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The effects of ARVs on ARG‐iNOS pathway in the brain: does the interaction play a role in microglial activation?
Author(s) -
Laudati Emilia,
Lucia Lisi,
Russo Cinzia Dello,
Navarra Pierluigi
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.705.6
Subject(s) - darunavir , efavirenz , microglia , atazanavir , arginase , abacavir , nitric oxide , pharmacology , interferon , immunology , chemistry , biology , inflammation , arginine , biochemistry , human immunodeficiency virus (hiv) , viral load , endocrinology , antiretroviral therapy , amino acid
Neurological complications affect approximately 50% of HIV patients undergoing HAART therapy; the occurrence of these complications may result from a combination of factors, and their underlying molecular mechanisms are not fully elucidated. The central nervous system is an immunological privileged site, representing a sanctuary and a reservoir for HIV‐1. Unlike other viral infections, once in the brain HIV‐1 does not directly infect neurons, but replication is mainly observed within microglia cells and perivascular macrophages. With this in mind, we carried out a screening of different AVRs (Atazanavir, Darunavir, Efavirenz, Nevirapine, Abacavir and Tenofovir) for their potential pro‐inflammatory effects on primary microglial cells. Efavirenz, Neviparine, Darunavir and Atazanavir increase nitric oxide production in microglial cells activated with Gp120CN54 and interferon (IFN)‐γ (a scenario mimicking the late stage of HIV infection), but not iNOS gene expression. In parallel the same drugs are able to inhibit arginase I (ARG) activity. Therefore, we hypothesize that ARVs interact with ARG; the subsequent increase in L‐arginine (a substrate for both ARG and iNOS) in turn modifies iNOS activity. However, when these ARVs are tested on microglial lysates, optimizing the in vitro conditions to assess ARG activity, we observe an effect opposite to that obtained in cell cultures: ARVs significant increase ARG activity. Biochemical approaches are now carried out in our laboratory, attempting to clarify the mechanism underlying such apparently paradoxical effect. Taken together, these data suggest that ARG‐iNOS interplay can be foreseen as an additional target of different ARVs, which may contribute to their pharmacological activity as well as explain, at least in part their neurotoxic potential.