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: 7796265
• 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 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7796265
• 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. 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.

描述（由申请人提供）： 丙型肝炎病毒（HCV）是一种血源性的肝RNA病毒，具有慢性感染倾向，可以发展为肝硬化和肝癌。 HCV持久性是一个重大的健康问题，尤其是在血清阳性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持续具有功能障碍的病毒特异性效应T细胞反应，而HCV相关的肝脏疾病进展在与HIV相关的CD4 T细胞功能障碍的情况下加速了。基于新兴文献和我们自己的初步数据，我们假设与HIV相关的免疫失调导致通过免疫抑制性信号直接通过结肠仿真受体（例如PD-1，CTLA-4）（例如PD-1，CTLA-4）（例如，通过Indirectionally difcultion thintotility thintotility thintoce thintoce thincultility thintoce to induction to intuction contuction contuction contuction contuction to to hcv-特异性效应T细胞功能障碍提高。我们还建议针对这些途径的靶向抑制可以增强病毒特异性效应子功能。为此，以下三个特定目标将检查以下三个特定目标：1）与HCV特异性T细胞效应功能丧失的慢性进化与抑制性刺激受体表达和调节性T细胞频率的增加相关。 2）与具有临床后果的HCV单感染患者相比，HIV/HCV共感染患者的免疫抑制途径突出了； 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阴性的共刺激和调节途径来逆转。拟议的研究将为HCV感染的HIV共感染患者的T细胞功能障碍的潜在免疫机制提供见解，具有潜在的治疗意义。在美国退伍军人中，对退伍军人卫生保健HCV的潜在影响非常普遍，这导致由于慢性丙型肝炎，进行性肝性肝硬化和肝癌发展而导致的显着发病和死亡率。 HIV共感染显着增加了HCV感染患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）将为T细胞功能障碍的潜在机制提供见解，以及HIV相关的免疫功能障碍在HCV发病机理中的影响，与免疫治疗性发育有关，可以使HCV感染的Veterans受益。 公共卫生相关性： 在美国退伍军人中，对退伍军人卫生保健HCV的潜在影响非常普遍，这导致由于慢性丙型肝炎，进行性肝性肝硬化和肝癌发展而导致的显着发病和死亡率。 HIV共感染明显增加了HCV感染患者的发病率和死亡率。拟议的研究（使用老兵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提供见解，以及与HIV相关的免疫功能障碍在HCV发病机理中的影响，与免疫治疗性发育有关，可以使HCV感染的Veterans受益。