HIV-Hepatitis C Virus Cooperative Interactions and Liver Disease Progression

HIV-丙型肝炎病毒协同相互作用与肝病进展

基本信息

  • 批准号:
    9143742
  • 负责人:
  • 金额:
    $ 58.93万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-09-01 至 2018-08-31
  • 项目状态:
    已结题

项目摘要

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 With the success of HAART, traditional opportunistic infections among HIV-infected persons have been replaced by end stage liver disease due to viral hepatitis, particularly HCV, as the second leading cause of death among HIV-infected persons today.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.
描述(由申请人提供):由于它们共有的传播途径,HCV与HIV合并感染在美国非常频繁,特别是在注射毒品使用者中。随着HAART的成功,HIV感染者中传统的机会性感染已被病毒性肝炎(特别是HCV)引起的终末期肝病所取代,成为当今HIV感染者死亡的第二大原因。与HIV阴性者相比,HIV感染者中HCV最重要的临床特征是:(1)其高持续率;(2)对基于干扰素(IFN)的抗病毒治疗的应答率低; (3)加速肝纤维化进程。迄今为止,我们努力破译HIV合并感染中加速HCV肝病进展的机制基础,取得了丰硕的成果,包括发现两种感染对肝细胞中促纤维化细胞因子(TGF-β 1)产生的会聚效应,通过其对氧化应激产生的独立影响,以及描述这两种病毒在促进肝细胞凋亡方面的合作相互作用。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,但无法完全概括人类疾病。例如,已知其他细胞类型对肝纤维化有显着贡献,特别是库普弗细胞。此外,HIV感染的一个中心紊乱是微生物易位增加,这可能显著促进肝纤维化。因此,目前的建议的目标是(1)扩展我们的研究,以评估具体的贡献,HCV和HIV的纤维化进展的第一次在体内模型;(2)评估的贡献,微生物易位的纤维化;(3)评估抗逆转录病毒治疗对合作的HCV-HIV纤维发病机制。为了实现这些目标,我们将采用两种新的模型系统,包括(1)微流控共培养系统,部署肝细胞,巨噬细胞和肝星状细胞系,配备了一系列的细胞报告,允许动态分析的事件周围的HCV和/或HIV感染,和(2)一个新描述的人源化小鼠模型,支持HCV和HIV感染和重演肝纤维化。这些研究将有很高的可能性,以确定关键过程,驱动观察到的肝脏病理生理变化的合并感染。他们还将通过识别和优先考虑有助于发病机制的分子靶点,很有可能揭示新的治疗策略,以延缓合并感染中观察到的加速肝脏疾病进展。拟议的研究将具有很高的影响力,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HCV-HIV合并感染者的肝脏疾病进展。

项目成果

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RAYMOND T CHUNG其他文献

RAYMOND T CHUNG的其他文献

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{{ truncateString('RAYMOND T CHUNG', 18)}}的其他基金

YAP signaling in the pathogenesis of NAFLD in people living with HIV
HIV 感染者 NAFLD 发病机制中的 YAP 信号传导
  • 批准号:
    10809266
  • 财政年份:
    2023
  • 资助金额:
    $ 58.93万
  • 项目类别:
Therapeutic modulation of a proteomic HCC risk signature with statins in patients with liver cirrhosis
他汀类药物对肝硬化患者蛋白质组 HCC 风险特征的治疗调节
  • 批准号:
    10853142
  • 财政年份:
    2023
  • 资助金额:
    $ 58.93万
  • 项目类别:
Trial of Statins for Chemoprevention in Hepatocellular Carcinoma
他汀类药物用于肝细胞癌化学预防的试验
  • 批准号:
    10297899
  • 财政年份:
    2021
  • 资助金额:
    $ 58.93万
  • 项目类别:
Trial of Statins for Chemoprevention in Hepatocellular Carcinoma
他汀类药物用于肝细胞癌化学预防的试验
  • 批准号:
    10478274
  • 财政年份:
    2021
  • 资助金额:
    $ 58.93万
  • 项目类别:
Immunologic correlates of functional cure of HBV with immune checkpoint blockade
乙型肝炎功能性治愈与免疫检查点阻断的免疫学相关性
  • 批准号:
    10170260
  • 财政年份:
    2020
  • 资助金额:
    $ 58.93万
  • 项目类别:
Immunologic correlates of functional cure of HBV with immune checkpoint blockade
乙型肝炎功能性治愈与免疫检查点阻断的免疫学相关性
  • 批准号:
    10388224
  • 财政年份:
    2020
  • 资助金额:
    $ 58.93万
  • 项目类别:
Cooperative mechanisms of HIV-enhanced liver fibrogenesis in HBV Coinfection
HBV 合并感染中 HIV 增强肝纤维化的协同机制
  • 批准号:
    10217038
  • 财政年份:
    2020
  • 资助金额:
    $ 58.93万
  • 项目类别:
Immunologic correlates of functional cure of HBV with immune checkpoint blockade
乙型肝炎功能性治愈与免疫检查点阻断的免疫学相关性
  • 批准号:
    10624243
  • 财政年份:
    2020
  • 资助金额:
    $ 58.93万
  • 项目类别:
Cooperative mechanisms of HIV-enhanced liver fibrogenesis in HBV Coinfection
HBV 合并感染中 HIV 增强肝纤维化的协同机制
  • 批准号:
    10082973
  • 财政年份:
    2020
  • 资助金额:
    $ 58.93万
  • 项目类别:
Cooperative mechanisms of HIV-enhanced liver fibrogenesis in HBV Coinfection
HBV 合并感染中 HIV 增强肝纤维化的协同机制
  • 批准号:
    10426106
  • 财政年份:
    2020
  • 资助金额:
    $ 58.93万
  • 项目类别:

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