Biomarkers of Atherosclerosis Risk in HIV-1 Infection

HIV-infected individuals are prone to accelerated atherosclerosis (ATH)1. The objective of this pilot award is to identify biomarkers that can be used to predict and monitor ATH in the setting of HIV infection. Circulating endothelial progenitor cells (EPCs) repair damaged vascular endothelium2, while circulating endothelial microparticles (EMPs) are derived from activated or apoptotic endothelial cells3. Reduced circulating EPCs and increased EMPs have been associated with endothelial dysfunction and with increased ATH in certain settings4, but EPCs and EMPs have not been investigated in individuals infected with HIV. To facilitate such an analysis, we propose to optimize and validate assays to quantify circulating EPCs and EMPs. We will compare their numbers among HIV-infected and matched HIV-uninfected subjects, and also correlate their numbers with endothelial function [measured as flow-mediated dilation in the brachial artery (FMD)] and with subclinical atherosclerosis (measured in the carotid artery by B-mode ultrasound). We will also measure other putative stimuli to ATH in HIV, particularly interleukin-6 (IL-6), bacterial lipopolysaccharide (LPS), and sCD14, the co-receptor (along with Toll-like receptor 4) for LPS. To validate the presence of rare circulating EPC, we will determine the phenotype (as measured by flow cytometry) of cells capable of forming endothelial colony-forming units (CFU-EC) and endothelial colony-forming cells (ECFCs) in vitro. A multivariate analysis will be performed to determine which biomarkers show the strongest association with subclinical measurements of ATH [i.e., endothelial function and carotid intima-media thickness (IMT)]. The results of this pilot development and validation study will be used to design a larger prospective study to evaluate how well these biomarkers predict early ATH in HIV-infected subjects.