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

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.

产品说明：更好地理解HIV感染的发病机制的一个中心问题是记忆性CD 4 T细胞如何被HIV感染并逐渐耗尽。目前对HIV感染对不同病原体或抗原特异性的CD 4 T细胞的影响知之甚少。探索这一领域对于更好地理解不同的时间安排是重要的。 艾滋病患者的机会性感染。此外，鉴定对HIV具有“抗性”的疫苗特异性CD 4 T细胞的功能群体对于HIV疫苗设计至关重要。 我们建立了一个新的系统来研究抗原特异性CD 4 T细胞对HIV的易感性，并发现不同抗原特异性CD 4 T细胞对HIV感染的易感性存在显著差异。我们的初步数据显示，与破伤风类毒素（TT）和白色念珠菌（念珠菌）特异性的CD 4 T细胞相比，这是允许艾滋病毒，巨细胞病毒（CMV）特异性的CD 4 T细胞是高度耐药的R5和X4艾滋病毒与后进入艾滋病毒的限制。我们的微阵列分析确定了一种新的病毒RNA传感器，IFIT 1，是高度上调CMV特异性CD 4 T细胞。重要的是，在我们正在进行的实验中，我们表明IFIT 1的过表达显著抑制A3 R5 CD 4 T细胞系中的HIV感染。基于已经产生的数据，我们假设IFIT 1可以抑制HIV在人原代CD 4 T细胞中的感染，并且IFIT 1的差异表达调节抗原特异性CD 4 T细胞对HIV的容许性。 我们进一步建议将新的系统和观察扩展到临床HIV疫苗研究。HIV对疫苗产生的CD 4 T细胞的优先感染降低了疫苗诱导免疫的效率。我们的假设是，保护性HIV疫苗将诱导一种疫苗特异性CD 4 T细胞，这些细胞对HIV“不容易易感”，并且不同的候选HIV疫苗（例如不同的载体）诱导疫苗特异性CD 4 T细胞的不同表型，这可能显著影响其对HIV的敏感性。我们会检测外周血 来自三个已完成的HIV疫苗试验的单核细胞样本：RV 144（ALVAC）、RV 158（MVA）和IPVC 001（Ad 26）。我们的假设将在2个具体目标中得到解决：1）确定IFIT 1在调节人类抗原特异性CD 4 T细胞对HIV的易感性中的作用，并进一步探索IFIT 1抑制HIV的机制; 2）在HIV疫苗试验中研究不同HIV疫苗诱导的抗原特异性CD 4 T细胞对HIV感染的易感性以及相关表型。 这些研究是探索性的，但有望为以下方面提供新的见解：1）了解艾滋病患者CMV特异性T细胞免疫持续存在的机制; 2）确定一种新的抗HIV分子，其抑制机制/途径以前未被确定，可能导致开发新的HIV治疗方法; 3）更好地理解疫苗产生的CD 4 T细胞免疫的质量，并提供关于是否以及如何通过HIV疫苗诱导功能性的“HIV抗性”CD 4 T细胞的概念知识的证明。

项目成果

Priming and Activation of Inflammasome by Canarypox Virus Vector ALVAC via the cGAS/IFI16-STING-Type I IFN Pathway and AIM2 Sensor.

• DOI: 10.4049/jimmunol.1700698
• 发表时间: 2017-11-01
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• 作者: Liu F;Niu Q;Fan X;Liu C;Zhang J;Wei Z;Hou W;Kanneganti TD;Robb ML;Kim JH;Michael NL;Sun J;Soong L;Hu H
• 通讯作者: Hu H

HIV Susceptibility of human antigen-specific CD4 T cells in AIDS pathogenesis and vaccine response.

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• DOI: 10.3171/2020.10.jns201787
• 发表时间: 2022
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• 通讯作者: Redmond,