HIV and hepatic inflammation and fibrosis

 描述(由申请人提供)：由于艾滋病毒的稳定发病率(2006年估计为53,600例/年)和有效的抗逆转录病毒疗法延长了预期寿命，美国的艾滋病毒流行率正在上升(7)。随着艾滋病毒患者在有效抗逆转录病毒治疗的环境中继续活得更长，活体疾病已成为非艾滋病相关死亡的主要原因(1)。由于传播途径相同，尽管酒精和脂肪肝等其他慢性肝病也在出现，但在艾滋病毒感染的患者中，丙型肝炎和乙肝病毒很常见。流行病学数据表明，艾滋病毒会加速各种肝病造成的肝纤维化。HIV/丙型肝炎病毒混合感染的患者发展为肝硬变的平均时间比单一感染丙型肝炎病毒的患者(11，12)早约12年。在艾滋病毒/乙肝病毒混合感染的情况下，艾滋病毒/乙肝病毒混合感染的患者死于肝病的可能性是单独感染艾滋病毒的患者的8倍以上，死于肝病的可能性是单一感染乙肝病毒的患者的19倍(14)。在HIV单一感染的患者中，NASH正在成为肝脏疾病的一个原因。鉴于捐献器官的短缺、移植的经济负担以及患有潜在肝病的HIV+患者的老龄化队列，迫切需要为这一群体开发抗纤溶药物。这项应用侧重于了解HIV如何与肝脏中的两个关键细胞相互作用，这两个细胞在肝脏炎症和纤维化中发挥重要作用：1)激活的肝星状细胞和2)肝巨噬细胞(Kupffer细胞)。我们还将检查库普弗细胞是否是正在接受抗逆转录病毒治疗的患者中艾滋病毒的储存库。由此得出的结论 应用将为HIV+患者带来创新的抗纤维化方法，可能防止 这将促进我们对艾滋病毒贮存库的了解，这对于找到艾滋病毒的治疗方法至关重要。

 DESCRIPTION (provided by applicant): HIV prevalence in the US is increasing due to a combination of the stable incidence of HIV (estimate at 53,600/cases year in 2006) and the longer life expectancy due to effective antiretroiral therapies (7). As HIV patients continue to live longer in the setting of effective ART, live disease has become the leading cause of non­AIDS related mortality (1). Because of shared routes of transmission, HCV and HBV are common in HIV­infected patients though other chronic liver diseases such as alcohol and fatty liver disease are also emerging.Epidemiologic data suggests that HIV accelerates liver fibrosis from a variety of liver diseases. Median time to cirrhosis in HIV/HCV coinfected patients is approximately 12 years sooner than HCV monoinfected patients(11,12). In the case of HIV/HBV coinfection, HIV/HBV coinfected patients are more than 8X likely to die from liver disease than those infected with HIV alone and 19X more likely to die from liver disease than HBV monoinfected individuals (14). In HIV monoinfected \ patients, NASH is emerging as a cause of liver disease. Given the shortage of donor organ, the economic burden of transplant (15), and the aging cohort of HIV + patients with underlying liver disease, there is an urgent need for the development of anti­fibotic treatments for this population. This application focuses on understanding how HIV interacts with 2 key cells in the liver which play an important in liver inflammation and fibrosis: 1) the activate hepatic stellate cell and 2) the liver macrophages (Kupffer cells). We will also examine if Kupffer cells are a reservoir for HIV in patients who are on anti­retroviral therapies. Findings from this application will lead to innovative antifibrotic approaches for HIV + patients that may prevent the need for transplant and will advance our understanding of HIV reservoirs which is critical to finding a cure for HIV.