title: Exosome-mediated shuttling of microRNA-29 regulates HIV Tat and morphine-mediated neuronal dysfunction.
abstract: Neuronal damage is a hallmark feature of HIV-associated neurological disorders (HANDs). Opiate drug abuse accelerates the incidence and progression of HAND; however, the mechanisms underlying the potentiation of neuropathogenesis by these drugs remain elusive. Opiates such as morphine have been shown to enhance HIV transactivation protein Tat-mediated toxicity in both human neurons and neuroblastoma cells. In the present study, we demonstrate reduced expression of the tropic factor platelet-derived growth factor (PDGF)-B with a concomitant increase in miR-29b in the basal ganglia region of the brains of morphine-dependent simian immunodeficiency virus (SIV)-infected macaques compared with the SIV-infected controls. In vitro relevance of these findings was corroborated in cultures of astrocytes exposed to morphine and HIV Tat that led to increased release of miR-29b in exosomes. Subsequent treatment of neuronal SH-SY5Y cell line with exosomes from treated astrocytes resulted in decreased expression of PDGF-B, with a concomitant decrease in viability of neurons. Furthermore, it was shown that PDGF-B was a target for miR-29b as evidenced by the fact that binding of miR-29 to the 3'-untranslated region of PDGF-B mRNA resulted in its translational repression in SH-SY5Y cells. Understanding the regulation of PDGF-B expression may provide insights into the development of potential therapeutic targets for neuronal loss in HIV-1-infected opiate abusers.
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA.
authors.forename: G
authors.initials: G
authors.lastname: Hu
authors.forename: H
authors.initials: H
authors.lastname: Yao
authors.forename: A D
authors.initials: AD
authors.lastname: Chaudhuri
authors.forename: M
authors.initials: M
authors.lastname: Duan
authors.forename: S V
authors.initials: SV
authors.lastname: Yelamanchili
authors.forename: H
authors.initials: H
authors.lastname: Wen
authors.forename: P D
authors.initials: PD
authors.lastname: Cheney
authors.forename: H S
authors.initials: HS
authors.lastname: Fox
authors.forename: S
authors.initials: S
authors.lastname: Buch
mesh_terms: D020413:3' Untranslated Regions; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D055354:Exosomes / Q000378:metabolism*; D005724:Ganglia / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008253:Macaca mulatta; D035683:MicroRNAs / Q000378:metabolism*; D009020:Morphine / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015302:Simian Immunodeficiency Virus / Q000472:pathogenicity; D014162:Transfection; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; D000701:Analgesics, Opioid; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D020574:Proto-Oncogene Proteins c-sis; D054322:tat Gene Products, Human Immunodeficiency Virus; D009020:Morphine