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HIV感染的一个公认特征，它可能导致HIV疾病进展以及越来越重要的非经典HIV并发症，如心血管疾病（CVD）。该提案将a)确定慢性治疗HIV感染背景下先天免疫与CVD之间的联系机制；b)开发单核细胞/巨噬细胞相关炎症和凝血的新型血清生物标志物，可能对hiv感染者的心血管疾病风险进行分层；c)利用rna的全局测序（RNA-Seq），通过研究来自HIV+和HIV-患者群体的CD14++和CD14+CD16+单核细胞亚群，来定义HIV和cvd相关的特定信号通路的功能增益和/或丧失。广泛表征艾滋病毒感染和未感染的入组者从WIHS和MACS NIH队列带来承担这个跨学科，多地点的调查。因此，该项目将为观察到的HIV感染和相关合并症（如HCV合并感染）与CVD风险之间的联系提供见解，确定先天免疫系统是一种新的、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，以及干预单核细胞/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.