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

 描述（由申请人提供）：肝脏疾病（LD）已上升为抗逆转录病毒治疗（ART）治疗的HIV-1感染者发病率和死亡率的主要原因。越来越多的证据表明，HIV-1通过全身炎症改变并加速了驱动LD的病理过程;然而，中性粒细胞和先天免疫失调在这些过程中的作用尚未得到评估。本申请提出，由肠相关淋巴组织（GALT）和肝脏中的巨噬细胞和嗜中性粒细胞群体的变化介导的先天免疫失调在HIV-1疾病进展中起重要作用。中性粒细胞是体内最丰富的免疫细胞群，专门用于对入侵的微生物和病毒病原体进行灵敏检测。HIV-1和SIV感染中的GALT上皮损伤在时间和空间上与直接导致粘膜损伤的嗜中性粒细胞的显著积累相关。IL-17作为嗜中性粒细胞功能的主要调节剂，并且与IL-10结合，它是诱导抗炎巨噬细胞所必需的，所述抗炎巨噬细胞通过细胞增殖清除凋亡的嗜中性粒细胞浸润并促进局部和全身炎症的愈合和消退。该提议的第一个基本假设是，HIV-1感染个体的GALT中产生IL-17的细胞的耗竭阻断了抗炎巨噬细胞组织巨噬细胞的诱导，并导致向促炎表型的极化。这导致活化的中性粒细胞的积累，其经历NETosis并驱动肠粘膜中的组织损伤。由于持续的GALT炎症而释放的因子诱导具有特定表型、表达谱和高NETosis能力的活化中性粒细胞群体的全身募集。第二个主要假设是，HIV-1感染与库普弗细胞（KCs）表现出抗炎表型的频率显著降低和向血液单核细胞源性促炎KCs的显著转变相关。这种状态在ART后不会逆转，可能是由于自我更新的组织驻留KC祖细胞的耗尽。活化的中性粒细胞与枯否细胞和血小板相互作用，并在肝脏微血管中发生NETosis。在HIV-1感染过程中，该机制导致慢性肝脏炎症、门静脉高压、肝星状细胞活化，并导致进展为非酒精性脂肪性肝炎（NASH）和肝纤维化。因此，我们提出，两个同时击中先天免疫群体的原发性和继发性粘膜防火墙，GALT和肝脏，驱动疾病进展的HIV-1/艾滋病。我们建议确定中性粒细胞活化和GALT和肝脏先天免疫失调对ART治疗的HIV-1感染者LD进展的影响。重要的是，由于中性粒细胞群体的功能失调和嗜中性粒细胞-巨噬细胞相互作用可以被靶向，因此对潜在致病机制的理解将导致HIV-1感染和其他慢性炎症性疾病的新治疗方法。

 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.