Abstract
The chronic irreversible regression of cognitive ability and memory function in human immunodeficiency virus (HIV)-associated dementia (HAND) is linked with late-stage HIV infection in the brain. The molecular-level signatures of neuroinflammation and neurodegeneration are linked with dysfunction in HAND patients. Protein expression changes and posttranslational modification are epigenetic cues for dementia and neurodegenerative disease. In this study quantitative proteome analysis was performed to comprehensively elucidate changes in protein profiles in HIV-positive (HIV+) human brains. Frontal and temporal lobes of normal and HIV+ brains were subjected to label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis using the data-independent acquisition method. Comprehensive proteomic identification and quantification analysis revealed that 3294 total proteins and 251 proteins were differentially expressed in HIV+ brains; specifically, HIV+ frontal and temporal lobes had 132 and 119 differentially expressed proteins, respectively. Proteomic and bioinformatic analyses revealed protein alterations predominantly in the HIV+ frontal lobe region. The expression of GOLPH3, IMPDH2, DYNLL1, RPL11, and GPNMB proteins was significantly altered in HIV+ frontal lobes compared to that in normal brains. These proteins are associated with metabolic pathways, neurodegenerative disorders, and dementia. These proteomic-level changes may be potential biological markers and therapeutic targets to relieve the dementia-associated symptoms in individuals with HAND.
Highlights
Human immunodeficiency virus (HIV) primarily targets immune cells, and microglia and macrophages in the brain
The brain tissue samples of frontal and temporal regions from three normal and three HIV+ individuals were subjected to dual mass spectrometry analysis followed by quantitative proteomic analysis
Each sample was analyzed twice with gas-phase fractionation (GPF); the first acquisition was performed for peptides in the 350–800 m/z range, while the second acquisition was performed for peptides in the 800 m/z to 1250 m/z range
Summary
Human immunodeficiency virus (HIV) primarily targets immune cells, and microglia and macrophages in the brain. Despite the advancement of antiretroviral therapy, perivascular macrophages and microglial cells of the central nervous system (CNS) are major reservoirs of HIV infection, and affect astrocytes and neurons, causing the acceleration of disease progression [1]. Clinical and experimental studies have emphasized that HIV infection is directly associated with an elevated level of reactive oxygen species (ROS) [2]. HIV infection disturbs the mitochondrial metabolic functions of adenosine triphosphate (ATP) production, electron transport oxidative phosphorylation (OXPHOS), and the oxidation of metabolites in the tricarboxylic acid cycle (TCA) [3]. HIV is known to hijack the host cellular protein regulatory network and affect cellular function. Studies have well documented the imbalance in dynamic equilibrium during posttranslational modifications of mitochondrial protein
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