title: Deregulation of microRNAs by HIV-1 Vpr protein leads to the development of neurocognitive disorders.
abstract: Studies have shown that HIV-infected patients develop neurocognitive disorders characterized by neuronal dysfunction. The lack of productive infection of neurons by HIV suggests that viral and cellular proteins, with neurotoxic activities, released from HIV-1-infected target cells can cause this neuronal deregulation. The viral protein R (Vpr), a protein encoded by HIV-1, has been shown to alter the expression of various important cytokines and inflammatory proteins in infected and uninfected cells; however the mechanisms involved remain unclear. Using a human neuronal cell line, we found that Vpr can be taken up by neurons causing: (i) deregulation of calcium homeostasis, (ii) endoplasmic reticulum-calcium release, (iii) activation of the oxidative stress pathway, (iv) mitochondrial dysfunction and v- synaptic retraction. In search for the cellular factors involved, we performed microRNAs and gene array assays using human neurons (primary cultures or cell line, SH-SY5Y) that we treated with recombinant Vpr proteins. Interestingly, Vpr deregulates the levels of several microRNAs (e.g. miR-34a) and their target genes (e.g. CREB), which could lead to neuronal dysfunctions. Therefore, we conclude that Vpr plays a major role in neuronal dysfunction through deregulating microRNAs and their target genes, a phenomenon that could lead to the development of neurocognitive disorders.
authors.affiliation: Department of Neurology, Molecular Studies of Neurodegenerative Diseases Laboratory, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
authors.forename: Ruma
authors.initials: R
authors.lastname: Mukerjee
authors.forename: J Robert
authors.initials: JR
authors.lastname: Chang
authors.forename: Luis
authors.initials: L
authors.lastname: Del Valle
authors.forename: Asen
authors.initials: A
authors.lastname: Bagashev
authors.forename: Monika M
authors.initials: MM
authors.lastname: Gayed
authors.forename: Randolph B
authors.initials: RB
authors.lastname: Lyde
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Hawkins
authors.forename: Eugen
authors.initials: E
authors.lastname: Brailoiu
authors.forename: Eric
authors.initials: E
authors.lastname: Cohen
authors.forename: Chris
authors.initials: C
authors.lastname: Power
authors.forename: S Ausim
authors.initials: SA
authors.lastname: Azizi
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Gelman
authors.forename: Bassel E
authors.initials: BE
authors.lastname: Sawaya
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003072:Cognition Disorders / Q000473:pathology / Q000821:virology*; D015967:Gene Expression Regulation, Viral; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism*; D008856:Microscopy, Fluorescence / Q000379:methods; D008928:Mitochondria / Q000378:metabolism*; D009422:Nervous System Diseases / Q000473:pathology / Q000821:virology*; D009474:Neurons / Q000378:metabolism; D018384:Oxidative Stress; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; D054325:vpr Gene Products, Human Immunodeficiency Virus; D002118:Calcium