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

描述(申请人提供)：乙肝病毒(乙肝病毒)是一种嗜肝的、包膜的、部分双链的DMA病毒，可导致急性和慢性肝炎，并进展为肝硬化和肝细胞癌(HCC)。尽管有一种有效的疫苗，但全世界有超过3.5亿人长期感染乙肝病毒，如果没有最佳的抗病毒治疗，可能会有患进行性肝病的风险。虽然病毒清除与强大和广泛的病毒特异性干扰素(+1型效应器T细胞反应)有关，但病毒血症持续存在于受损的病毒特异性效应器T细胞中，这些T细胞无法清除病毒血症，但仍可能有助于疾病的发病。根据已发表的文献和我们自己的初步数据，涉及包括乙肝病毒在内的慢性病毒感染的免疫调节(FoxP3+Tregs，IL-10)和共刺激(PD-1)途径，我们假设，乙肝病毒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，而调节性T细胞反应进一步由先天信号塑造。我们还提出，靶向抑制负免疫调节通路可能逆转抗病毒效应器功能障碍，并揭示延长病毒控制的潜在效应器能力。为此，我们将检查以下3个具体目标，以确定是否：1)乙肝病毒持续与不同的效应者和调节性T细胞反应，可以预测临床和治疗结果；2)在乙肝治疗期间抑制病毒将增强抗病毒效应者T细胞功能，减少抑制性免疫调节因子；3)调节性免疫反应与治疗性乙肝病毒抑制是由先天免疫反应定义的。这项拟议的研究将对乙肝病毒持续存在的免疫功能障碍的机制提供见解，确定潜在的早期免疫学标记物来预测治疗结果，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.