Lentiviral transduction of neuroprotective microglia with HIV1 Nef protein induces toxic change

AIDS patients frequently develop an human immunodeficiency virus type 1 (HIV-1)-asso-ciated abnormalities in cognition and par-kinsonian motor dysfunction. HIV-infected macrophages were observed in the striatum, and dopamine concentrations were significantly reduced in the striatum (Sarder et al., 1996).

Nef is the first viral protein detectable after human HIV-1 infection, enhances virus production and infectivity, and exerts pathologic effects independently of viral replication. Microglia are phagocytes of myeloid origin and the principal target of HIV infection in the brain. Microglia produce superoxide, and express all components of the superoxide generating phagocyte NADPH oxidase (Vilhardt et al., 2002). We transduced Nef protein using lenti virus vector into nontoxic Ra2 microglia. Both Ra2 and nefRa2 microglia were similar in GM-CSF dependency. Ra2 microglia did not produce ROS by stimulation with PMA. In contrast, nefRa2 robustly produced ROS owing to activation of NADPH oxidase. When N18 neuronal cells were co-cultured with Ra2 or nefRa2 microglia, Ra2 microglia were shown to be neuroprotective, but nefRa2 neurotoxic, indicating toxic change of Ra2 microglia by transduction of Nef protein. Addition of superoxide diamutase (SOD) partially recovered the neurotoxicity of nefRa2 to change the glial cell line to be neuroprotective. These results suggest that toxic change in nefRa2 microglia may be partially due to increased ROS production by increased NADPH oxidase. Another possibility of toxic change is increased production of myeloper-oxidase (MPO).

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