title: Cocaine enhances HIV-1 infectivity in monocyte derived dendritic cells by suppressing microRNA-155.
abstract: Cocaine and other drugs of abuse increase HIV-induced immunopathogenesis; and neurobiological mechanisms of cocaine addiction implicate a key role for microRNAs (miRNAs), single-stranded non-coding RNAs that regulate gene expression and defend against viruses. In fact, HIV defends against miRNAs by actively suppressing the expression of polycistronic miRNA cluster miRNA-17/92, which encodes miRNAs including miR-20a. IFN-g production by natural killer cells is regulated by miR-155 and this miRNA is also critical to dendritic cell (DC) maturation. However, the impact of cocaine on miR-155 expression and subsequent HIV replication is unknown. We examined the impact of cocaine on two miRNAs, miR-20a and miR-155, which are integral to HIV replication, and immune activation. Using miRNA isolation and analysis, RNA interference, quantitative real time PCR, and reporter assays we explored the effects of cocaine on miR-155 and miR-20 in the context of HIV infection. Here we demonstrate using monocyte-derived dendritic cells (MDCCs) that cocaine significantly inhibited miR-155 and miR-20a expression in a dose dependent manner. Cocaine and HIV synergized to lower miR-155 and miR-20a in MDDCs by 90%. Cocaine treatment elevated LTR-mediated transcription and PU.1 levels in MDCCs. But in context of HIV infection, PU.1 was reduced in MDDCs regardless of cocaine presence. Cocaine increased DC-SIGN and and decreased CD83 expression in MDDC, respectively. Overall, we show that cocaine inhibited miR-155 and prevented maturation of MDDCs; potentially, resulting in increased susceptibility to HIV-1. Our findings could lead to the development of novel miRNA-based therapeutic strategies targeting HIV infected cocaine abusers.
authors.affiliation: Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, United States of America.
authors.forename: Jessica
authors.initials: J
authors.lastname: Napuri
authors.affiliation: Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, United States of America ; Institute of NeuroImmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, United States of America ; Center for Personalized Nanomedicine, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, United States of America.
authors.forename: Sudheesh
authors.initials: S
authors.lastname: Pilakka-Kanthikeel
authors.affiliation: Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, United States of America ; Institute of NeuroImmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, United States of America.
authors.forename: Andrea
authors.initials: A
authors.lastname: Raymond
authors.affiliation: Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, United States of America ; Institute of NeuroImmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, United States of America.
authors.forename: Marisela
authors.initials: M
authors.lastname: Agudelo
authors.affiliation: Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, United States of America ; Institute of NeuroImmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, United States of America ; Center for Personalized Nanomedicine, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, United States of America.
authors.forename: Adriana
authors.initials: A
authors.lastname: Yndart-Arias
authors.affiliation: CSIR-Centre for Cellular & Molecular Biology, Hyderabad, India.
authors.forename: Shailendra K
authors.initials: SK
authors.lastname: Saxena
authors.affiliation: Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, United States of America ; Institute of NeuroImmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, United States of America ; Center for Personalized Nanomedicine, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, United States of America.
authors.forename: Madhavan
authors.initials: M
authors.lastname: Nair
mesh_terms: D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003042:Cocaine / Q000494:pharmacology*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000821:virology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000821:virology*; D020411:Oligonucleotide Array Sequence Analysis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*; D000099232:Proto-Oncogene Protein Spi-1; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015815:Cell Adhesion Molecules; D003042:Cocaine; D018765:Dopamine Uptake Inhibitors; D037181:Lectins, C-Type; D008156:Luciferases; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C524942:MIRN155 microRNA, human