title: Cocaine enhances HIV-1 replication in CD4+ T cells by down-regulating MiR-125b.
abstract: The main objective of this study was to examine effects of cocaine on HIV-1 replication in primary CD4+ T cells. Cocaine a commonly used drug among HIV-1 positive individuals serves as a cofactor for HIV-1 infection and progression to acquired immunodeficiency syndrome (AIDS). Accumulating evidence suggest that cocaine increases HIV-1 replication in cell cultures, peripheral blood mononuclear cells (PBMCs) and animal models. Intriguingly, there are no studies on cocaine-induced alterations in HIV-1 replication in primary CD4+ T cells that serve as the main targets for HIV-1 replication in vivo. In this report, we demonstrate cocaine-induced enhancement of HIV-1 replication in primary CD4+ T cells isolated from human PBMCs. To decipher a potential mechanism, we examined whether cocaine targets the innate antiviral immunity of CD4+ T cells mediated by cellular microRNAs (miRNAs). This is because recently a network of anti-HIV miRNAs in CD4+ T cells is highlighted to suppress viral replication. Our genome wide miRNA expression analysis indicated downregulation of several anti-HIV miRNAs (miR-28, miR-125b, miR-150, miR-223, and miR-382) in cocaine treated CD4+ T cells. However, our real-time quantitative PCR analysis revealed significant downregulation of miR-125b only. Our results illustrated that miR-125b knockdown enhances HIV-1 replication, whereas overexpression of miR-125b decreases HIV-1 replication in these cells. Therefore, we believe miR-125b is a key player for the cocaine induced enhancement of HIV-1 replication in CD4+ T cells. Since, miR-125b targets the 3' UTR regions of HIV-1 transcripts and inhibits viral protein translation, our data suggest modulation of post entry steps of HIV-1 by cocaine. Given that a plethora of studies suggest that cocaine regulates HIV entry, our results implicate a potentially novel mechanism by which cocaine can increase viral replication in CD4+ T cells.
authors.affiliation: The Laboratory of Retrovirology and Epigenetics, Center For AIDS Health Disparities Research, Vanderbilt-Meharry Center for AIDS Research, Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN, USA.
authors.forename: Chinmay K
authors.initials: CK
authors.lastname: Mantri
authors.forename: Jui
authors.initials: J
authors.lastname: Pandhare Dash
authors.forename: Jyoti Velamarti
authors.initials: JV
authors.lastname: Mantri
authors.forename: Chandravanu C V
authors.initials: CC
authors.lastname: Dash
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000821:virology; D002478:Cells, Cultured; D003042:Cocaine / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D014779:Virus Replication / Q000187:drug effects*
chemical_list: C531888:MIRN125 microRNA, human; D035683:MicroRNAs; D003042:Cocaine