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bioRxiv · 10.1101/2022.09.26.508302

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

White, C. J.·Gausepohl, A. M.·Seneviratne, H. K.·Bumpus, N. N.·Williams, D. W.
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Abstract

Human immunodeficiency virus (HIV) infection 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 comprehensive characterization of the spatial heterogeneity of brain lipids during infection that may impact neurologic function. To address this gap, we evaluated the spatial 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 (CARs)] and critical structural lipids [phosphatidylcholines (PCs) and phosphatidylethanolamines (PEs)] across fatty acid chain lengths and degrees of unsaturation. CARs with very long-chain, polyunsaturated fatty acids (PUFAs) were more abundant across all brain regions than shorter chain, saturated or monounsaturated species. We observed distinct brain lipid distribution patterns for CARs and PCs. However, no clear expression patterns emerged for PEs. Surprisingly, kidney was nearly devoid of ions corresponding to PUFAs common in brain. PEs and PCs with PUFAs had little intensity and less density than other species and, only one CAR species was observed in kidney at high intensity. Overall, our study provides substantial evidence for persistent bioenergetic changes to the brain despite viral suppression, including region-dependent mobilization of CARs 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 antiretroviral therapy. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/508302v3_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@598d53org.highwire.dtl.DTLVardef@14d5cf1org.highwire.dtl.DTLVardef@10f6c9org.highwire.dtl.DTLVardef@1ba1aab_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG

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White, C. J., Gausepohl, A. M., Seneviratne, H. K., Bumpus, N. N., Williams, D. W.. 2022-09-27. Antiretroviral Therapy Does Not Restore Brain Lipids During SIV Infection: Regional Analysis of Metabolic Homeostasis and Depletion. https://doi.org/10.1101/2022.09.26.508302

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