title: HIV-1 Tat protein promotes neuronal dysfunction through disruption of microRNAs.
abstract: Over the last decade, small noncoding RNA molecules such as microRNAs (miRNAs) have emerged as critical regulators in the expression and function of eukaryotic genomes. It has been suggested that viral infections and neurological disease outcome may also be shaped by the influence of small RNAs. This has prompted us to suggest that HIV infection alters the endogenous miRNA expression patterns, thereby contributing to neuronal deregulation and AIDS dementia. Therefore, using primary cultures and neuronal cell lines, we examined the impact of a viral protein (HIV-1 Tat) on the expression of miRNAs due to its characteristic features such as release from the infected cells and taken up by noninfected cells. Using microRNA array assay, we demonstrated that Tat deregulates the levels of several miRNAs. Interestingly, miR-34a was among the most highly induced miRNAs in Tat-treated neurons. Tat also decreases the levels of miR-34a target genes such as CREB protein as shown by real time PCR. The effect of Tat was neutralized in the presence of anti-miR-34a. Using in situ hybridization assay, we found that the levels of miR-34a increase in Tat transgenic mice when compared with the parental mice. Therefore, we conclude that deregulation of neuronal functions by HIV-1 Tat protein is miRNA-dependent.
authors.affiliation: Department of Neurology, Molecular Studies of Neurodegenerative Diseases Laboratory, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
authors.forename: J Robert
authors.initials: JR
authors.lastname: Chang
authors.forename: Ruma
authors.initials: R
authors.lastname: Mukerjee
authors.forename: Asen
authors.initials: A
authors.lastname: Bagashev
authors.forename: Luis
authors.initials: L
authors.lastname: Del Valle
authors.forename: Tinatin
authors.initials: T
authors.lastname: Chabrashvili
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Hawkins
authors.forename: Johnny J
authors.initials: JJ
authors.lastname: He
authors.forename: Bassel E
authors.initials: BE
authors.lastname: Sawaya
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D016655:HIV Core Protein p24 / Q000378:metabolism; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D015203:Reproducibility of Results; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D016655:HIV Core Protein p24; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; C514799:p24 protein, Human Immunodeficiency Virus Type 1; D054322:tat Gene Products, Human Immunodeficiency Virus; D002118:Calcium