Antiretroviral Therapy Does Not Restore Brain Lipids During SIV Infection: Regional Analysis of Metabolic Homeostasis and Depletion

Abstract

ABSTRACTHuman immunodeficiency virus infection (HIV) continues to promote neurocognitive impairment, mood disorders, and brain atrophy even in the modern era of viral suppression. Brain lipids are vulnerable to HIV-associated energetic strain and contribute to HIV-associated neurologic dysfunction due to alterations in lipid breakdown and structural lipid composition. HIV neuropathology is region dependent, yet there has not been a comprehensive spatial evaluation of brain lipids during infection that may impact neurologic function. To address this gap, we evaluated brain lipid distribution using matrix laser desorption/ionization imaging mass spectrometry (MALDI-IMS) across four brain regions (parietal cortex, midbrain, thalamus, and temporal cortex), as well as kidney for a peripheral tissue control, in a virally suppressed simian immunodeficiency virus (SIV)-infected rhesus macaque. We assessed lipids indicative of fat breakdown (acylcarnitines) and critical structural lipids (phosphatidylcholines and phosphatidylethanolamines) across fatty acid chain lengths and degrees of unsaturation. Acylcarnitines with very long-chain, polyunsaturated fatty acids were more abundant across all brain regions than shorter chain, saturated or monounsaturated species. We observed two distinct brain lipid distribution patterns for acylcarnitines and phosphatidylcholines. However, no clear expression patterns emerged for phosphatidylethanolamines. Surprisingly, acylcarnitines were largely missing in kidney, while common phosphatidylcholines and phosphatidylethanolamines were absent in kidney. Overall, our study provides substantial evidence for persistent bioenergetic changes to the brain despite viral suppression, including region-dependent mobilization of acylcarnitines for oxidation and disparities in the presence of key phospholipids necessary for maintaining proper brain structure and function. These data indicate that region-specific interventions to restore proper lipid metabolism are essential for treating HIV neurologic disease in the era of ART.