Immune regulation and co-stimulation in treatment outcome of chronic hepatitis B

描述（由申请人提供）：乙型肝炎病毒（HBV）是一种嗜肝、包膜、部分双链DMA病毒，可引起急性和慢性肝炎，并进展为肝硬化和肝细胞癌（HCC）。尽管有有效的疫苗，全世界仍有超过3.5亿人慢性感染乙肝病毒，如果没有最佳的抗病毒治疗，他们可能面临进展性肝病的风险。虽然HBV清除与强大和广泛的病毒特异性IFN(+ 1型效应T细胞反应相关，但病毒血症持续存在，病毒特异性效应T细胞受损，不能清除病毒血症，但仍可能有助于疾病发病机制。基于已发表的文献和我们自己的初步数据，涉及慢性病毒感染（包括HBV）的免疫调节（FoxP3+ Tregs, IL-10）和共刺激（PD-1）途径，我们假设HBV感染和治疗的结果是由抗病毒效应和调节性t细胞反应之间的平衡决定的，这些反应进一步受到先天信号的影响。我们还提出，有针对性地抑制负免疫调节途径可能逆转抗病毒效应物功能障碍，并揭示潜在的效应物长期控制病毒的能力。为此，我们将研究以下3个具体目标，以确定：1)HBV是否持续存在不同的效应和调节性t细胞反应，可以预测临床和治疗结果；2) HBV治疗过程中的病毒抑制会增强抗病毒效应t细胞功能，降低抑制性免疫调节因子；3)治疗性HBV抑制对适应性免疫反应的调节是由先天免疫反应定义的。拟议的研究将为HBV持续存在的免疫功能障碍机制提供见解，确定潜在的早期免疫标志物以预测治疗结果，并确定未来基于免疫的策略以提高长期治疗结果。

DESCRIPTION (provided by applicant): Hepatitis B virus (HBV) is a hepatotropic, enveloped, partially double-stranded DMA virus that causes acute and chronic hepatitis with progression to cirrhosis and hepatocellular carcinoma (HCC). Despite an effective vaccine, over 350 million people throughout the world are chronically infected with HBV and may be at risk for progressive liver disease without optimal antiviral therapy. While HBV clearance is associated with robust and broad virus-specific IFN(+ type 1 effector T cell responses, viremia persists with impaired virus-specific effector T cells that cannot clear viremia but may nonetheless contribute to disease pathogenesis. Based on published literature and our own preliminary data implicating immune regulatory (FoxP3+ Tregs, IL-10) and costimulatory (PD-1) pathways in chronic viral infections including HBV, we hypothesize that the outcome of HBV infection and therapy is defined by the balance between antiviral effector and regulatory T-cell responses that are further shaped by innate signals. We also propose that targeted inhibition of negative immune regulatory pathways may reverse the antiviral effector dysfunction and unmask the underlying effector capacity for prolonged virus control. To this end, we will examine the following 3 specific aims to determine if: 1) HBV persists with distinct effector and regulatory T-cell responses that can predict clinical and therapeutic outcomes; 2) Virus suppression during HBV therapy will enhance antiviral effector T-cell function and reduce inhibitory immune regulatory factors; 3) Modulation in adaptive immune responses with therapeutic HBV suppression is defined by innate immune response. The proposed studies will provide insights to the mechanisms of immune dysfunction in HBV persistence, define potential early immunological markers to prognosticate therapeutic outcome and to define future immune-based strategies to enhance long term therapeutic outcome.