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HIV疫苗对于实现HIV/AIDS大流行的持久末端至关重要。优惠通常由疫苗诱导的激活的人CD4 T细胞的HIV感染提出了独特的开发安全和保护性艾滋病毒疫苗的挑战。知识的差距是是否是疫苗诱导的CD4 T细胞是疫苗接种中的优先HIV靶标。因此，了解疫苗生成的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理性HIV疫苗设计提供新的见解。病毒载体是HIV疫苗发育的核心。迄今为止，许多HIV疫苗向量（例如 Poxviral载体ALVAC和腺病毒载体AD5）已在临床试验中进行了测试，但出乎意料的是与不同的疫苗结果相关。目前，另一个知识差距是主机对艾滋病毒疫苗接种后的不同病毒载体仍然了解不足。给定CD4 T细胞的双重作用在HIV疫苗接种期间的保护性免疫中，我们推测成功的HIV疫苗方法，尤其是使用病毒载体的方法，必须诱导抗性或抗性的载体CD4 T细胞不太容易受到艾滋病毒的影响。因此，我们最近的研究表明，不同矢量诱导的CD4 T细胞（ALVAC和AD5）表现出对HIV的明显敏感性，这与载体的表型有关诱导的T细胞以及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HIV疫苗的发育变得越来越重要并且正在进行密集的临床测试。由于AD5矢量的失败以及AD5疫苗接种的担忧在某些疫苗接收者中可能与增强的HIV感染有关，了解是否了解是否是否没有，以及HIV优先感染AD26载体诱导的CD4 T细胞。我们假设AD26矢量诱导载体反应性CD4 T细胞，与ALVAC在表型和HIV中诱导的载体不同易感性，有助于差异疫苗结果。在此R21应用程序中，我们将合作与IAVI（国际艾滋病疫苗倡议），HVTN（HIV疫苗试验网络），MHRP（军事HIV 研究计划）和Genoveffa Franchini，以检查Ad26载体的体外和体内易感性在接种的人类中（AIM 1）和非人类灵长类动物（AIM 2）诱导CD4 T细胞诱导艾滋病毒/SIV 与ALVAC诱导的那些相比。我们还将定义潜在的先天免疫机制，尤其对炎症途径的影响。我们希望这个R21项目将对它提出了系统地研究由两个临床上诱导的CD4 T细胞的HIV/SIV敏感性并联重要的向量。我们的长期目标是基于确定的免疫参数可增强疫苗诱导的CD4 T细胞在HIV疫苗接种中的HIV耐药性。