HIV Antiretroviral Therapy and Hepatic Injury

 描述（由申请方提供）：肝病的病因复杂，包括慢性病毒性肝炎（B、C、D）、酒精、药物相关肝毒性和代谢紊乱。然而，肝纤维化导致肝硬化和终末期肝病是肝损伤的常见途径。纤维化进展的速率是高度可变的，并且反映了宿主对疾病的反应的差异。趋化因子受体CCR 5可能在肝纤维化的调控中发挥重要作用，是本研究的主要探索对象。我们将在NIH多中心血友病队列研究（MHCS）中随访长达18年的血友病患者的大型和良好表征队列中检查CCR 5缺失突变（CCR 5-CCR 32）的影响。此外，我们将利用来自一项用独特的CCR 5/CCR 2抑制剂赛尼克韦罗治疗的HIV感染患者研究的样本。在具体目标1中，我们将描述CCR 5对体内肝纤维化发生的影响，重点关注内在（基因多态性）和外在（CVC）相关的CCR 5阻断。具体目标2将使用淋巴细胞和肝组织检查可能影响与CCR 5突变或阻断相关的纤维化发展的免疫调节机制。具体目标3将利用体内方法来表征CCR 5拮抗作用对HCV和免疫环境的影响。使用RNAseq和其他实验方法，我们将确定参与HCV复制和肝纤维化发生调节的途径。我们假设宿主CCR 5编码基因突变或药物阻断将减少肝纤维化，并试图阐明其发生的机制。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.