Antiretrovirals inhibit arginase in human microglia

作者：Lisi Lucia; Laudati Emilia; Miscioscia Teresa F; Dello Russo Cinzia; Topai Alessandra; Navarra Pierluigi^*

来源：Journal of Neurochemistry, 2016, 136(2): 363-372.

DOI：10.1111/jnc.13393

• antiretroviral drugs
• ARG
• arginase-I
• microglia
• microglial polarization

Preliminary evidence in an animal model, that is, primary cultures of rat microglia cells, suggested that some antiretroviral drugs (ARVs), namely darunavir, atazanavir, efavirenz, and nevirapine, increase NO production through a mechanism involving the inhibition of arginase (ARG) activity. This study was conceived to investigate the effects of ARVs on ARG activity in a human experimental model. We compared CHME-5 human microglial immortalized cells under basal conditions with cells exposed to either IL-4, a mix of inflammatory cytokines, or both stimuli given together. We also tested the effects of ARVs on CHME-5 cell lysates after exposure to the above stimuli. Moreover, the interaction between the ARVs and ARG was investigated via computational chemistry. We found that ARVs consistently inhibit ARG activity both in intact and lysed cells. In docking studies, darunavir and atazanavir showed similar scores compared with both l-arginine and the ARG antagonist nor-NOHA. Efavirenz and nevirapine, which are less potent in inhibiting ARG in the biochemical assay, also had lower scores. In conclusion, the present findings in a human model support the notion that ARG pathway can present a new, additional molecular target for different ARVs in HIV treatments.

• 出版日期2016-1