Opioids, HIV/HCV and Host Cell Innate Immunity

描述（由申请人提供）：项目摘要。由于HIV和HCV具有共同的感染风险因素，因此在注射吸毒者（IDUs）中经常发现HIV和HCV的合并感染。这两种病原体也可能是造成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HCV感染的最大风险群体。然而，我们对直接阿片类药物-病毒（HIV和/或HCV）以及病毒-病毒（HIV-HCV）相互作用知之甚少，这是从根本上了解HIV/HCV合并感染的注射吸毒者中HCV疾病和HCV相关发病率的免疫发病机制的主要障碍。在体外解决这一关键问题的主要障碍是缺乏HCV感染性细胞模型系统。最近，三个独立的研究小组报告了一个强大的HCV感染系统在体外的发展。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。我们已经在实验室中从该细胞模型中产生了感染性HCV。本研究的目标是解决我们的总体假设，即阿片类药物之间的相互作用（例如，吗啡）、HIV和HCV是HCV/HCV感染结果的关键决定因素。我们将讨论以前未认识到的机制，吗啡和/或HIV/HCV损害宿主细胞的先天免疫，导致病毒感染和复制的持续性。具体而言，我们将研究吗啡和HIV蛋白（达特和gp 120）对HCV感染、细胞内先天免疫的影响，以及IFN-α/利巴韦林在人肝细胞中的抗HCV作用。我们将利用创新的人类肝细胞与枯否细胞的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。由于枯否细胞是肝脏的常驻巨噬细胞，并且是HIV感染的靶标，因此在本研究中纳入枯否细胞是非常重要的。本研究的数据对于更好地理解阿片类药物作为HIV/HCV感染免疫发病机制中的辅助因子至关重要。该提案的长期目标是为HIV/HCV感染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在不同细胞系统中相互作用的直接证据很少，这是从根本上了解HIV/HCV感染的注射吸毒者中HCV相关发病率和死亡率的主要障碍。这项研究不仅有助于我们对HIV/HCV宿主细胞先天免疫的基本了解，而且有助于设计和开发基于先天免疫的HIV/HCV感染阿片类药物滥用者的治疗和预防策略。

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.