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

• 批准号: 10371657
• 负责人: Alexander Ploss
• 金额: $ 76.43万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-24 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371657
• 关键词: Modeling; immune; impairments; pathogenesis; novel

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。