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(丙型肝炎病毒)是一种血液传播的嗜肝RNA病毒，具有高度的慢性感染倾向，可发展为肝硬化和肝癌。丙型肝炎持续存在是一个重大的健康问题，特别是在血清阳性率上升的美国退伍军人中。与T细胞在病毒感染中的作用一致，丙型肝炎病毒持续存在功能障碍的病毒特异性效应T细胞反应，而在HIV相关的CD4T细胞功能障碍的背景下，丙型肝炎病毒相关的肝病进展加速。根据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免疫抑制信号直接通过共刺激受体(如PD-1、CTLA-4)或间接通过诱导免疫调节T细胞和细胞因子而导致丙型肝炎病毒特异性效应器T细胞功能障碍。我们还提出，靶向抑制这些途径可以增强病毒特异性效应器的功能。为此，以下3个特定目标将检验是否：1)慢性演变与丙型肝炎病毒特异性T细胞效应器功能丧失相关，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)与单一感染丙型肝炎病毒的患者相比，HIV/丙型肝炎病毒混合感染患者的免疫抑制通路明显增强；3)艾滋病毒/丙型肝炎病毒感染者的丙型肝炎病毒特异性效应器T细胞功能障碍可以通过阻断负的共刺激和调节通路来逆转。这项拟议的研究将为丙型肝炎病毒感染合并艾滋病毒感染患者T细胞功能障碍的潜在免疫学机制提供见解，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、进行性肝硬变和肝癌的显著发病率和死亡率。HIV合并感染显著增加了丙型肝炎病毒感染者的发病率和死亡率。拟议的研究(使用退伍军人和非退伍军人受试者的样本)将为T细胞功能障碍的潜在机制以及艾滋病毒相关免疫功能障碍在丙型肝炎发病中的影响提供洞察力，这与免疫治疗开发相关，从而使丙型肝炎病毒感染的老兵受益。 公共卫生相关性： 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、进行性肝硬变和肝癌的显著发病率和死亡率。HIV合并感染显著增加了丙型肝炎病毒感染者的发病率和死亡率。拟议的研究(使用退伍军人和非退伍军人受试者的样本)将为T细胞功能障碍的潜在机制以及艾滋病毒相关免疫功能障碍在丙型肝炎发病中的影响提供洞察力，这与免疫治疗开发相关，从而使丙型肝炎病毒感染的老兵受益。

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. PUBLIC HEALTH RELEVANCE: 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.