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Cannabinoid Receptor 2-Mediated Attenuation of CXCR4-Tropic HIV Infection in Primary CD4 + TCells (M

Cannabinoid Receptor 2-Mediated Attenuation of CXCR4-Tropic HIV Infection in Primary CD4 + TCells (M

  1. corvardus
    Cristina Maria Costantino; Achla Gupta; Alice W. Yewdall; Benjamin M. Dale; Lakshmi A. Devi; Benjamin K. Chen

    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[sub]1[/sub])R and CB[sub]2[/sub]R) and the HIV-1 co-receptors, CCR5 and CXCR4, all signal via Gai-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[sub]2[/sub]R, but not CB[sub]1[/sub]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[sub]2[/sub]R agonism on to CXCR4-induced signaling following binding of chemokine or virus to the co-receptor. We found that CB[sub]2[/sub]R agonism decreased CXCR4-activation mediated G-protein activity and MAPK phosphorylation. Furthermore, CB[sub]2[/sub]R agonism altered the cytoskeletal architecture of resting CD4+T cells by decreasing F-actin levels. Our findings suggest that CB[sub]2[/sub]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[sub]2[/sub]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.