HIV-1 gp120-induced neuroinflammation: Relationship to neuron loss and protection by rSV40-delivered antioxidant enzymes

• Published in: Experimental neurology 2010, Vol.221 (1), p.231-245
• Main Authors: Louboutin, Jean-Pierre, Reyes, Beverly A.S., Agrawal, Lokesh, Van Bockstaele, Elisabeth J., Strayer, David S.
• Format: Article
• Language: English
• Subjects: Animals; Antigens, CD - metabolism; Antigens, Differentiation, Myelomonocytic - metabolism; Antioxidants; Antioxidants - pharmacology; Aquaporins - metabolism; Biological and medical sciences; Calcium-Binding Proteins - metabolism; CD11b Antigen - metabolism; Cell Death - drug effects; Cell Proliferation; Chemokine CCL2 - metabolism; Disease Models, Animal; Dose-Response Relationship, Drug; Encephalitis - chemically induced; Encephalitis - pathology; Encephalitis - prevention & control; Eye Proteins - metabolism; Female; Gene Expression Regulation - drug effects; Genetic Therapy - methods; Genetic Vectors - administration & dosage; Genetic Vectors - genetics; Glutathione Peroxidase - genetics; Glutathione Peroxidase - pharmacology; gp120; HIV Envelope Protein gp120; HIV-1; Human immunodeficiency virus 1; Human viral diseases; Indoles; Infectious diseases; Medical sciences; Microfilament Proteins; Microglia - drug effects; Microglia - virology; Neuroinflammation; Neurology; Neurons - metabolism; Neurons - virology; Neurotensin - metabolism; Nitric Oxide Synthase Type II - metabolism; Putamen - drug effects; Putamen - virology; Rats; Rats, Sprague-Dawley; Simian virus 40 - genetics; Statistics, Nonparametric; Superoxide Dismutase - genetics; Superoxide Dismutase - pharmacology; SV40; Time Factors; Transduction, Genetic - methods; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2009.11.004

HIV-1 gp120 neurotoxicity and oxidant injury are well documented, but consequent neuroinflammation is less understood. Rat caudate–putamens (CPs) were challenged with 100–500 ng HIV-1BaL gp120, with or without prior rSV40-delivered superoxide dismutase or glutathione peroxidase. CD11b-positive microglia were increased 1 day post-challenge; Iba-1- and ED1-positive cells peaked at 7 days and 14 days. Astrocyte infiltration was maximal at 7–14 days. MIP-1alpha was produced immediately, mainly by neurons. ED1- and GFAP-positive cells correlated with neuron loss and gp120 dose. We also tested the effect of more chronic gp120 exposure on neuroinflammation using an experimental model of continuing gp120 exposure. SV(gp120), a recombinant SV40-derived gene transfer vector was inoculated into the rat CP, leading to chronic expression of gp120, ongoing apoptosis in microglia and neurons, and oxidative stress. Increase in microglia and astrocytes was seen following intra-CP SV(gp120) injection, suggesting that continuing gp120 production increased neuroinflammation. SV(SOD1) or SV(GPx1) significantly reduced MIP-1alpha and limited neuroinflammation following gp120 administration into the CP, as well as microglia and astrocytes proliferation after injection of SV(gp120) in the striatum. Thus, gp120-induced CNS injury, neuron loss and inflammation may be mitigated by antioxidant gene delivery.