HIV-Hepatitis C Virus Cooperative Interactions and Liver Disease Progression

描述(申请人提供)：由于共同的传播途径，丙型肝炎病毒与艾滋病毒的混合感染在美国非常频繁，特别是在注射吸毒者(IDU)中。随着HAART的成功，艾滋病毒感染者中的传统机会性感染已被病毒性肝炎，特别是丙型肝炎引起的终末期肝病取代，成为当今艾滋病毒感染者的第二大死因。与HIV阴性者相比，HIV感染者感染丙型肝炎病毒的最重要的临床特征是：(1)其持续率较高；(2)对以干扰素为基础的抗病毒治疗的应答率低； (3)肝纤维化进程加快。到目前为止，我们在破解艾滋病毒合并感染中丙型肝炎肝病加速进展的机制方面所做的努力已经产生了丰硕的见解，包括发现两种感染通过其对氧化应激产生的独立作用而对肝细胞产生转化生长因子-�1的趋同作用，以及描述了这两种病毒在促进肝细胞凋亡方面的协同作用。这些发现是从必然有限的(单一培养)模型系统中得出的，虽然它们代表了有意义的进步，但不能完全概括人类疾病。例如，众所周知，其他类型的细胞对肝纤维化的形成有重要贡献，特别是库普弗细胞。此外，HIV感染的一个中心紊乱是微生物移位增加，这可能对肝纤维化有重大贡献。因此，本方案的目标是(1)扩大我们的研究范围，首次在体内模型中评估丙型肝炎病毒和艾滋病病毒对纤维化进展的特定贡献；(2)评估微生物易位在纤维化形成中的作用；(3)评估抗逆转录病毒治疗对协同的丙型肝炎病毒-艾滋病病毒肝纤维化发病机制的影响。为了实现这些目标，我们将采用两个新的模型系统，包括(1)微流控共培养系统，它部署了肝细胞、巨噬细胞和肝星状细胞系，配备了一系列细胞报告器，使得能够动态分析围绕丙型肝炎病毒和/或艾滋病毒感染的事件；(2)新描述的人源化小鼠模型，它同时支持丙型肝炎病毒和艾滋病病毒感染，并重述肝纤维化。这些研究将有很高的可能性确定在合并感染中驱动所观察到的肝脏病理生理变化的关键过程。他们还将通过识别和优先考虑有助于发病的分子靶点，很有可能揭示新的治疗策略，以延缓观察到的合并感染中肝病的加速进展。拟议的研究将产生很大的影响，因为它们将极大地帮助我们努力开发有效的干预措施，以阻止或逆转丙型肝炎病毒-艾滋病毒混合感染者的肝病进展。

DESCRIPTION (provided by applicant): Because of their shared routes of transmission, HCV coinfection with HIV is remarkably frequent in the U.S., particularly among injection drug users (IDU). With the success of HAART, traditional opportunistic infections among HIV-infected persons have been replaced by end stage liver disease due to viral hepatitis, particularly HCV, as the second leading cause of death among HIV-infected persons today. The most important clinical features of HCV in HIV-infected persons compared to HIV-negative persons are (1) its higher rates of persistence; (2) low rates of response to interferon (IFN) based antiviral therapy; and (3) accelerated hepatic fibrosis progression. Our efforts to date to decipher the mechanistic underpinnings of accelerated HCV liver disease progression in HIV coinfection have yielded fruitful insights, including discovery of the convergent effects of both infections on profibrogeni cytokine (TGF-�1) production in hepatocytes through their independent effects on generation of oxidative stress, as well as description of the cooperative interactions between these two viruses in promoting hepatocyte apoptosis. These findings have been drawn from necessarily limited (monoculture) model systems, and, while they represent meaningful advances, cannot fully recapitulate human disease. For instance, it is known that other cell types contribute significantly to hepatic fibrogenesis, particularly the Kupffer cell. Moreover, a central derangement in HIV infection is increased microbial translocation, which may contribute significantly to hepatic fibrogenesis. Therefore, the goals of the current proposal are to (1) extend our studies to evaluate the specific contributions of HCV and HIV to fibrosis progression for the first time in in vivo models; (2) evaluate the contribution of microbial translocation to fibrogenesis; and (3) evaluate the effect of antiretroviral therapy on cooperative HCV-HIV fibropathogenesis. To accomplish these goals, we will employ two novel model systems, including (1) a microfluidic coculture systems that deploys hepatocyte, macrophage, and hepatic stellate cell lines that are equipped with an array of cellular reporters that permit dynamic analysis of the events surrounding HCV and/or HIV infection, and (2) a newly described humanized mouse model that supports both HCV and HIV infections and recapitulates hepatic fibrosis. These studies will have a very high likelihood of identifying key processes that drive th observed hepatic pathophysiologic changes in coinfection. They will also, by virtue of identifying and prioritizing molecular targets that contribute to pathogenesis, have a high likelihood of revealing new therapeutic strategies to retard the observed accelerated liver disease progression in coinfection. The proposed studies will be of high impact, since they will greatly aid our efforts to develop effective interventions to halt or reverse liver disease progression among HCV-HIV coinfected persons.