In vitro and in vivo analysis of susceptibility of Ad26 vector-induced CD4 T cells to HIV/SIV

Ad26载体诱导的CD4 T细胞对HIV/SIV敏感性的体外和体内分析

• 批准号: 10010193
• 负责人: Haitao Hu
• 金额: $ 23.7万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10010193
• 关键词: AIDS Vaccines; AIDS/HIV problem; ALVAC; Acquired Immunodeficiency Syndrome; Adenovirus Vector; Adenoviruses; Adjuvant; Antigens; Biological; Biological Assay; CCR5 gene; CD4 Positive T Lymphocytes; Clinical; Clinical Trials; Data; Development; Failure; Generations; Goals; HIV; HIV Infections; HIV Vaccine Trials Network; HIV resistance; HIV vaccine; Human; Immune; Immune response; Immunity; In Vitro; Individual; Inflammasome; International AIDS; Knowledge; Measures; Military Personnel; Modeling; Monkeys; Natural Immunity; Outcome; Pathway interactions; Peripheral Blood Mononuclear Cell; Phenotype; Predisposition; Research; Resistance; Role; SIV; Sampling; Signal Transduction; T-Cell Proliferation; T-Lymphocyte; Testing; Transgenes; Vaccinated; Vaccination; Vaccine Design; Vaccines; Viral Vector; base; experience; improved; in vivo; innate immune mechanisms; insight; interest; nonhuman primate; novel; novel strategies; pandemic disease; programs; research clinical testing; response; transcriptomics; vaccine development; vector; vector vaccine; vector-induced

ABSTRACT An effective HIV vaccine is essential to achieve a durable end to the HIV/AIDS pandemic. Preferential HIV infection of activated human CD4 T cells, which are usually induced by vaccination, has posed a unique challenge for the development of a safe and protective HIV vaccine. A gap in knowledge is whether or not vaccine-induced CD4 T cells are preferential HIV targets in vaccination. Therefore, understanding the susceptibility of vaccine-generated CD4 T cells to HIV and its potential impact on vaccine outcomes is critical and will provide novel insights into rational HIV vaccine design. Viral vectors are central to HIV vaccine development. To date, a number of HIV vaccine vectors (e.g. poxviral vector ALVAC and adenoviral vector Ad5) have been tested in clinical trials but were unexpectedly associated with distinct vaccine outcomes. Currently, another knowledge gap is that the host response to different viral vectors following HIV vaccination remains poorly understood. Given the dual roles of CD4 T cells in the generation of protective immunity during HIV vaccination, we speculate that a successful HIV vaccine approach, especially those utilizing viral vectors, must induce vector-reactive CD4 T cells that are resistant or less susceptible to HIV. As such, our recent studies have shown that CD4 T cells induced by different vectors (ALVAC and Ad5) manifest distinct susceptibility to HIV, which is associated with the phenotypes of vector- induced T cells as well as with the innate signals (inflammasome activation) primed by these two vectors. Human adenovirus 26 (Ad26) vector has become increasingly important for HIV vaccine development and is under intensive clinical testing. Due to the failure of Ad5 vector and the concern that Ad5 vaccination may be associated with enhanced HIV infection in some vaccine recipients, it is critical to understand whether or not, and how, HIV preferentially infects Ad26 vector-induced CD4 T cells. We hypothesize that Ad26 vector induces vector-reactive CD4 T cells that are distinct from those induced by ALVAC in phenotype and HIV susceptibility, which contributes to the differential vaccine outcomes. In this R21 application, we will collaborate with IAVI (International AIDS Vaccine Initiatives), HVTN (HIV Vaccine Trial Network), MHRP (Military HIV Research Program), and Genoveffa Franchini, to examine in vitro and in vivo susceptibility of Ad26 vector- induced CD4 T cells to HIV/SIV in vaccinated human individuals (Aim 1) and non-human primates (Aim 2) as compared to those induced by ALVAC. We will also define the underlying innate immune mechanisms, especially effects on the inflammasome pathway. We expect that this R21 project will be highly impactful since it presents an effort to systematically investigate HIV/SIV susceptibility of CD4 T cells induced by two clinically important vectors in parallel. Our long-term goal is to discover novel approaches (e.g. adjuvants) based on the identified immune parameters to enhance HIV resistance of vaccine-induced CD4 T cells in HIV vaccination.

摘要 一种有效的艾滋病毒疫苗对于持久结束艾滋病毒/艾滋病流行病至关重要。优惠 HIV感染活化的人类CD4T细胞，通常是通过接种疫苗诱导的，已经构成了一种独特的 开发安全和保护性的艾滋病毒疫苗面临挑战。知识上的鸿沟在于 疫苗诱导的CD4T细胞是HIV疫苗接种的首选靶点。因此，理解 疫苗产生的CD4T细胞对艾滋病毒的易感性及其对疫苗结果的潜在影响至关重要 并将为合理的艾滋病毒疫苗设计提供新的见解。 病毒载体是艾滋病毒疫苗开发的核心。到目前为止，一些艾滋病毒疫苗载体(例如， 痘病毒载体ALVAC和腺病毒载体Ad5)已经在临床试验中进行了测试，但出人意料地被 与不同的疫苗结果相关。目前，另一个知识缺口是宿主对 接种艾滋病毒疫苗后的不同病毒载体仍然知之甚少。鉴于CD4T细胞的双重作用 在产生保护性免疫接种HIV疫苗的过程中，我们推测一种成功的HIV疫苗 方法，特别是那些利用病毒载体的方法，必须诱导具有抵抗力或 不太容易感染艾滋病毒。因此，我们最近的研究表明，不同载体诱导的CD4T细胞 (ALVAC和Ad5)对HIV表现出明显的易感性，这与载体的表型有关- 诱导的T细胞以及由这两个载体启动的天然信号(炎症体激活)。 人腺病毒26(AD26)载体对HIV疫苗的开发变得越来越重要 目前正在进行密集的临床测试。由于Ad5载体的失败和人们对Ad5疫苗接种的担忧 可能与一些疫苗接受者艾滋病毒感染增加有关，关键是要了解 HIV是否以及如何优先感染AD26载体诱导的CD4T细胞。我们假设AD26向量 诱导在表型和HIV方面与ALVAC不同的载体反应性CD4T细胞 敏感性，这是造成不同疫苗结果的原因。在此R21应用程序中，我们将协作 与IAVI(国际艾滋病疫苗倡议)、HVTN(艾滋病毒疫苗试验网络)、MHRP(军事艾滋病毒 研究计划)和Genoveffa Franchini，以检测AD26载体的体内外敏感性。 在接种疫苗的人(目标1)和非人灵长类动物(目标2)中诱导CD4T细胞产生HIV/SIV 与ALVAC诱导的相比。我们还将定义潜在的先天免疫机制， 尤其是对炎症体途径的影响。我们预计这个R21项目将产生很大的影响，因为 本研究旨在系统研究人类免疫缺陷病毒(HIV/SIV)诱导的CD4T细胞对HIV/SIV的敏感性。 重要的并行向量。我们的长期目标是发现新的方法(例如佐剂)基于 确定了在HIV疫苗接种中增强疫苗诱导的CD4T细胞对HIV抵抗力的免疫参数。