title: Methamphetamine inhibits Toll-like receptor 9-mediated anti-HIV activity in macrophages.
abstract: Toll-like receptor 9 (TLR9) is one of the key sensors that recognize viral infection/replication in the host cells. Studies have demonstrated that methamphetamine (METH) dysregulated host cell innate immunity and facilitated HIV infection of macrophages. In this study, we present new evidence that METH suppressed TLR9-mediated anti-HIV activity in macrophages. Activation of TLR9 by its agonist CpG-ODN 2216 inhibits HIV replication, which was demonstrated by increased expression of TLR9, interferon (IFN)-α, IFN regulatory factor-7 (IRF-7), myeloid differentiation factor 88 (MyD88), and myxovirus resistance gene A (MxA) in macrophages. However, METH treatment of macrophages greatly compromised the TLR9 signaling-mediated anti-HIV effect and inhibited the expression of TLR9 downstream signaling factors. Dopamine D1 receptor (D1R) antagonists (SCH23390) could block METH-mediated inhibition of anti-HIV activity of TLR9 signaling. Investigation of the underlying mechanisms of the METH action showed that METH treatment selectively down-regulated the expression of TLR9 on macrophages, whereas it had little effect on the expression of other TLRs. Collectively, our results provide further evidence that METH suppresses host cell innate immunity against HIV infection by down-regulating TLR9 expression and its signaling-mediated antiviral effect in macrophages.
authors.affiliation: Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Cen
authors.forename: Li
authors.initials: L
authors.lastname: Ye
authors.forename: Qi-Jian
authors.initials: QJ
authors.lastname: Su
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.forename: Jie-Liang
authors.initials: JL
authors.lastname: Li
authors.forename: Xin-Qin
authors.initials: XQ
authors.lastname: Lin
authors.forename: Hao
authors.initials: H
authors.lastname: Liang
authors.forename: Wen-Zhe
authors.initials: WZ
authors.lastname: Ho
mesh_terms: D000328:Adult; D000697:Central Nervous System Stimulants / Q000009:adverse effects*; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism; D016898:Interferon-alpha / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008694:Methamphetamine / Q000009:adverse effects*; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D051217:Toll-Like Receptor 9 / Q000037:antagonists & inhibitors* / Q000276:immunology; D014779:Virus Replication / Q000187:drug effects* / Q000276:immunology
chemical_list: D000697:Central Nervous System Stimulants; D050839:Interferon Regulatory Factor-7; D016898:Interferon-alpha; D053594:Myeloid Differentiation Factor 88; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D008694:Methamphetamine