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Principal Investigator: Elena Aikawa
Organization: BRIGHAM AND WOMEN'S HOSPITAL
Fiscal Year: 2024
Award: $771,902
Funding agency: National Heart Lung and Blood Institute
Project Summary
Anti-retroviral therapy (ART) has protected many HIV patients against the development of AIDS. HIV
infection has become a treatable disease. Increased risk for atherosclerotic vascular diseases in long-term
HIV survivors or people living with HIV (PLWH) with no detectable virus load, however, is projected to
become a global health burden. Despite its clinical impact, underlying mechanisms for accelerated
atherogenesis in PLWH remain obscure. Macrophages promote the formation of high-risk plaques prone to
vascular events (e.g., macrophage-rich, large necrotic core, think fibrous cap). Macrophages are
heterogeneous and the imbalance of their subpopulations may accelerate atherogenesis. Evidence
suggests that extracellular vesicles (EVs) that contain the HIV-associated protein Nef (Nef EVs) promote
chronic inflammation. We will examine the effects of Nef EVs in the heterogeneity and functions of
macrophages and the formation of atherogenesis.
Our study represents a dynamic interplay of biology and data science to identify novel mechanisms
and therapeutic targets. We will use a systems approach to test the central hypothesis that Nef EVs
modulate macrophage heterogeneity, shifting the balance toward an atherogenic or less atheroprotective
phenotype. Our preliminary data have led us to the specific biological hypothesis that Nef EVs impair
efferocytosis and contribute to the formation of high-risk atherosclerotic plaques that we will test in three
Specific Aims. In Specific Aim 1, we will conduct a systems-based macrophage profiling, involving unbiased
multi-omics, data integration, and network analysis to identify novel mechanisms for macrophage activation
by Nef EVs. Pilot multi-omics data suggested that Nef EVs suppresses efferocytosis. In Specific Aim 2, we
will validate omics data in vitro and in vivo and address underlying mechanisms for impaired macrophage
efferocytosis by Nef EVs.
Terms: <AIDS><AIDS Virus><ATAC sequencing><ATAC-seq><ATACseq><Acceleration><Acquired Immune Deficiency><Acquired Immune Deficiency Syndrome><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome><Acquired Immunodeficiency Syndrome Virus><Address><Aging><Apoptotic><Area><Arterial Fatty Streak><Arterial Fatty Streaks><Assay><Assay for Transposase-Accessible Chromatin using sequencing><Atheroma><Atheromatous><Atheromatous degeneration><Atheromatous plaque><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Attenuated><Bioassay><Biological><Biological Assay><Biology><Blood Vessels><Cell Body><Cells><Chronic><Clinical><Data><Data Science><Development><Disease><Disorder><Drugs><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Equilibrium><Event><Family><Feedback><Future><General Population><General Public><Goals><HIV><HIV Infections><HIV Long-Term Survivors><HIV Longterm Survivors><HIV-1 Long-Term Survivors><HIV-1 Longterm Survivors><HTLV-III Infections><HTLV-III-LAV Infections><Heterogeneity><Human><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Immune><Immunes><Impairment><In Vitro><Inflammation><Inflammatory><Inflammatory Response><Interdisciplinary Research><Interdisciplinary Study><KI mice><Kinases><Knock-in Mouse><LAV-HTLV-III><Leanness><Lesion><Lymphadenopathy-Associated Virus><Macrophage><Macrophage Activation><Mediator><Medication><Mice><Mice Mammals><Modern Man><Modernization><Molecular><Multidisciplinary Collaboration><Multidisciplinary Research><Multiomic Data><Murine><Mus><Mφ><Necrosis><Necrotic><Network Analysis><Pathway Analysis><Pathway interactions><Patients><Persons><Phagocytosis><Pharmaceutical Preparations><Phenotype><Phosphotransferase Gene><Phosphotransferases><Play><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Proteins><Proteomics><RNA Interference><RNA Silencing><RNAi><Receptor Protein><Resolution><Role><Sequence-Specific Posttranscriptional Gene Silencing><Survivors><System><Testing><Thinness><Transphosphorylases><Vascular Diseases><Vascular Disorder><Viral Burden><Viral Load><Viral Load result><Viral load measurement><Virion><Virus Particle><Virus-HIV><antiretroviral therapy><antiretroviral treatment><assay for transposase accessible chromatin followed by sequencing><assay for transposase accessible chromatin seq><assay for transposase accessible chromatin sequencing><assay for transposase-accessible chromatin with sequencing><atherogenesis><atheromatosis><atheroprotection><atheroprotective><atherosclerosis plaque><atherosclerosis risk><atherosclerotic disease><atherosclerotic lesions><atherosclerotic plaque><atherosclerotic risk><atherosclerotic vascular disease><attenuate><attenuates><balance><balance function><base><bases><biologic><blood vessel disorder><cardiovascular risk><cardiovascular risk factor><clinical translation><clinically translatable><data integration><developmental><drug/agent><epigenetically><experiment><experimental research><experimental study><experiments><extracellular vesicles><global health><high risk><in vivo><knockin mice><latent HIV reservoir><latent HIV-1 reservoir><latent HIV1 reservoir><lipid based nanoparticle><lipid nanoparticle><multiomics><multiple omic data><multiple omics><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><panomics><pathway><precision medicine><precision-based medicine><receptor><resolutions><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell analysis><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><therapeutic target><transcriptomics><vascular><vascular dysfunction><vascular inflammation><vasculopathy><virus load><vulnerable plaque>