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（由适用提供）：CD4 T细胞是针对HIV和其他病毒的免疫复杂的重要组成部分，但CD4 T细胞是HIV感染的主要靶标。因此，人们担心刺激和扩展CD4 T细胞的HIV疫苗可能为病毒提供更多的靶细胞并增加宿主对HIV感染的敏感性。然而，在HIV感染过程中，并非所有抗原特异性CD4 T细胞都屈服于HIV并感染。已证明对某些HIV表位的CD4 T细胞的抗原刺激使这些细胞对CCR5-纤维化HIV具有更具耐药性，并且这种耐药性与CCR5配体的产生有关，即CC趋化因子MIP-1A，MIP-1，MIP-1和Rantes和Rantes由细胞提供。虽然CC趋化因子表达与Th1反应有关，但并非所有TH1细胞都响应其特异性抗原而分泌这些趋化因子。 CD4 TH1细胞总是显示出MIP-1的差异表达与其他Th1细胞因子，例如IFN-？，IL-2和TNF-A，以及响应T细胞产生的趋化因子和细胞因子的总体谱图，取决于用于刺激的抗原所使用的不同。可能会解释许多因素，并且尚未完全理解。在这一建议中，我们集中精力评估一个因素，即。我们假设要检验这些假设，我们将定义来自HIV-1 Invelope（ENV）GP120和GP41抗原的一组辅助表位，并根据其刺激CD4 T细胞的能力来表达不同的粒细胞动物和CC Chemokines（AIM 1）。然后，我们将评估CCR5配体对其ENV表位反应的CCR5配体分泌是否与对体外HIV攻击的耐药性的增加有关，以及在活性慢性HIV感染期间，是否确实选择性地保护了表达CCR5配体CD4 T细胞的CCR5表达CD4 T细胞（AIM 2）。我们还建议评估可以调节不同ENV表位的能力以引起不同细胞因子和趋化因子集的能力的参数，包括表位浓度，表位-HLA II类配合物的相对亲和力以及表位内的氨基酸取代（AIM 3）。最后，我们计划使用不同的ENV表位来从健康未感染受试者的体外天真的CD4 T细胞中启动，并确定这些表位是否还刺激了启动的CD4 T细胞，以产生一组不同的细胞因子和趋化因子，以及产生CCR5配体的启动CCR5液体是否对HIV的CCR5细胞是否更具抗HIV挑战（AIM 4）。优先引起病毒特异性CD4 T细胞产生CCR5配体和其他B细胞或CD8 T细胞帮助的其他细胞因子的选择性辅助表位是一种潜在的抗HIV免疫，也可以保护CD4 T细胞抗病毒。 预防性HIV疫苗是唯一可以打击艾滋病毒和艾滋病全球大流行的可行工具，但是在过去二十年中在临床和临床前试验中已测试的候选疫苗尚未被证明是有效的。该建议旨在利用CD4 T细胞的能力产生具有潜在抗HIV活性的CC趋化因子，以便可以保护这些细胞免受HIV的影响，同时执行其关键功能以帮助其他免疫细胞。这项研究的数据将提供有关CD4 T细胞反应的类型的信息，因此应直接适用于急需的HIV疫苗的开发。