential expression of MIP-1¿ vs. other Th1 cytokines such as IFN-?, IL-2, and TNF- a, and the overall profiles of chemokines and cytokines produced by the responding T cells vary depending on the antigens used for stimulation. Many factors may account for and they are not fully understood. In this proposal we focus to evaluate one factor, i.e.. We hypothesize that To test these hypotheses, we will define a panel of helper epitopes from HIV-1 envelope (Env) gp120 and gp41 antigens and characterize them in terms of their ability to stimulate CD4 T cells to express different sets of cytokines and CC chemokines (Aim 1). We will then evaluate if CCR5 ligand secretion by CD4 T cells responding to their Env epitopes is specifically associated with increased resistance against in vitro HIV challenge and if CCR5 ligand-expressing CD4 T cells are indeed selectively protected and preserved in vivo during active chronic HIV infection (Aim 2). We also propose to evaluate parameters that can modulate the capacity of the different Env epitopes to elicit the distinct sets of cytokines and chemokines, including epitope concentrations, relative affinities of the epitope-HLA class II complexes, and amino acid substitutions within the epitopes (Aim 3). Finally, we plan to use the different Env epitopes to prime in vitro naive CD4 T cells from healthy uninfected subjects and determine if these epitopes also stimulate the primed CD4 T cells to produce distinct sets of cytokines and chemokines and if the primed CD4 T cells producing CCR5 ligands are more resistant to HIV challenge (Aim 4). The use of selective helper epitopes that preferentially elicit virus-specific CD4 T cells to produce CCR5 ligands and other cytokines necessary for B cell or CD8 T cell help, is one potential strategy for inducing potent anti-HIV immunity that also protects the CD4 T cells against the virus. A prophylactic HIV vaccine is the only feasible tool for combating the global pandemic of HIV and AIDS, but the candidate vaccines that have been tested in the clinical and preclinical trials in the past two decades have not been proven to be effective. This proposal aims to harness the capacity of CD4 T cells to produce CC chemokines with potent anti-HIV activities so that these cells can be protected from HIV, while performing their critical functions to help other immune cells. Data from this study will provide information about the types of CD4 T cell responses need for protection against HIV and thus should be directly applicable to the development of the much needed HIV vaccines.

描述（由申请人提供）：CD4 T 细胞是针对 HIV 和其他病毒的免疫反应的重要组成部分，但 CD4 T 细胞是 HIV 感染的主要目标，因此，人们担心 HIV 疫苗会刺激和扩大 CD4 T。细胞可能为病毒提供更多的靶细胞，增加宿主对 HIV 感染的易感性。然而，在 HIV 感染过程中，并非所有抗原特异性 CD4 T 细胞都会受到 HIV 抗原刺激而被感染。对于某些 HIV 表位，已显示使这些细胞对 CCR5 嗜性 HIV 具有更强的抵抗力，并且这种抵抗力与 CCR5 配体（即 CC 趋化因子 MIP-1a、MIP-1）的产生有关。虽然 CC 趋化因子表达与 Th1 反应相关，但并非所有 Th1 细胞都会分泌这些趋化因子来响应其特定抗原。 CD4 Th1 细胞总是表现出 MIP-1 的差异表达。与其他 Th1 细胞因子（例如 IFN-α、IL-2 和 TNF-α）相比，响应 T 细胞产生的趋化因子和细胞因子的总体特征会根据用于刺激的抗原而变化。在本提案中，我们重点评估一个因素，即，为了测试这些假设，我们将从 HIV-1 包膜 (Env) gp120 和 gp41 中定义一组辅助表位。抗原并根据其刺激 CD4 T 细胞表达不同组细胞因子和 CC 趋化因子的能力来表征它们（目标 1），然后我们将评估 CD4 T 细胞响应其 Env 表位的 CCR5 配体分泌是否与增加有特异性相关。对体外 HIV 攻击的抵抗力，以及表达 CCR5 配体的 CD4 T 细胞在活动性慢性 HIV 感染期间是否确实在体内受到选择性保护和保存（目标 2）。不同的 Env 表位来引发不同的细胞因子和趋化因子组，包括表位浓度、表位-HLA II 类复合物的相对亲和力以及表位内的氨基酸取代（目标 3）。体外启动来自健康未感染受试者的初始 CD4 T 细胞，并确定这些表位是否也刺激启动的 CD4 T 细胞产生不同的细胞因子和趋化因子组，如果产生 CCR5 配体的引发 CD4 T 细胞对 HIV 攻击具有更强的抵抗力（目标 4），则使用优先诱导病毒特异性 CD4 T 细胞产生 CCR5 配体和 B 细胞或 CD8 T 细胞所需的其他细胞因子的选择性辅助表位。帮助，是诱导有效的抗 HIV 免疫的一种潜在策略，该免疫也可以保护 CD4 T 细胞免受病毒侵害。 预防性艾滋病毒疫苗是对抗艾滋病毒和艾滋病全球大流行的唯一可行工具，但过去二十年在临床和临床前试验中进行测试的候选疫苗尚未被证明有效。这一提议旨在。利用 CD4 T 细胞产生具有有效抗 HIV 活性的 CC 趋化因子的能力，从而保护这些细胞免受 HIV 感染，同时发挥其关键功能来帮助其他免疫细胞。这项研究的数据将提供有关 CD4 类型的信息。 T 细胞反应需要预防艾滋病毒，因此应该直接应用于急需的艾滋病毒疫苗的开发。