title: Cannabinoid receptor 2-mediated attenuation of CXCR4-tropic HIV infection in primary CD4+ T cells.
abstract: Agents that activate cannabinoid receptor pathways have been tested as treatments for cachexia, nausea or neuropathic pain in HIV-1/AIDS patients. The cannabinoid receptors (CB(1)R and CB(2)R) and the HIV-1 co-receptors, CCR5 and CXCR4, all signal via Gαi-coupled pathways. We hypothesized that drugs targeting cannabinoid receptors modulate chemokine co-receptor function and regulate HIV-1 infectivity. We found that agonism of CB(2)R, but not CB(1)R, reduced infection in primary CD4+ T cells following cell-free and cell-to-cell transmission of CXCR4-tropic virus. As this change in viral permissiveness was most pronounced in unstimulated T cells, we investigated the effect of CB(2)R agonism on to CXCR4-induced signaling following binding of chemokine or virus to the co-receptor. We found that CB(2)R agonism decreased CXCR4-activation mediated G-protein activity and MAPK phosphorylation. Furthermore, CB(2)R agonism altered the cytoskeletal architecture of resting CD4+ T cells by decreasing F-actin levels. Our findings suggest that CB(2)R activation in CD4+ T cells can inhibit actin reorganization and impair productive infection following cell-free or cell-associated viral acquisition of CXCR4-tropic HIV-1 in resting cells. Therefore, the clinical use of CB(2)R agonists in the treatment of AIDS symptoms may also exert beneficial adjunctive antiviral effects against CXCR4-tropic viruses in late stages of HIV-1 infection.
authors.affiliation: Department of Infectious Diseases, Department of Medicine, Immunology Institute, Mount Sinai School of Medicine, New York, New York, United States of America.
authors.forename: Cristina Maria
authors.initials: CM
authors.lastname: Costantino
authors.forename: Achla
authors.initials: A
authors.lastname: Gupta
authors.forename: Alice W
authors.initials: AW
authors.lastname: Yewdall
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Dale
authors.forename: Lakshmi A
authors.initials: LA
authors.lastname: Devi
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Chen
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D002186:Cannabinoids / Q000494:pharmacology*; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control* / Q000821:virology*; D015497:HIV-1 / Q000472:pathogenicity; D006801:Humans; D008561:Membrane Fusion; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D002186:Cannabinoids; D018925:Chemokines; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D019718:Receptors, CXCR4