Opioids, HIV/HCV and host cell innate immunity

阿片类药物、HIV/HCV 和宿主细胞先天免疫

• 批准号: 8704399
• 负责人: WENZHE HO
• 金额: $ 23.84万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8704399
• 关键词: Address; Antiviral Agents; Antiviral Response; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; Cell Count; Cells; Chinese People; Cohort Studies; Conflict (Psychology); Data; Disease; Disease Progression; Genes; Goals; Grant; HIV; HIV Infections; Hepatitis C; Hepatitis C Prevalence; Hepatitis C virus; Hepatocyte; Heroin; Heroin Users; Highly Active Antiretroviral Therapy; In Vitro; Indium; Infection; Injecting drug user; Knowledge; Life; Mediating; Morphine; Natural Immunity; Opiates; Opioid; Opioid Receptor; Peripheral Blood Mononuclear Cell; Persons; Plasma; Population; Predisposition; Prevention strategy; Progress Reports; Public Health; Research; Risk Factors; Route; Signal Pathway; Signal Transduction; Specimen; Tretinoin; Virus; Virus Diseases; base; clinically relevant; human TLR3 protein; improved; in vivo; macrophage; public health relevance; sensor; transmission process; treatment strategy

DESCRIPTION (provided by applicant): Coinfection with HIV and HCV is a rapidly growing public health issue. HIV/HCV coinfection is common in injection drug users (IDUs), the single largest group for HCV infection in the USA. HCV coinfection is becoming even more significant, as HIV-infected people are living longer with HAART. However, we have limited and conflicting information about the interactions between opioids, host innate immunity and HIV/HCV. Importantly, no study to date has addressed combined effects of heroin use and HCV on HIV infection as well as on TLR3/RIG-I-mediated innate immunity, which is a major barrier of fundamental understanding of the immunopathogenesis of HIV disease in HIV and/or HCV-infected IDUs. The goal of this proposal is to address our overarching hypothesis that the negative impact of opioids (heroin, morphine) on the antiviral innate immunity is crucial in facilitating HIV or HCV infection. We will investigate the impact of heroin use and/or HCV on host innate immunity and HIV/HCV infection. We will determine previously unrecognized mechanisms by which opioids compromise TLR3/RIG-I (the key sensors of viral infection)-mediated innate immunity against HIV/HCV infection. We propose the following specific aims: Aim 1. Determine in vivo impact of heroin and/or HCV infection on plasma and PBMC levels of HIV, CD4 T cell counts and antiviral cellular factors related to HIV or HCV infection; Aim 2. Determine the ex vivo effects of heroin and/or HIV/HCV infection on the activation of TLR3/RIG-I signaling pathways; Aim 3. Determine the mechanism(s) by which morphine and/or HIV/HCV infection compromise TLR3/RIG-I signaling- mediated anti-HIV/HCV effects in primary macrophages and hepatocytes. Data arising from this study using the specimens from the unique Chinese heroin-dependent subjects with or without HIV and/or HCV infection will be clinically relevant and important in our understanding of the in vivo interplays between opioids, host innate immunity and viral infections. Long term goal of this project is to develop host innate immunity-based treatment and prevention strategies for HIV/HCV-infected opioid-abusers.

描述(由申请人提供)：艾滋病毒和丙型肝炎病毒混合感染是一个迅速增长的公共卫生问题。艾滋病毒/丙型肝炎病毒混合感染在注射吸毒者中很常见，注射吸毒者是美国丙型肝炎病毒感染的最大单一群体。丙型肝炎病毒合并感染变得更加严重，因为感染艾滋病毒的人患HAART的寿命更长。然而，关于阿片类药物、宿主先天免疫和艾滋病毒/丙型肝炎之间的相互作用，我们掌握的信息有限且相互矛盾。重要的是，到目前为止还没有研究讨论海洛因使用和丙型肝炎病毒对艾滋病毒感染以及对TLR3/rig-I介导的先天免疫的联合影响，这是从根本上理解艾滋病毒感染和/或丙型肝炎病毒感染的注射吸毒者艾滋病毒疾病的免疫发病机制的主要障碍。这项建议的目的是解决我们的总体假设，即阿片类药物(海洛因、吗啡)对抗病毒天然免疫的负面影响在促进艾滋病毒或丙型肝炎病毒感染方面至关重要。我们将调查海洛因使用和/或丙型肝炎病毒对宿主先天免疫和艾滋病毒/丙型肝炎病毒感染的影响。我们将确定以前未知的机制，通过阿片类药物损害TLR3/RIG-I(病毒感染的关键传感器)介导的针对艾滋病毒/丙型肝炎病毒感染的先天免疫。目的1.在体内检测海洛因和/或丙型肝炎病毒感染对血浆和PBMC中HIV、CD4T细胞计数和抗病毒细胞因子水平的影响；目的2.体外研究海洛因和/或HIV/丙型肝炎病毒感染对TLR3/RIG-I信号通路激活的影响；目的3.确定吗啡和/或HIVRIG-I信号转导原代巨噬细胞和肝细胞抗HIVR3/RIG-I信号通路的机制(S)。这项研究的数据来自中国海洛因依赖者中感染或不感染艾滋病毒和/或丙型肝炎病毒的独特个体，这将对我们理解体内阿片类药物、宿主天然免疫和病毒感染之间的相互作用具有临床意义和重要意义。这个项目的长期目标是发展宿主先天 感染艾滋病毒/丙型肝炎病毒的阿片类药物滥用者的基于免疫的治疗和预防战略。