Modeling immune impairments and pathogenesis in novel humanized mice for HBV-HIV co-infection

新型人源化小鼠 HBV-HIV 共感染的免疫损伤和发病机制建模

基本信息

批准号：
9981621
负责人：
Alexander Ploss
金额：
$ 3.05万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-24 至 2020-10-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9981621
关键词：
Acquired Immunodeficiency Syndrome Address Animal Model Antigens CD8-Positive T-Lymphocytes Cells Chronic Cirrhosis Data Disease Disease Progression Double Stranded DNA Virus Education Exhibits Family HIV HIV Infections HIV-1 HIV-1 integrase HLA-A2 Antigen Hematopoietic Hepadnaviridae Hepatitis B Hepatitis B Virus Hepatitis B virus Pol Protein Hepatitis Viruses Hepatocyte Highly Active Antiretroviral Therapy Homeostasis Human IFNAR1 gene Immune Immune response Immunological Models Immunology Impairment Incidence Individual Infection Inflammation Integrase Inhibitors Interferon Type I Interferons Liver Liver Fibrosis Liver diseases Mediating Modeling Monitor Morbidity - disease rate Mouse Strains Mus Myeloid Cells Natural Killer Cells Pathogenesis Pathogenicity Patients Phenotype Pongidae Primary carcinoma of the liver cells Public Health Reporting Research Risk Spleen Symptoms T-Cell Depletion T-Lymphocyte Technology Vaccinated Vaccines Viral hepatitis Viremia Virus Virus Diseases Work antiretroviral therapy chronic infection clinically relevant co-infection cohort effective therapy exhaustion functional disability humanized mouse immune activation immune function immunogenicity immunopathology improved in vivo inhibitor/antagonist innovation macrophage mortality mouse model novel pathogen prevent single-cell RNA sequencing stellate cell transcriptomics viral liver disease virology

项目摘要

Project Summary Co-infection with HBV and HIV-1 is common, and HIV co-infection can exacerbate progression of viral hepatitis and accelerate liver disease progression. A major hurdle to elucidating potential mechanisms underlying these common and serious diseases, and thus to developing effective therapies, is the lack of small animal models that reproduce human-like infection with HBV and HIV-1. Both viruses exhibit a narrow host range in which infection is largely limited to humans and other great apes. Our labs (Ploss and Su) have developed novel humanized mice that are co-engrafted with human livers and human immune cells (FNRGF/A2-hu HEP/HSC mice), with human hepatocytes and improved human myeloid cell/DC and NK cell subsets that are underrepresented in conventional humanized mouse models. We have demonstrated that these refinements yield vaccine-induced immunogenicity profiles resembling those of humans who have been vaccinated with the same well-defined YFV-17D vaccine. We will capitalize on these promising breakthroughs to investigate the following: 1) We will infect cohorts of FNRGF/A2- hu mice dually engrafted with human HLA-matched hepatocytes and human hematopoietic cells with HBV and/or HIV-1. We will monitor, and quantify longitudinally, HBV and HIV viremia and immune activation, including antigen- specific CD8+ T cells and liver disease progression (Aim 1A). We will also perform analyses in cohorts of HBV/HIV co-infected mice which have been treated with HAART (including HBV polymerase inhibitors), to suppress HIV-1 and HBV, to model accurately clinically relevant situations (Aim 1B). 2) We will study HIV/HBV-induced T cell impairment. We will monitor T cell exhaustion markers on HIV and HBV specific T cells and profile functional impairments in antigen specific CD8+ T cells during HBV/HIV co-infections using single-cell transcriptomics (Aim 2A). We will also evaluate the impact of blocking INFAR1 on HIV/HBV-induced immune impairment. We will monitor reversion of T cell exhaustion functions of HIV- and HBV-specific T cells and profile IFN-induced functional impairments in antigen specific CD8+ T cells during HBV/HIV co-infections (Aim 2B). 3) We will investigate how HIV-1 infection elevates HBV-induced pathogenic macrophages in the liver of humanized mice in vivo (Aim 3A). We will also study how HIV and HBV interact with M2-like macrophages to activate human stellate cells (Aim 3B). Finally, we will study how inhibiting M2-like macrophages prevents or reverses HIV/HBV-induced liver diseases in humanized mice (Aim 3C). We will thus capitalize on our extensive complimentary expertise in virology and immunology of HIV-1/HBV (Su), hepatitis viruses (Ploss) and in humanized mouse technology to achieve the exciting aims. Our work will advance the field of HBV and HIV-1 research by showing that a novel small animal model can be successfully used to understand HIV/HBV coinfection and immune responses, and to model treatments for the associated liver diseases.

项目摘要与HBV和HIV-1共同感染很常见，HIV共感染会加剧病毒肝炎的进展并加速肝病进展。阐明这些潜在机制的主要障碍常见和严重的疾病，因此要开发有效的疗法，是缺乏小动物模型用HBV和HIV-1再现类似人类的感染。两种病毒均表现出狭窄的宿主范围，其中感染是很大程度上限于人类和其他伟大的猿猴。我们的实验室（Ploss and Su）开发了新颖的人性化小鼠与人肝和人类免疫细胞共促成（FNRGF/A2-HU HEP/HSC小鼠），与人类肝细胞和改进的人髓样细胞/DC和NK细胞子集，这些细胞在常规中的代表性不足人源化的小鼠模型。我们已经证明了这些改进产生疫苗诱导的免疫原性类似于接受过相同定义的YFV-17D疫苗接种的人类的概况。我们将利用这些有前途的突破来调查以下情况：1）我们将感染FNRGF/A2-的队列 HU小鼠用人HLA匹配的肝细胞和人类造血细胞与HBV和/或 HIV-1。我们将纵向监测并量化HBV和HIV病毒血症以及免疫激活，包括抗原特定的CD8+ T细胞和肝病进展（AIM 1A）。我们还将对HBV/HIV的同类进行分析通过HAART处理的共感染小鼠（包括HBV聚合酶抑制剂），以抑制HIV-1 和HBV，以准确地对临床相关的情况进行建模（AIM 1B）。 2）我们将研究HIV/HBV诱导的T细胞损害。我们将在HIV和HBV特定T细胞上监视T细胞耗尽标记，以及配置文件功能 HBV/HIV共感染期间抗原特异性CD8+ T细胞的损伤使用单细胞转录组学（AIM 2a）。我们还将评估阻断INBAR1对HIV/HBV诱导的免疫损伤的影响。我们将监视 HIV和HBV特异性T细胞的T细胞耗尽函数的恢复以及轮廓IFN诱导的功能 HBV/HIV共感染期间抗原特异性CD8+ T细胞的损伤（AIM 2B）。 3）我们将调查如何 HIV-1感染升高了体内人性化小鼠肝脏中HBV诱导的致病巨噬细胞（AIM 3A）。我们还将研究HIV和HBV如何与M2样巨噬细胞相互作用以激活人类星状细胞（AIM 3B）。最后，我们将研究如何抑制M2样巨噬细胞阻止或逆转HIV/HBV诱导的肝病人性化小鼠（AIM 3C）。因此，我们将利用HIV-1/HBV（SU）的病毒学和免疫学方面的广泛免费专业知识，肝炎病毒（PLOSS）和人源化的小鼠技术，以实现令人兴奋的目标。我们的工作将进步 HBV和HIV-1研究领域通过表明新型小动物模型可以成功地用于了解HIV/HBV共感染和免疫反应，并为相关肝脏疾病建模。