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

基本信息

批准号：
10115603
负责人：
Haitao Hu
金额：
$ 19.75万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10115603
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 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 vaccination outcome vaccine development vector vector vaccine vector-induced

项目摘要

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.

抽象的有效的艾滋病毒疫苗对于持久结束艾滋病毒/艾滋病流行至关重要。优惠 HIV 感染激活的人类 CD4 T 细胞（通常由疫苗接种诱导），形成了独特的开发安全且具有保护性的艾滋病毒疫苗面临的挑战。知识的差距在于是否疫苗诱导的 CD4 T 细胞是疫苗接种中 HIV 的优先目标。因此，了解疫苗产生的 CD4 T 细胞对 HIV 的敏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。迄今为止，许多 HIV 疫苗载体（例如痘病毒载体 ALVAC 和腺病毒载体 Ad5）已在临床试验中进行测试，但出乎意料与不同的疫苗结果相关。目前，另一个知识差距是主机对 HIV 疫苗接种后的不同病毒载体仍知之甚少。鉴于 CD4 T 细胞的双重作用在艾滋病毒疫苗接种期间产生保护性免疫力的过程中，我们推测成功的艾滋病毒疫苗方法，特别是那些利用病毒载体的方法，必须诱导载体反应性 CD4 T 细胞，这些细胞具有抗性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 CD4 T 细胞（ALVAC 和 Ad5）对 HIV 表现出明显的易感性，这与载体的表型相关诱导 T 细胞以及由这两个载体引发的先天信号（炎性体激活）。人类腺病毒 26 (Ad26) 载体对于 HIV 疫苗的开发变得越来越重要并正在进行密集的临床测试。由于Ad5载体的失败以及Ad5疫苗接种的担忧可能与某些疫苗接种者的艾滋病毒感染增强有关，因此了解是否存在这一点至关重要 HIV 是否优先感染 Ad26 载体诱导的 CD4 T 细胞以及如何优先感染。我们假设 Ad26 载体诱导载体反应性 CD4 T 细胞，其表型和 HIV 与 ALVAC 诱导的细胞不同易感性，这会导致不同的疫苗结果。在这个 R21 应用程序中，我们将合作与 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，检查 Ad26 载体的体外和体内敏感性在已接种疫苗的人类个体（目标 1）和非人类灵长类动物（目标 2）中诱导 CD4 T 细胞感染 HIV/SIV 与 ALVAC 诱导的结果相比。我们还将定义潜在的先天免疫机制，尤其是对炎症小体途径的影响。我们预计这个 R21 项目将产生巨大影响，因为它提出了系统研究两种临床试验诱导的 CD4 T 细胞对 HIV/SIV 敏感性的努力。重要的并行向量。我们的长期目标是基于以下发现新的方法（例如佐剂）：确定了免疫参数，以增强 HIV 疫苗接种中疫苗诱导的 CD4 T 细胞的 HIV 抵抗力。