title: Methamphetamine activates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and induces human immunodeficiency virus (HIV) transcription in human microglial cells.
abstract: Human immunodeficiency virus (HIV) primarily infects glial cells in the central nervous system (CNS). Recent evidence suggests that HIV-infected individuals who abuse drugs such as methamphetamine (METH) have higher viral loads and experience more severe neurological complications than HIV-infected individuals who do not abuse drugs. The aim of this study was to determine the effect of METH on HIV expression from the HIV long terminal repeat (LTR) promoter and on an HIV integrated provirus in microglial cells, the primary host cells for HIV in the CNS. Primary human microglial cells immortalized with SV40 T antigen (CHME-5 cells) were cotransfected with an HIV LTR reporter and the HIV Tat gene, a key regulator of viral replication and gene expression, and exposed to METH. Our results demonstrate that METH treatment induced LTR activation, an effect potentiated in the presence of Tat. We also found that METH increased the nuclear translocation of the nuclear factor kappa B (NF-κB), a key cellular transcriptional regulator of the LTR promoter, and the activity of an NF-κB-specific reporter plasmid in CHME-5 cells. The presence of a dominant-negative regulator of NF-κB blocked METH-related activation of the HIV LTR. Furthermore, treatment of HIV-latently infected CHME-5 (CHME-5/HIV) cells with METH induced HIV expression and nuclear translocation of the p65 subunit of NF-κB. These results suggest that METH can stimulate HIV gene expression in microglia cells through activation of the NF-κB signaling pathway. This mechanism may outline the initial biochemical events leading to the observed increased neurodegeneration in HIV-positive individuals who use METH.
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Emily S
authors.initials: ES
authors.lastname: Wires
authors.forename: David
authors.initials: D
authors.lastname: Alvarez
authors.forename: Curtis
authors.initials: C
authors.lastname: Dobrowolski
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Marisela
authors.initials: M
authors.lastname: Morales
authors.forename: Jonathan
authors.initials: J
authors.lastname: Karn
authors.forename: Brandon K
authors.initials: BK
authors.lastname: Harvey
mesh_terms: D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism / Q000821:virology; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008694:Methamphetamine / Q000009:adverse effects*; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000819:agonists / Q000235:genetics* / Q000378:metabolism
chemical_list: D000952:Antigens, Polyomavirus Transforming; D016328:NF-kappa B; D021122:Protein Subunits; D054322:tat Gene Products, Human Immunodeficiency Virus; D008694:Methamphetamine