Spatial Lipidomic Profiling of Kidney Functional Units in SIV-Infected and ART-Treated Rhesus Macaques

Human immunodeficiency virus (HIV) disrupts lipid metabolism, contributing to renal dysfunction seen in acute kidney injury (AKI), chronic kidney disease (CKD), and HIV-associated nephropathy (HIVAN). While antiretroviral therapies (ARTs) slow viral replication, prolonged use causes lipid dysregulation, leading to nephrotoxicity. Lipid metabolism has been hypothesized to be altered through viral manipulation, altering the metabolism, storage, and physical properties of lipids. These manipulations have been observed to generate increased levels of polyunsaturated fatty acids, cholesterol/sphingomyelin domains, and pro-inflammatory phospholipid tails. Since the kidney is composed of a network of spatially distinct functional units, each with a unique physiological role and differential vulnerability to infection and drug toxicity, methods capable of preserving native molecular context are critical for identifying region-specific perturbations. In this paper, we investigate the lipidomic changes in simian immunodeficiency virus (SIV)-infected and ART-treated rhesus macaque kidneys using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI). By using this approach, we can analyze discrete tissue functional units, such as glomeruli, proximal tubules, distal tubules, and collecting ducts, and gain insights into how viral infection and ART reshape lipid metabolism. Through this work, we further elaborate on the lipidomic changes in glomeruli specifically, identifying the critical role that sphingomyelins play in the context of viral fusion and budding, in addition to other phospholipids and their role in altered oxidative phosphorylation and inflammatory signaling.