The Guts of HIV: Innate Immune Dysregulation as a Central Mechanism of Gastrointestinal and Liver Disease in HIV-1-infected Individuals

HIV 的本质：先天免疫失调是 HIV-1 感染者胃肠道和肝脏疾病的核心机制

• 批准号: 9755236
• 负责人: Zdenek Hel
• 金额: $ 32.5万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-24 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9755236
• 关键词: Acquired Immunodeficiency Syndrome; Adult; Anti-inflammatory; Apoptotic; Automobile Driving; Biopsy; Blood Circulation; Blood Platelets; CD4 Positive T Lymphocytes; Cells; Cessation of life; Chronic; Detection; Development; Diagnostic; Disease Progression; Enrollment; Epithelial; Equilibrium; Erythro; Exhibits; Expression Profiling; Fibrosis; Frequencies; Gastrointestinal Diseases; Gut associated lymphoid tissue; HIV; HIV-1; Hematopoietic stem cells; Hepatic Stellate Cell; Hepatitis; Hepatocyte; Immune; Individual; Infection; Inflammation; Inflammatory; Interleukin-10; Interleukin-17; Intestinal Mucosa; Intestinal permeability; Invaded; Kupffer Cells; Left; Liver; Liver Fibrosis; Liver diseases; Mediating; Monitor; Morbidity - disease rate; Mucous Membrane; Myelogenous; Neutrophil Activation; Neutrophilic Infiltrate; Pathogenesis; Pathogenicity; Pathologic; Pathologic Processes; Patients; Persons; Pharmacology; Phenotype; Play; Population; Portal Hypertension; Process; Production; Reporting; Resolution; Role; SIV; Sampling; Stem cells; Testing; Thrombosis; Tissues; Viral; Virus Diseases; Yolk Sac; antiretroviral therapy; biobank; chronic liver inflammation; cohort; disorder risk; extracellular; firewall; healing; immune activation; interleukin-22; macrophage; microbial; monocyte; mortality; neutrophil; nonalcoholic steatohepatitis; novel; outcome forecast; pathogenic microbe; pathogenic virus; predictive marker; progenitor; prognostic value; public health relevance; recruit; release factor; self-renewal; virology; Acquired Immunodeficiency Syndrome; Adult; Anti-inflammatory; Apoptotic; Automobile Driving; Biopsy; Blood Circulation; Blood Platelets; CD4 Positive T Lymphocytes; Cells; Cessation of life; Chronic; Detection; Development; Diagnostic; Disease Progression; Enrollment; Epithelial; Equilibrium; Erythro; Exhibits; Expression Profiling; Fibrosis; Frequencies; Gastrointestinal Diseases; Gut associated lymphoid tissue; HIV; HIV-1; Hematopoietic stem cells; Hepatic Stellate Cell; Hepatitis; Hepatocyte; Immune; Individual; Infection; Inflammation; Inflammatory; Interleukin-10; Interleukin-17; Intestinal Mucosa; Intestinal permeability; Invaded; Kupffer Cells; Left; Liver; Liver Fibrosis; Liver diseases; Mediating; Monitor; Morbidity - disease rate; Mucous Membrane; Myelogenous; Neutrophil Activation; Neutrophilic Infiltrate; Pathogenesis; Pathogenicity; Pathologic; Pathologic Processes; Patients; Persons; Pharmacology; Phenotype; Play; Population; Portal Hypertension; Process; Production; Reporting; Resolution; Role; SIV; Sampling; Stem cells; Testing; Thrombosis; Tissues; Viral; Virus Diseases; Yolk Sac; antiretroviral therapy; biobank; chronic liver inflammation; cohort; disorder risk; extracellular; firewall; healing; immune activation; interleukin-22; macrophage; microbial; monocyte; mortality; neutrophil; nonalcoholic steatohepatitis; novel; outcome forecast; pathogenic microbe; pathogenic virus; predictive marker; progenitor; prognostic value; public health relevance; recruit; release factor; self-renewal; virology

