Protecting neurons from hiv-1 gp120-induced oxidant stress using both localized intracerebral and generalized intraventricular administration of antioxidant enzymes delivered by sv40-derived vectors

ABSTRACT Human immunodeficiency virus-1 (HIV-1) is the most frequent cause of dementia in adults under 40. We sought to use gene delivery to protect from HIV-1-related neuron loss. Because

HIV-1 envelope (Env) gp120 elicits oxidant stress and apoptosis in cultured neurons, we established reproducible parameters of Env-mediated neurotoxicity _in vivo_, then tested

neuroprotection using gene delivery of antioxidant enzymes. We injected 100–500 ng μl−1gp120 stereotaxically into rat caudate–putamens (CP) and assayed brains for apoptosis by terminal

deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) 6-h to 14-day post-injection. Peak apoptosis occurred 1 day after injection of 250 and 500 ng μl−1gp120.

TUNEL-positive cells mostly expressed neuronal markers (NeuroTrace), although some expressed CD68 and so were most likely microglial cells. Finally, we compared neuroprotection from

gp120-induced apoptosis provided by localized and generalized intra-central nervous system (CNS) gene delivery. Recombinant SV40 vectors carrying Cu/Zn superoxide dismutase (SOD1) or

glutathione peroxidase (GPx1) were injected into the CP, where gp120 was administered 4–24 weeks later. Alternatively, we inoculated the vector into the lateral ventricle (LV), with or

without prior intraperitoneal (i.p.) administration of mannitol. Intracerebral injection of SV(SOD1) or SV(GPx1) significantly protected neurons from gp120-induced apoptosis throughout the

24-week study. Intraventricular vector administration protected from gp120 neurotoxicity comparably, particularly if preceded by mannitol i.p. Thus, HIV-1 gp120 is neurotoxic _in vivo_, and

intracerebral or intra-ventricular administration of rSV40 vectors carrying antioxidant enzymes is neuroprotective. These findings suggest the potential utility of both localized and

widespread gene delivery in treating neuroAIDS and other CNS diseases characterized by excessive oxidative stress. Access through your institution Buy or subscribe This is a preview of

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2001; 158: 355–359. Article  CAS  PubMed  PubMed Central  Google Scholar  Download references ACKNOWLEDGEMENTS We thank Mr David Knowlton for technical assistance. We are also grateful to Dr

Pierre Cordelier for important scientific discussions, suggestions and advice. This work was supported by NIH Grants MH69122, MH70287 and AI48244. AUTHOR INFORMATION AUTHORS AND

AFFILIATIONS * Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA J-P Louboutin, L Agrawal & D S Strayer * Department of Neurosurgery,

Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, PA, USA B A S Reyes & E J Van Bockstaele Authors * J-P Louboutin View author publications You can also

search for this author inPubMed Google Scholar * L Agrawal View author publications You can also search for this author inPubMed Google Scholar * B A S Reyes View author publications You can

also search for this author inPubMed Google Scholar * E J Van Bockstaele View author publications You can also search for this author inPubMed Google Scholar * D S Strayer View author

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ARTICLE CITE THIS ARTICLE Louboutin, JP., Agrawal, L., Reyes, B. _et al._ Protecting neurons from HIV-1 gp120-induced oxidant stress using both localized intracerebral and generalized

intraventricular administration of antioxidant enzymes delivered by SV40-derived vectors. _Gene Ther_ 14, 1650–1661 (2007). https://doi.org/10.1038/sj.gt.3303030 Download citation *

Received: 16 April 2007 * Revised: 23 July 2007 * Accepted: 23 July 2007 * Published: 04 October 2007 * Issue Date: December 2007 * DOI: https://doi.org/10.1038/sj.gt.3303030 SHARE THIS

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Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * Cu/Zn superoxide dismutase * glutathione peroxidase * neuroAIDS