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感染的公认特征，可能导致HIV疾病进展以及日益重要的非经典HIV并发症，如心血管疾病（CVD）。该提案将a）鉴定在慢性治疗的HIV感染的情况下将先天免疫与CVD联系起来的机制; B）开发单核细胞/巨噬细胞相关炎症和凝血的新的血清生物标志物，其可以对HIV感染人群中的CVD风险进行分层; c）使用RNA的全局测序（RNA-Seq），通过研究CD 14 ++来确定HIV和CVD相关的特定信号传导途径的功能获得和/或丧失，以及来自充分表征的HIV+和HIV-患者组的CD 14 + CD 16+单核细胞亚群。广泛表征的HIV感染和HIV未感染的WIHS和MACS NIH队列的入组者被带到承担这个跨学科，多站点的调查。因此，该项目将深入了解观察到的艾滋病毒感染与相关合并症的联系（例如，HCV合并感染）与心血管疾病风险，确定先天免疫系统作为一种新的和可修改的解释途径。考虑到需要改善CVD风险分层以及干预单核细胞/巨噬细胞活性介导的机制的可行性，这具有高度临床相关性。

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.