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: 7886753
• 负责人: WENZHE HO
• 金额: $ 29.49万
• 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 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7886753
• 关键词: Address; Biological Models; CD81 gene; Cell Culture Techniques; 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; 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（由申请人提供）：项目概述。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（IDUs）中经常发现艾滋病毒和丙型肝炎病毒合并感染。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。注射吸毒者是美国最大的HCV感染风险群体。然而，我们对阿片类药物-病毒（HIV和/或HCV）以及病毒-病毒（HIV-HCV）的直接相互作用知之甚少，这是了解HCV疾病的免疫发病机制和HIV/HCV合并感染注射吸毒者中HCV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HCV感染细胞模型系统。最近，三个独立的研究小组报告了一种强大的HCV体外感染系统的发展。这个新建立的细胞模型为这个提议的项目提供了一个极好的机会。我们在实验室用这种细胞模型产生了传染性HCV。本研究的目的是解决我们的首要假设，即阿片类药物（如吗啡）、HIV和HCV之间的相互作用是HCV/HCV感染结果的关键决定因素。我们将解决以前未被认识的吗啡和/或HIV/HCV损害宿主细胞先天免疫，导致病毒感染和复制持续的机制。具体来说，我们将研究吗啡和HIV蛋白（Tat和gp120）对HCV感染、细胞内先天免疫的影响，以及IFN-a/利巴韦林在人肝细胞中的抗HCV作用。我们将利用人类肝细胞与Kupffer细胞的创新共培养来研究在吗啡存在或不存在的情况下HIV与HCV的相互作用。由于Kupffer细胞是肝脏的常驻巨噬细胞，是HIV感染的靶点，因此本研究将Kupffer细胞纳入研究具有重要意义。这项研究产生的数据对于更好地理解阿片类药物在HIV/HCV感染的免疫发病机制中的辅助因素至关重要。本提案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策略。与公共卫生相关。关于吗啡、HIV和HCV在不同细胞系统中的相互作用的直接证据很少，这是对HIV/HCV感染注射吸毒者中HCV相关发病率和死亡率的基本了解的主要障碍。这项研究不仅有助于我们对宿主细胞抗HIV/HCV先天免疫的基本认识，而且有助于设计和开发基于先天免疫的治疗和预防HIV/HCV感染阿片类药物滥用者的策略。