Deregulation of microRNAs by HIV-1 Vpr Protein Leads to the Development of Neurocognitive Disorders

• Published in: The Journal of biological chemistry 2011-10, Vol.286 (40), p.34976-34985
• Main Authors: Mukerjee, Ruma, Chang, J. Robert, Del Valle, Luis, Bagashev, Asen, Gayed, Monika M., Lyde, Randolph B., Hawkins, Brian J., Brailoiu, Eugen, Cohen, Eric, Power, Chris, Azizi, S. Ausim, Gelman, Benjamin B., Sawaya, Bassel E.
• Format: Article
• Language: English
• Subjects: Animals; Calcium; Calcium - metabolism; Cognition Disorders - pathology; Cognition Disorders - virology; Endoplasmic Reticulum (ER); Gene Expression Regulation, Viral; HIV; Humans; Immunohistochemistry - methods; Mice; Mice, Transgenic; MicroRNA; MicroRNAs - metabolism; Microscopy, Fluorescence - methods; Mitochondria; Mitochondria - metabolism; Molecular Bases of Disease; Nervous System Diseases - pathology; Nervous System Diseases - virology; Neurodegeneration; Neurons - metabolism; Oxidative Stress; vpr Gene Products, Human Immunodeficiency Virus - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.241547

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.