Role of platelet- monocyte interaction in promoting pro-atherogenic state in HIV-infected individuals

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Clinical and epidemiological studies have consistently connected HIV infection with increased risk of cardio- vascular disease (CVD). This is due to dysregulated health status associated with residual virus replication, release of soluble viral proteins, and HIV-induced immune activation, which may also be associated with premature immune senescence and persistent inflammation. Chronic inflammation is associated with acceleration of atherosclerosis (AS) and is increasingly prominent among the HIV+ individuals on cART. Monocytes respond to inflammatory stimuli and are precursors of the macrophages within atherosclerotic lesions, including lipid-laden foam cells, and lesion-associated macrophages represent a major source of a number of cytokines and chemokines that direct monocytes into vascular lesions, thus creating a positive- feedback loop. Differentiation of monocytes is enhanced upon interaction with platelets. We and others have shown that platelet-monocyte complexes (PMCs) are increased during HIV infection and CVD. Therefore, we propose to investigate a hypothesis that the PMCs promote atherogenic processes in persons with HIV by triggering monocyte differentiation through horizontal transfer of micro-RNA and protein encapsulated in the platelet-derived microparticles (PMs) to the monocytes and thereafter their interaction with endothelial cells. To test these hypotheses in first aim we define and model molecular networks in monocytes that have or have not interacted with activated platelets in HIV+/- patients with/without carotid plaques using state-of-art CITE-seq. We will employ discrete-state modeling approaches to identify pathways and subnetworks dysregulated in HIV+ individuals with carotid plaques. In second aim, we propose to characterize micro-RNA (miRNA) and proteins encapsulated in platelet-derived microparticles by small-RNA sequencing and proteomics in HIV+/- individuals with/without carotid plaques. The list of miRNAs and proteins will be integrated with the network model from aim 1 to simulate the effect on signaling cascades and their cross-talk. The network model will reveal the role of miRNAs and proteins on the monocyte differentiation into pro-inflammatory phenotype. Additional analysis by machine-learning techniques will allow further prioritization and selection of genes. The ex-vivo experiments will test binding to human carotid endothelial cells and receptiveness of endothelial cells to the differentiated monocytes. In conclusion, our multidisciplinary approach of integrated omics, computational modeling and ex- vivo experiments will reveal mechanisms by which AS is prematurely induced in HIV+ individuals, novel targets to curb AS in HIV+ individuals and biomarkers for early detection of AS. This study holds strong prospects to significantly improve aging related comorbidities in persons living with HIV in general and AS in particular.