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

丙型肝炎病毒和病毒感染患者细胞免疫功能障碍的机制

• 批准号: 8397545
• 负责人: Kyong-Mi Chang
• 金额: --
• 依托单位: PHILADELPHIA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8397545
• 关键词: Acute Hepatitis C; Blood; CD4 Positive T Lymphocytes; CTLA4 gene; Cessation of life; Chronic; Chronic Hepatitis C; Cirrhosis; Clinical; Cytotoxic T-Lymphocyte-Associated Protein 4; Data; Dendritic Cells; Development; Disease Progression; Evolution; Frequencies; Functional disorder; General Population; HIV; Health; Healthcare; Hepatitis C; Hepatitis C virus; Immune; Immune System Diseases; Immunotherapeutic agent; Infection; Interleukin-10; Ligands; Literature; Liver Cirrhosis; Liver diseases; Malignant neoplasm of liver; Monitor; Morbidity - disease rate; Outcome; Pathway interactions; Patients; Peripheral; RNA Viruses; Regulation; Regulatory Pathway; Regulatory T-Lymphocyte; Relative (related person); Role; Sampling; Seroprevalences; Signal Transduction; T cell response; T-Lymphocyte; Therapeutic; Transforming Growth Factor beta; Veterans; Virus; Virus Diseases; base; cytokine; insight; mortality; programs; public health relevance; receptor; receptor expression; response; virus pathogenesis

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.

描述（由申请人提供）： 丙型肝炎病毒 (HCV) 是一种血源性亲肝 RNA 病毒，极易发生慢性感染，可发展为肝硬化和肝癌。 HCV 持续存在是一个严重的健康问题，尤其是在血清流行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 持续存在功能失调的病毒特异性效应 T 细胞反应，而在 HIV 相关 CD4 T 细胞功能障碍的情况下，HCV 相关肝病进展会加速。根据新兴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（例如 PD-1、CTLA-4）或通过诱导免疫调节 T 细胞和细胞因子间接导致 HCV 特异性效应 T 细胞功能障碍加剧。我们还提出，靶向抑制这些途径可以增强病毒特异性效应子功能。为此，将检查以下 3 个具体目标是否： 1) 在伴或不伴 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 细胞频率的增加相关； 2) 与 HCV 单一感染患者相比，HIV/HCV 双重感染患者的免疫抑制途径更为明显，并产生临床后果； 3) HIV/HCV感染患者的HCV特异性效应T细胞功能障碍可以通过阻断负向共刺激和调节途径来逆转。拟议的研究将为 HCV 感染者与 HIV 合并感染患者 T 细胞功能障碍的潜在免疫学机制提供见解，并具有潜在的治疗意义。对退伍军人医疗保健的潜在影响 HCV 在美国退伍军人中非常流行，导致慢性丙型肝炎、进行性肝硬化和肝癌发展导致显着的发病率和死亡率。 HIV 合并感染显着增加 HCV 感染患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）将深入了解 T 细胞功能障碍的潜在机制以及 HIV 相关免疫功能障碍对 HCV 发病机制的影响，这与免疫治疗的开发相关，可以使 HCV 感染的退伍军人受益。