title: Methamphetamine inhibits HIV-1 replication in CD4+ T cells by modulating anti-HIV-1 miRNA expression.
abstract: Methamphetamine is the second most frequently used illicit drug in the United States. Methamphetamine abuse is associated with increased risk of HIV-1 acquisition, higher viral loads, and enhanced HIV-1 pathogenesis. Although a direct link between methamphetamine abuse and HIV-1 pathogenesis remains to be established in patients, methamphetamine has been shown to increase HIV-1 replication in macrophages, dendritic cells, and cells of HIV transgenic mice. Intriguingly, the effects of methamphetamine on HIV-1 replication in human CD4(+) T cells that serve as the primary targets of infection in vivo are not clearly understood. Therefore, we examined HIV-1 replication in primary CD4(+) T cells in the presence of methamphetamine in a dose-dependent manner. Our results demonstrate that methamphetamine had a minimal effect on HIV-1 replication at concentrations of 1 to 50 μmol/L. However, at concentrations >100 μmol/L, it inhibited HIV-1 replication in a dose-dependent manner. We also discovered that methamphetamine up-regulated the cellular anti-HIV-1 microRNAs (miR-125b, miR-150, and miR-28-5p) in CD4(+) T cells. Knockdown experiments illustrated that up-regulation of the anti-HIV miRNAs inhibited HIV-1 replication. These results are contrary to the paradigm that methamphetamine accentuates HIV-1 pathogenesis by increasing HIV-1 replication. Therefore, our findings underline the complex interaction between drug use and HIV-1 and necessitate comprehensive understanding of the effects of methamphetamine on HIV-1 pathogenesis.
authors.affiliation: Laboratory of Retrovirology and Epigenetics, Center for AIDS Health Disparities Research, Vanderbilt-Meharry Center for AIDS Research, Nashville, Tennessee.
authors.forename: Chinmay K
authors.initials: CK
authors.lastname: Mantri
authors.affiliation: Laboratory of Retrovirology and Epigenetics, Center for AIDS Health Disparities Research, Vanderbilt-Meharry Center for AIDS Research, Nashville, Tennessee.
authors.forename: Jyoti V
authors.initials: JV
authors.lastname: Mantri
authors.affiliation: Laboratory of Retrovirology and Epigenetics, Center for AIDS Health Disparities Research, Vanderbilt-Meharry Center for AIDS Research, Nashville, Tennessee.
authors.forename: Jui
authors.initials: J
authors.lastname: Pandhare
authors.affiliation: Laboratory of Retrovirology and Epigenetics, Center for AIDS Health Disparities Research, Vanderbilt-Meharry Center for AIDS Research, Nashville, Tennessee; Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, Tennessee; Division of Infectious Diseases, Vanderbilt University School of Medicine, Nashville, Tennessee. Electronic address: cdash@mmc.edu.
authors.forename: Chandravanu
authors.initials: C
authors.lastname: Dash
mesh_terms: D018663:Adrenergic Agents / Q000008:administration & dosage*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000821:virology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008694:Methamphetamine / Q000008:administration & dosage*; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D018663:Adrenergic Agents; D035683:MicroRNAs; D012333:RNA, Messenger; D008694:Methamphetamine