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

• 批准号: 9070878
• 负责人: Haitao Hu
• 金额: $ 13.95万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-05 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9070878
• 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; Clinical; Clinical Research; Cytomegalovirus; Data; Development; Differentiation Antigens; Exposure to; Gene Expression; Genes; HIV; HIV Infections; HIV therapy; HIV vaccine; HIV-1; HIV/SIV vaccine; Homing; Human; Immunity; Immunization; Infection; Knowledge; Label; Laboratories; Lead; Measures; Memory; Microarray Analysis; Molecular; Opportunistic Infections; Outcome; Pathogenesis; Pathway interactions; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Phenotype; Population; Predisposition; Principal Investigator; Proliferating; Proteins; Public Health; RNA; Relative (related person); Reporting; Resistance; Risk; Role; Sampling; Site; Small Interfering RNA; Sorting - Cell Movement; Specificity; Surrogate Markers; System; T cell response; T-Lymphocyte; Testing; Tetanus Toxoid; Time; Transcript; Vaccine Design; Vaccines; Viral; base; cytokine; differential expression; genome-wide; in vitro Assay; insight; memory CD4 T lymphocyte; novel; pandemic disease; pathogen; permissiveness; pre-clinical; programs; public health relevance; research study; sensor; vaccine efficacy; vaccine trial; vaccine-induced immunity; vector; vector-induced; viral RNA; ALVAC; Acquired Immunodeficiency Syndrome; Address; Affect; Antigens; Antiviral Agents; Area; Biological Assay; CD4 Positive T Lymphocytes; Candida; Candida albicans; Cell Line; Cells; Clinical; Clinical Research; Cytomegalovirus; Data; Development; Differentiation Antigens; Exposure to; Gene Expression; Genes; HIV; HIV Infections; HIV therapy; HIV vaccine; HIV-1; HIV/SIV vaccine; Homing; Human; Immunity; Immunization; Infection; Knowledge; Label; Laboratories; Lead; Measures; Memory; Microarray Analysis; Molecular; Opportunistic Infections; Outcome; Pathogenesis; Pathway interactions; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Phenotype; Population; Predisposition; Principal Investigator; Proliferating; Proteins; Public Health; RNA; Relative (related person); Reporting; Resistance; Risk; Role; Sampling; Site; Small Interfering RNA; Sorting - Cell Movement; Specificity; Surrogate Markers; System; T cell response; T-Lymphocyte; Testing; Tetanus Toxoid; Time; Transcript; Vaccine Design; Vaccines; Viral; base; cytokine; differential expression; genome-wide; in vitro Assay; insight; memory CD4 T lymphocyte; novel; pandemic disease; pathogen; permissiveness; pre-clinical; programs; public health relevance; research study; sensor; vaccine efficacy; vaccine trial; vaccine-induced immunity; vector; vector-induced; viral RNA

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 significantly 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-generated CD4 T cells by HIV reduces the efficiency of vaccine-induced immunity. Our hypothesis is that a protective HIV vaccine would 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-specific CD4 T cells that may significantly impact their sensitivities to HIV. We will test peripheral blood mononuclear cell samples from three completed HIV vaccine trials: RV144 (ALVAC), RV158 (MVA) and IPVC001 (Ad26). Our hypotheses will be addressed in 2 Specific Aims: 1) To determine the role of IFIT1 in regulating the susceptibility of human 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/pathways that could lead to the development of novel HIV therapies; 3) better understand the quality of vaccine-generated CD4 T cell immunity and to provide proof of concept knowledge on whether and how to induce functional, "HIV-resistant" CD4 T cells by an 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的过表达显着抑制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对疫苗生成的CD4 T细胞的优先感染降低了疫苗诱导的免疫力的效率。我们的假设是，一种保护性的HIV疫苗将诱导一种疫苗特异性的CD4 T细胞“不容易易感” HIV，并且不同的候选HIV疫苗（例如不同的载体）会诱导其对HIV敏感的疫苗特异性CD4 T细胞的独特表现型。我们将测试外周血 来自三个完成的HIV疫苗试验的单核细胞样品：RV144（ALVAC），RV158（MVA）和IPVC001（AD26）。我们的假设将在2个具体目的中解决：1）确定IFIT1在调节人类抗原特异性CD4 T细胞HIV的敏感性中的作用，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）确定具有先前未鉴定的抑制性机制/途径的新型抗HIV分子，该分子可能导致新型HIV疗法的发展； 3）更好地了解疫苗生成的CD4 T细胞免疫的质量，并提供有关HIV疫苗是否以及如何诱导功能性的“耐HIV” CD4 T细胞的概念验证。