Mechanisms of Cellular Immune Dysfunction in Patients with Hepatitis C Virus and

描述（由申请人提供）： 丙型肝炎病毒（HCV）是一种血液传播的嗜肝RNA病毒，具有慢性感染的高倾向，可进展为肝硬化和肝癌。HCV持续存在是一个重要的健康问题，特别是在血清阳性率增加的美国退伍军人中。与T细胞在病毒感染中的作用一致，HCV持续存在功能障碍的病毒特异性效应T细胞应答，而HCV相关的肝病进展在HIV相关的CD 4 T细胞功能障碍的情况下加速。基于新出现的文献和我们自己的初步数据，我们假设HIV相关的免疫失调通过直接通过共刺激受体（例如PD-1、CTLA-4）或间接通过诱导免疫调节性T细胞和细胞因子的免疫抑制信号导致HCV特异性效应T细胞功能障碍增强。我们还提出，有针对性地抑制这些途径可以增强病毒特异性效应子功能。为此，以下3个具体目标将检查：1）在有和没有HIV合并感染的急性丙型肝炎患者中，HCV特异性T细胞效应器功能丧失的慢性演变与抑制性共刺激受体表达和调节性T细胞频率增加相关; 2）与具有临床后果的HCV单感染患者相比，HIV/HCV合并感染患者的免疫抑制途径加重; 3）HIV/HCV感染患者中HCV特异性效应T细胞功能障碍可以通过阻断负性共刺激和调节途径来逆转。这些研究将为HCV感染合并HIV感染患者T细胞功能障碍的免疫学机制提供新的见解，并具有潜在的治疗意义。对退伍军人医疗保健的潜在影响丙型肝炎病毒在美国退伍军人中非常普遍，导致慢性丙型肝炎、进行性肝硬化和肝癌发展导致的显著发病率和死亡率。HIV合并感染可显著增加HCV感染者的发病率和死亡率。拟议的研究（使用来自退伍军人和非退伍军人受试者的样本）将提供对T细胞功能障碍的潜在机制以及HIV相关免疫功能障碍在HCV发病机制中的影响的见解，这些免疫功能障碍与可以使HCV感染的退伍军人受益的免疫发展相关。

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) is a blood-borne, hepatotropic RNA virus with a high propensity for chronic infection that can progress to cirrhosis and liver cancer. HCV persistence is a significant health problem particularly among U.S. veterans with increased seroprevalence. Consistent with a role for T cells in the viral infections, HCV persists with a dysfunctional virus-specific effector T cell response while HCV-associated liver disease progression is accelerated in the setting of HIV-associated CD4 T cell dysfunction. Based on emerging literature and our own preliminary data, we hypothesize that HIV-associated immune dysregulation results in heightened HCV- specific effector T cell dysfunction through immune inhibitory signals either directly through the costimulatory receptors (e.g. PD-1, CTLA-4) or indirectly by the induction of immune regulatory T cells and cytokines. We also propose that targeted inhibition of these pathways can enhance virus-specific effector function. To this end, the following 3 specific aims will examine if: 1) Chronic evolution with the loss of HCV-specific T cell effector function correlates with increased inhibitory costimulatory receptor expression and regulatory T cell frequency in patients with acute hepatitis C with and without HIV coinfection; 2) Immune inhibitory pathways are accentuated in HIV/HCV coinfected patients compared to HCV monoinfected patients with clinical consequence; 3) HCV-specific effector T cell dysfunction in HIV/HCV-infected patients can be reversed by blocking negative costimulatory and regulatory pathways. The proposed studies will provide insights to underlying immunological mechanisms of T cell dysfunction in HCV-infected patients with HIV coinfection, with potential therapeutic implications. Potential Impact on Veterans Health Care HCV is highly prevalent among U.S. veterans, contributing to significant morbidity and mortality due to chronic hepatitis C, progressive liver cirrhosis and liver cancer development. HIV coinfection markedly increases the morbidity and mortality in HCV-infected patients. The proposed studies (using samples from both veteran and non-veteran subjects) will provide insights to underlying mechanisms of T cell dysfunction and the impact of HIV-associated immune dysfunction in HCV pathogenesis, relevant for immunotherapeutic development that can benefit HCV-infected veterans.