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. ?
Public Health Relevance Statement This research project 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. This project will elucidate the innate immune system as a novel independent pathway linking HIV and CVD. It will refine a serum biomarker panel for prospective CVD risk which has potential clinical application. We also uncover the mechanisms for the already-established link between macrophage/monocyte biomarkers and CVD using both candidate and discovery approaches. The results have high clinical relevance leading to: 1) development of strategies to intervene on innate immune system pathways (PPAR, statins, mTOR);2) vetting a new research biomarker of innate immunity;and 3) better risk prediction and thus accurate targeting of CVD prevention, overcoming inaccuracy of existing CVD risk scores in HIV+ patients. ?