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: 7418922
• 负责人: WENZHE HO
• 金额: $ 40.29万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 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 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7418922
• 关键词: Address; Biological Models; CD81 gene; Cell model; Cells; Coculture Techniques; Communicable Diseases; Data; Development; Disease; Goals; Growth; HIV; HIV Envelope Protein gp120; HIV Infections; HIV tat Protein; Hepatitis; Hepatitis C; Hepatitis C Transmission; Hepatitis C virus; Hepatocyte; Human; In Vitro; Infection; Injecting drug user; Kupffer Cells; Laboratories; Mediating; Morbidity - disease rate; Morphine; Natural Immunity; Opioid; Outcome; Patients; Prevention strategy; Proteins; Public Health; Rate; Recombinants; Reporting; Research; Ribavirin; Risk; Risk Factors; Role; System; United States; Virus; Virus Diseases; base; cofactor; cytotoxicity; design; innovation; intrahepatic; mortality; pathogen; receptor expression; transmission process; virus virus interaction

DESCRIPTION (provided by applicant): Project Summary. Since HIV and HCV share common risk factors for infection, co-infections with HIV and HCV are frequently found in Injection drug users (IDUs). These two pathogens are also likely to be responsible for the highest infectious disease morbidity and mortality rates among IDUs. IDUs are the single largest risk group for HCV infection in the United States. However, we know little about direct opioids-virus (HIV and/or HCV) as well as virus-virus (HIV-HCV) interactions, which is a major barrier to a fundamental understanding of the immunopathogenesis of HCV disease and HCV-related morbidity in HIV/HCV- coinfected IDUs. A major barrier to address this key issue in vitro is the lack of a HCV infectious cell model system. Recently, three independent research groups have reported the development of a robust HCV infectious system in vitro. This newly established cell model provides an excellent opportunity for this proposed project. We have generated infectious HCV from this cell model in our laboratory. The goal of this study is to address our overarching hypothesis that the interactions between opioids (e.g., morphine), HIV, and HCV are a key determinant of the outcome of HCV/HCV infection. We will address previously un- recognized mechanisms by which morphine and/or HIV/HCV compromise the host cell innate immunity, leading to the persistence of viral infection and replication. Specifically, we will investigate the effects of morphine and the HIV proteins (Tat and gp120) on HCV infection, intracellular innate immunity, and the anti- HCV effects of IFN-a/Ribavirin in the human hepatic cells. We will utilize innovative cocultures of human hepatic cells with Kupffer cells to study the interactions of HIV with HCV in the presence or absence of morphine. Since Kupffer cells are the resident macrophages of liver, and are the target for HIV infections, the inclusion of Kupffer cells in this study is highly significant. Data arising from this study will be critical for a better understanding of opioids as a cofactor in the immunopathogenesis of HIV/HCV infection. The long term goal of this proposal is to develop host innate immunity-based treatment and prevention strategies for HIV/HCV-infected opioid abusers. Relevance to Public Health. There is little direct evidence available about the interactions between morphine, HIV and HCV in different cell systems, which is a major barrier to a fundamental understanding of HCV-related morbidity and mortality in HIV/HCV-infected IDUs. This research will contribute not only to our basic understanding of host cell innate immunity against HIV/HCV, but also to the design and development of innate immunity-based treatment and prevention strategies for HIV/HCV-infected opioid abusers.

描述(申请人提供)：项目摘要。由于艾滋病毒和丙型肝炎病毒具有共同的感染危险因素，因此在注射吸毒者中经常发现艾滋病毒和丙型肝炎病毒的混合感染。这两种病原体也可能是注射吸毒者中传染病发病率和死亡率最高的原因。在美国，注射吸毒者是感染丙型肝炎病毒的最大风险群体。然而，我们对直接阿片类病毒(艾滋病毒和/或丙型肝炎病毒)以及病毒与病毒(艾滋病毒-丙型肝炎)的相互作用知之甚少，这是从根本上理解丙型肝炎疾病的免疫发病机制和艾滋病毒/丙型肝炎病毒合并感染的静脉吸毒者中丙型肝炎病毒相关发病率的主要障碍。在体外解决这一关键问题的一个主要障碍是缺乏丙型肝炎病毒感染细胞模型系统。最近，三个独立的研究小组报道了一种强大的体外丙型肝炎病毒感染系统的开发。这个新建立的细胞模型为这个拟议的项目提供了一个很好的机会。我们已经在我们实验室的这个细胞模型中产生了传染性丙型肝炎病毒。这项研究的目的是解决我们的总体假设，即阿片类药物(如吗啡)、艾滋病毒和丙型肝炎病毒之间的相互作用是丙型肝炎病毒/丙型肝炎病毒感染结局的关键决定因素。我们将讨论以前未知的机制，通过这些机制，吗啡和/或艾滋病毒/丙型肝炎病毒损害宿主细胞的天然免疫，导致病毒感染和复制的持久性。具体地说，我们将研究吗啡和HIV蛋白(TAT和gp120)对丙型肝炎病毒感染、细胞内天然免疫的影响，以及干扰素-a/利巴韦林在人肝细胞中的抗丙型肝炎病毒作用。我们将利用创新的人类肝细胞与Kupffer细胞的共培养来研究在存在或不存在吗啡的情况下艾滋病毒与丙型肝炎病毒的相互作用。由于Kupffer细胞是肝脏的常驻巨噬细胞，也是HIV感染的靶细胞，因此将Kupffer细胞纳入本研究具有非常重要的意义。这项研究的数据对于更好地理解阿片类药物作为艾滋病毒/丙型肝炎病毒感染的免疫病理机制中的辅助因素至关重要。这项提议的长期目标是为感染艾滋病毒/丙型肝炎病毒的阿片类药物滥用者制定基于宿主先天免疫的治疗和预防战略。与公共卫生的相关性。关于吗啡、艾滋病毒和丙型肝炎病毒在不同细胞系统中的相互作用，几乎没有直接的证据可用，这是从根本上理解艾滋病毒/丙型肝炎病毒感染的静脉吸毒者与丙型肝炎病毒相关的发病率和死亡率的主要障碍。这项研究不仅有助于我们对宿主细胞对HIV/丙型肝炎的天然免疫的基本了解，也将有助于设计和开发针对HIV/丙型肝炎感染的阿片类药物滥用者的基于天然免疫的治疗和预防策略。