HIV-Hepatitis C Virus Cooperative Interactions and Liver Disease Progression

描述（由申请人提供）：由于其共同的传播途径，HCV与HIV合并感染在美国非常频繁，特别是在注射吸毒者（IDU）中。随着高效抗逆转录病毒疗法的成功，艾滋病毒感染者中传统的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所取代，成为当今艾滋病毒感染者死亡的第二大原因。与hiv阴性者相比，hiv感染者的HCV最重要的临床特征是：(1)其较高的持续性；(2)以干扰素（IFN）为基础的抗病毒治疗应答率低；

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 With the success of HAART, traditional opportunistic infections among HIV-infected persons have been replaced by end stage liver disease due to viral hepatitis, particularly HCV, as the second leading cause of death among HIV-infected persons today.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.