Susceptibility of antigen-specific CD4 T cells to HIV: implications for HIV vacci

抗原特异性 CD4 T 细胞对 HIV 的敏感性：对 HIV 疫苗的影响

基本信息

批准号：
8732199
负责人：
Haitao Hu
金额：
$ 21.73万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-05 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8732199
关键词：
ALVAC Acquired Immunodeficiency Syndrome Address Affect Antigens Antiviral Agents Area Biological Assay CD4 Positive T Lymphocytes Candida Candida albicans Cell Line Cells Chronic Clinical Clinical Research Cytomegalovirus Data Development Differentiation Antigens Exposure to Figs - dietary Gene Expression Genes HIV HIV Infections HIV vaccine HIV-1 HIV/SIV vaccine Homing Human Immunity Immunization In Vitro Infection Interleukin-17 Intervention Knowledge Label Lead Measures Memory Microarray Analysis Molecular Opportunistic Infections Outcome Pathogenesis Patients Peripheral Peripheral Blood Mononuclear Cell Phenotype Population Predisposition Principal Investigator Proliferating Proteins Public Health Recombinants Relative (related person)Reporting Resistance Risk Role Sampling Small Interfering RNA Sorting - Cell Movement Specificity Surrogate Markers System T cell response T-Lymphocyte Testing Tetanus Toxoid Time Vaccine Design Vaccines Viral base cytokine genome-wide in vitro Assay insight interest memory CD4 T lymphocyte novel pandemic disease pathogen permissiveness pre-clinical programs public health relevance research study sensor vaccine efficacy vector vector vaccine vector-induced viral RNA

项目摘要

DESCRIPTION: A central question to better understanding the pathogenesis of HIV infection is how memory CD4 T cells are infected and progressively depleted by HIV. Little is currently known about the impact of HIV infection on CD4 T cells of different pathogen or antigen specificities. Exploring this area is important for better understanding of the timing of different opportunistic infections in AIDS patients. In addition, identification of a functional population o vaccine-specific CD4 T cells that is "resistant" to HIV is critical for HIV vaccine design. We have established a novel system for studying the susceptibility of antigen-specific CD4 T cells to HIV, and have found that different antigen-specific CD4 T cells manifest marked differences in susceptibility to HIV infection. Our preliminary data show that compared to CD4 T cells specific to tetanus toxoid (TT) and Candida albicans (Candida), which are permissive to HIV, cytomegalovirus (CMV)-specific CD4 T cells are highly resistant to both R5 and X4 HIV with post-entry HIV restriction. Our microarray analysis identified a novel viral RNA sensor, IFIT1 that is highly upregulated in CMV-specific CD4 T cells. Of importance, in our ongoing experiments, we show that over-expression of IFIT1 inhibits HIV infection in A3R5 CD4 T cell line. Based on data already generated, we hypothesize that IFIT1 can inhibit HIV infection in human primary CD4 T cells and differential expression of IFIT1 regulates the permissiveness of antigen-specific CD4 T cells to HIV. We further propose to extend the novel system and observations to clinical HIV vaccine studies. Preferential infection of vaccine-induced CD4 T cells by HIV reduces the efficiency of vaccine-generated immunity. Our hypothesis is that a protective HIV vaccine should induce a type of vaccine-specific CD4 T cells that are "not readily susceptible" to HIV, and that different candidate HIV vaccines (e.g. different vectors) induce distinct phenotypes of vaccine- and/or vector-specific CD4 T cells that may impact their sensitivities to HIV. We will test peripheral blood mononuclear cell samples from three completed HIV vaccine trials: RV144 (ALVAC), RV158 (MVA) and IPCAVD 001(Ad26). Our hypotheses will be addressed in 2 Specific Aims: 1) To determine the role of IFIT1 in regulating the susceptibility of antigen-specific CD4 T cells to HIV and to further explore the mechanisms for inhibition of HIV by IFIT1; 2) To investigate the susceptibilities of different HIV vaccine-induced, antigen-specific CD4 T cells to HIV infection and the associated phenotypes in HIV vaccine trials. The proposed studies are exploratory, but expected to provide new insights to: 1) understand the mechanisms for the persistence of CMV-specific T cell immunity in AIDS patients; 2) identify a novel anti-HIV molecule with previously unidentified inhibitory mechanisms that could possibly lead to development of novel interventional strategies; 3) more thoroughly understand the quality of vaccine-generated CD4 T cell immunity and to provide proof of concept knowledge as to whether and how to induce functional, "HIV-resistant" CD4 T cells by an efficacious HIV vaccine.

描述：更好地理解HIV感染的发病机理的一个核心问题是记忆CD4 T细胞如何感染并逐渐被HIV耗尽。目前，关于HIV感染对不同病原体或抗原特异性的CD4 T细胞的影响知之甚少。探索该领域对于更好地理解不同的时间很重要艾滋病患者的机会性感染。此外，鉴定对HIV具有“抗药性”的功能人群O疫苗特异性CD4 T细胞对于HIV疫苗设计至关重要。我们已经建立了一个新的系统，用于研究抗原特异性CD4 T细胞对HIV的敏感性，并发现不同的抗原特异性CD4 T细胞表现出明显的HIV感染敏感性差异。我们的初步数据表明，与特异性的Tetanus毒素（TT）和白色念珠菌（念珠菌）相比，它们允许HIV，巨细胞病毒（CMV）特异性CD4 T细胞对R5和X4 HIV具有R5和X4 HIV，并具有入选后HIV HIV限制。我们的微阵列分析确定了一种新型的病毒RNA传感器，即在CMV特异性CD4 T细胞中高度上调的IFIT1。重要的是，在我们正在进行的实验中，我们表明IFIT1的过表达抑制了A3R5 CD4 T细胞系中的HIV感染。根据已经生成的数据，我们假设IFIT1可以抑制人类原发性CD4 T细胞中的HIV感染，而IFIT1的差异表达调节抗原特异性CD4 T细胞对HIV的允许性。我们进一步建议将新型系统和观察结果扩展到临床HIV疫苗研究。通过HIV对疫苗诱导的CD4 T细胞的优先感染降低了疫苗生成的免疫的效率。我们的假设是，保护性HIV疫苗应诱导一种“不容易易感” HIV的疫苗特异性CD4 T细胞，并且不同的候选HIV疫苗（例如不同的载体）会诱导疫苗和/或载体特异性CD4 T细胞的独特表型，这些表型可能影响其敏感性HIV。我们将从三个完成的HIV疫苗试验中测试外周血单核细胞样品：RV144（ALVAC），RV158（MVA）和IPCAVD 001（AD26）。我们的假设将在两个具体目的中解决：1）确定IFIT1在调节抗原特异性CD4 T细胞易感性中的作用，并进一步探索IFIT1抑制HIV的机制； 2）研究不同HIV疫苗诱导的抗原特异性CD4 T细胞对HIV感染的敏感性以及HIV疫苗试验中的相关表型。拟议的研究是探索性的，但有望提供新的见解：1）了解艾滋病患者中CMV特异性T细胞免疫持续性的机制； 2）确定一种具有先前未鉴定的抑制性机制的新型抗HIV分子，可能会导致新型介入策略的发展； 3）更彻底地了解疫苗生成的CD4 T细胞免疫的质量，并提供有关是否以及如何通过有效的HIV疫苗诱导功能性的“抗HIV抗HIV” CD4 T细胞的概念验证。