HIV Antiretroviral Therapy and Hepatic Injury

 说明(申请人提供)：肝脏疾病的原因很复杂，包括慢性病毒性肝炎(乙型、丙型、丁型)、酒精、与药物有关的肝毒性和代谢紊乱。然而，纤维化导致的肝硬变和终末期肝病是肝损伤的常见途径。纤维化进展的速度是高度可变的，反映了宿主对疾病反应的差异。一种名为CCR5的趋化因子受体可能在调节肝纤维化中发挥核心作用，这将是本研究的主要探索主题。我们将在美国国立卫生研究院多中心血友病队列研究(MHC)中对一大批特征良好的血友病患者进行长达18年的跟踪调查，以检验CCR5缺失突变(CCR5-∆32)的影响。此外，我们还将利用一项对使用独特的CCR5/CCR2抑制剂Cenicriviroc治疗的HIV感染患者进行研究的样本。在特定的目标1中，我们将描述CCR5在体内肝纤维化形成中的作用，重点是内源性(基因多态性)和外源性(CVC)相关的CCR5阻断。具体目标2将使用淋巴细胞和肝组织来研究与CCR5突变或阻断有关的可能影响纤维化发展的免疫调节机制。特异靶3将利用体内方法来表征CCR5拮抗对丙型肝炎病毒和免疫环境的影响。利用RNAseq和其他实验方法，我们将确定参与调控丙型肝炎病毒复制和肝纤维化的途径(S)。我们假设CCR5编码基因的宿主突变或药物阻断可以减轻肝纤维化，并试图阐明其发生的机制(S)。这项研究可能为预防HIV感染者的肝纤维化提供新的范例。

 DESCRIPTION (provided by applicant): The causes of liver disease are complex and include chronic viral hepatitis (B,C,D), alcohol, drug-associated hepatotoxicities and metabolic disorders. However, fibrosis leading to cirrhosis and end-stage liver disease is the common pathway for hepatic injury. Rates of fibrotic progression are highly variable, and reflect differences in host response to disease. One host factor, a chemokine receptor named CCR5 may play a central role in modulating hepatic fibrosis, and will be the primary subject of exploration in this study. We will examine the effects of CCR5 deletion mutations (CCR5- ∆32) in a large and well- characterized cohort of patients with hemophilia who were followed for up to 18 years in the NIH Multicenter Hemophilia Cohort Studies (MHCS). In addition we will utilize samples derived from a study of HIV-infected patients treated with a unique CCR5/CCR2 inhibitor, Cenicriviroc. In Specific Aim 1 we will characterize the effect of CCR5 on in vivo hepatic fibrogenesis, focusing on both intrinsic (gene polymorphism) and extrinsic (CVC) associated CCR5 blockade. Specific Aim 2 will examine the immune regulatory mechanisms which may affect fibrosis development in relation to CCR5 mutation or blockade using both lymphocytes and liver tissue. Specific Aim 3 will utilize in vivo methods to characterize the effec of CCR5 antagonism on HCV and the immune environment. Using RNAseq and other experimental methods we will determine the pathway(s) involved with modulation of HCV replication and hepatic fibrogenesis. We hypothesize that either host mutation in CCR5 coding genes or pharmacologic blockade will reduce hepatic fibrosis and will attempt to elucidate the mechanism(s) by which this occurs. This study may generate new paradigms for prevention of hepatic fibrosis in those with HIV infection.