 DESCRIPTION (provided by applicant): Liver disease (LD) has risen as a major cause of morbidity and mortality in antiretroviral therapy (ART)-treated HIV-1-infected individuals. A growing body of evidence suggests that HIV-1 alters and accelerates the pathologic processes driving LD via systemic inflammation; however, the role of neutrophils and innate immune dysregulation in these processes has not been evaluated. This application proposes that innate immune dysregulation mediated by changes in macrophage and neutrophil populations in gut- associated lymphoid tissue (GALT) and liver plays a fundamental role in HIV-1 disease progression. Neutrophils, the most abundant immune cell population in the body, are specifically geared for a sensitive detection of invading microbial and viral pathogens. GALT epithelial damage in both HIV-1 and SIV infections is temporally and spatially associated with a significant accumulation of neutrophils that directly contribute to mucosal damage. IL-17 serves as a master regulator of neutrophil function and, in conjunction with IL-10, it is required for an induction of anti-inflammatory macrophages that clear apoptotic neutrophilic infiltrates via efferocytosis and promote healing and resolution of local and systemic inflammation. The first underlying hypothesis of this proposal is that the depletion of IL-17-producing cells in the GALT of HIV-1-infected individuals blocks the induction of anti-inflammatory efferocytic tissue macrophages and causes polarization towards pro-inflammatory phenotype. This results in an accumulation of activated neutrophils that undergo NETosis and drive tissue damage in intestinal mucosa. Factors released as a result of ongoing GALT inflammation induce systemic recruitment of a population of activated neutrophils with specific phenotype, expression profile, and high capacity for NETosis. The second principal hypothesis is that HIV-1 infection is associated with a significantly decreased frequency of Kupffer cells (KCs) exhibiting anti-inflammatory phenotype and a significant shift towards blood monocyte-derived proinflammatory KCs. This state is not reversed following ART, possibly due to the depletion of self-renewing tissue-resident KC progenitors. Activated neutrophils interact with Kupffer cells and platelet and undergo NETosis in liver microvasculature. In the course of HIV-1 infection, this mechanism causes chronic liver inflammation, portal hypertension, activation of hepatic stellate cells, and results in a progression to non-alcoholic steatohepatitis (NASH) and liver fibrosis. Thus, we propose that two simultaneous hits to innate immune populations in primary and secondary mucosal firewalls, the GALT and the liver, drive disease progression in HIV-1/AIDS. We propose to determine the effect of neutrophil activation and innate immune dysregulation in GALT and liver on the progression of LD in ART- treated HIV-1-infected individuals. Importantly, since functional dysregulation of neutrophil population and neutrophil-macrophage interaction can be pharmacologically targeted, understanding of the underlying pathogenic mechanisms will lead to novel treatment approaches in HIV-1 infection and other chronic inflammatory conditions.

 描述（应用程序提供）：肝病（LD）已成为抗逆转录病毒疗法（ART）处理的HIV-1感染的个体发病率和死亡率的主要原因。越来越多的证据表明，HIV-1通过全身性炎症改变了驱动LD的病理过程。但是，尚未评估中性粒细胞和先天免疫失调在这些过程中的作用。这项应用提出的提议是，与肠道相关淋巴组织（GALT）和肝脏中巨噬细胞和中性粒细胞种群变化介导的先天免疫调节和肝脏中嗜中性粒细胞群体介导的。中性粒细胞是人体中最丰富的免疫细胞细胞群，专门接地，以敏感地检测入侵的微生物和病毒病原体。 HIV-1和SIV感染中的Galt上皮损伤暂时且经常与直接导致粘膜损伤的大量中性粒细胞积累有关。 IL-17是嗜中性粒细胞功能的主要调节剂，与IL-10结合使用，需要诱导抗炎巨噬细胞，以通过肿瘤细胞增多症清除凋亡性嗜中性粒细胞性浸润，并促进部位的愈合和分辨率和精神炎症。该提议的第一个基本假设是，HIV-1感染个体的Galt中IL-17产生细胞的耗竭阻止了抗炎效率组织巨噬细胞的诱导，并导致极化对促炎的表型。这导致积累的嗜中性粒细胞的积累，这些嗜中性粒细胞经历肠病并驱动肠粘膜的组织损伤。由于持续的GALT炎症而释放的因素会导致具有特定表型，表达概况和高能力净化能力的激活中性粒细胞的全身募集。第二个主要假设是，HIV-1感染与表现出抗炎表型的库普弗细胞（KCS）的频率显着降低，并显着向血液单核细胞衍生的促炎性促炎性KCS显着转移。由于自我更新组织居民KC祖细胞的耗尽，这种状态并没有逆转，因此可能会逆转。活化的嗜中性粒细胞与kupffer细胞和血小板相互作用，并在肝微举行中经历肠病。在HIV-1感染过程中，这种机制会导致慢性肝感染，门静脉高压，肝星状细胞的激活，并导致非酒精性脂肪性肝炎（NASH）和肝纤维化的发展。因此，我们建议在原发性和继发性粘膜防火墙，galt和肝脏中的先天免疫吞吐量中进行两次简单命中，驱动HIV-1/AIDS中的疾病进展。我们建议确定GALT和肝脏对ART处理的HIV-1感染个体LD进展的中性粒细胞激活和先天免疫失调的影响。重要的是，由于可以在药理学方面靶向中性粒细胞种群和中性粒细胞巨噬细胞相互作用的功能失调，因此对潜在的致病机制的理解将导致HIV-1感染和其他慢性炎症状况的新型治疗方法。