title: Attenuation of HIV-1 replication in macrophages by cannabinoid receptor 2 agonists.
abstract: Infiltrating monocytes and macrophages play a crucial role in the progression of HIV-1 infection in the CNS. Previous studies showed that activation of the CB₂ can attenuate inflammatory responses and affect HIV-1 infectivity in T cells and microglia. Here, we report that CB₂ agonists can also act as immunomodulators on HIV-1-infected macrophages. First, our findings indicated the presence of elevated levels of CB₂ expression on monocytes/macrophages in perivascular cuffs of postmortem HIV-1 encephalitic cases. In vitro analysis by FACS of primary human monocytes revealed a step-wise increase in CB₂ surface expression in monocytes, MDMs, and HIV-1-infected MDMs. We next tested the notion that up-regulation of CB₂ may allow for the use of synthetic CB₂ agonist to limit HIV-1 infection. Two commercially available CB₂ agonists, JWH133 and GP1a, and a resorcinol-based CB₂ agonist, O-1966, were evaluated. Results from measurements of HIV-1 RT activity in the culture media of 7 day-infected cells showed a significant decrease in RT activity when the CB₂ agonist was present. Furthermore, CB₂ activation also partially inhibited the expression of HIV-1 pol. CB₂ agonists did not modulate surface expression of CXCR4 or CCR5 detected by FACS. We speculate that these findings indicate that prevention of viral entry is not a central mechanism for CB₂-mediated suppression in viral replication. However, CB₂ may affect the HIV-1 replication machinery. Results from a single-round infection with the pseudotyped virus revealed a marked decrease in HIV-1 LTR activation by the CB₂ ligands. Together, these results indicate that CB₂ may offer a means to limit HIV-1 infection in macrophages.
authors: Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA. servio.ramirez@temple.edu
authors: Servio H
authors: SH
authors: Ramirez
authors: Nancy L
authors: NL
authors: Reichenbach
authors: Shongshan
authors: S
authors: Fan
authors: Slava
authors: S
authors: Rom
authors: Steven F
authors: SF
authors: Merkel
authors: Xu
authors: X
authors: Wang
authors: Wen-Zhe
authors: WZ
authors: Ho
authors: Yuri
authors: Y
authors: Persidsky
mesh_terms: D000840:Anisoles / Q000494:pharmacology; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D002186:Cannabinoids / Q000494:pharmacology; D002478:Cells, Cultured; D003511:Cyclohexanols; D016325:HIV Long Terminal Repeat / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007192:Indenes / Q000494:pharmacology; D008264:Macrophages / Q000821:virology*; D011720:Pyrazoles / Q000494:pharmacology; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000032:analysis / Q000502:physiology; D019713:Receptors, CCR5 / Q000032:analysis; D019718:Receptors, CXCR4 / Q000032:analysis; D014779:Virus Replication / Q000187:drug effects*
chemical_list: C531961:1-(4-(1,1-dimethylheptyl)-2,6-dimethoxyphenyl)-3-methylcyclohexanol; D000840:Anisoles; C527276:CXCR4 protein, human; D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids; D003511:Cyclohexanols; D007192:Indenes; C553580:N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-1,4-dihydro-6-methylindeno(1,2-c)pyrazole-3-carboxamide; D011720:Pyrazoles; D043885:Receptor, Cannabinoid, CB2; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC