| Autor: |
Chandra PK; Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, USA., Braun SE; Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, USA.; Division of Immunology, Tulane National Primate Research Center, Covington, LA 70433, USA., Maity S; Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA., Castorena-Gonzalez JA; Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, USA., Kim H; Department of Urology, Tulane University School of Medicine, New Orleans, LA 70112, USA., Shaffer JG; Department of Biostatistics and Data Science, Tulane University, New Orleans, LA 70112, USA., Cikic S; Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, USA., Rutkai I; Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, USA., Fan J; Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA., Guidry JJ; Proteomics Core Facility, Louisiana State University, New Orleans, LA 70112, USA., Worthylake DK; Proteomics Core Facility, Louisiana State University, New Orleans, LA 70112, USA., Li C; Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA., Abdel-Mageed AB; Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, USA.; Department of Urology, Tulane University School of Medicine, New Orleans, LA 70112, USA., Busija DW; Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, USA. |
| Abstrakt: |
Despite the suppression of human immunodeficiency virus (HIV) replication by combined antiretroviral therapy (cART), 50-60% of HIV-infected patients suffer from HIV-associated neurocognitive disorders (HAND). Studies are uncovering the role of extracellular vesicles (EVs), especially exosomes, in the central nervous system (CNS) due to HIV infection. We investigated links among circulating plasma exosomal (crExo) proteins and neuropathogenesis in simian/human immunodeficiency virus (SHIV)-infected rhesus macaques (RM) and HIV-infected and cART treated patients (Patient-Exo). Isolated EVs from SHIV-infected (SHIV-Exo) and uninfected (CTL-Exo) RM were predominantly exosomes (particle size < 150 nm). Proteomic analysis quantified 5654 proteins, of which 236 proteins (~4%) were significantly, differentially expressed (DE) between SHIV-/CTL-Exo. Interestingly, different CNS cell specific markers were abundantly expressed in crExo. Proteins involved in latent viral reactivation, neuroinflammation, neuropathology-associated interactive as well as signaling molecules were expressed at significantly higher levels in SHIV-Exo than CTL-Exo. However, proteins involved in mitochondrial biogenesis, ATP production, autophagy, endocytosis, exocytosis, and cytoskeleton organization were significantly less expressed in SHIV-Exo than CTL-Exo. Interestingly, proteins involved in oxidative stress, mitochondrial biogenesis, ATP production, and autophagy were significantly downregulated in primary human brain microvascular endothelial cells exposed with HIV+/cART+ Patient-Exo. We showed that Patient-Exo significantly increased blood-brain barrier permeability, possibly due to loss of platelet endothelial cell adhesion molecule-1 protein and actin cytoskeleton structure. Our novel findings suggest that circulating exosomal proteins expressed CNS cell markers-possibly associated with viral reactivation and neuropathogenesis-that may elucidate the etiology of HAND. |
