Role of innate immunity in HIV related vascular disease: biomarkers & mechanisms

描述(由申请人提供)：先天免疫系统激活是慢性艾滋病毒感染的公认特征，可能会导致艾滋病毒疾病的进展，以及越来越重要的非典型艾滋病毒并发症，如心血管疾病(CVD)。这项建议将a)在慢性、经治疗的艾滋病毒感染的背景下确定先天免疫与心血管疾病之间的联系；b)为单核/巨噬细胞相关的炎症和凝血开发新的血清生物标记物，可以对艾滋病毒感染人群中的心血管疾病风险进行分层；c)通过研究具有良好特征的HIV+和HIV患者群体的CD14++和CD14+CD16+单核细胞亚群，使用RNA全球测序(RNA-Seq)来确定与艾滋病毒和心血管疾病相关的特定信号通路的功能的获得和/或丧失。来自WIHS和MACS NIH队列的具有广泛特征的艾滋病毒感染和未感染艾滋病毒的参与者将在这项跨学科、多地点的调查中发挥作用。因此，该项目将提供对观察到的艾滋病毒感染和相关共病(例如，丙型肝炎病毒合并感染)与心血管疾病风险的联系的洞察，将先天性免疫系统确定为一种新的和可修改的解释途径。考虑到改善心血管疾病风险分层的需要，以及干预单核/巨噬细胞活性介导的机制的可行性，这具有很高的临床相关性。

DESCRIPTION (provided by applicant): Innate immune system activation is a recognized feature of chronic HIV infection that may contribute to HIV disease progression as well increasingly important non-classic HIV complications such as cardiovascular disease (CVD). This proposal will a) identify mechanisms linking innate immunity with CVD in the setting of chronic, treated HIV infection; b) develop novel serum biomarkers for monocyte/macrophage related inflammation and coagulation that may stratify CVD risk in the HIV-infected population; c) use global sequencing of RNAs (RNA-Seq) to define HIV- and CVD-associated gain and/or loss of function of specific signaling pathways by studying CD14++ and CD14+CD16+ monocyte subsets from well-characterized HIV+ and HIV- patient groups. Extensively characterized HIV infected and HIV uninfected enrollees from the WIHS and MACS NIH cohorts are brought to bear in this interdisciplinary, multi-site investigation. This project will thereby provide insight into the observed links of HIV infection and related comorbidities (e.g., HCV coinfection) with CVD risk, identifying the innate immune system as a novel and modifiable explanatory pathway. This is of high clinical relevance given the need for improved CVD risk stratification, as well as the feasibility of intervening on mechanisms mediated by monocyte/macrophage activity.