Intracisternal rSV40 administration provides effective pan-CNS transgene expression

Louboutin, J-P; Reyes, Beverly A.S.; Agrawal, Lokesh; Bockstaele, Elisabeth J. Van; Strayer, David S.

doi:10.1038/gt.2011.75

Cited by 7 publications

(6 citation statements)

References 38 publications

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“…Vector administration into the lateral ventricle (LV) [ 110 ] or cisterna magna (CM) [ 115 ], particularly if preceded by intraperitoneal mannitol, protects from intra-CP gp120-induced neurotoxicity comparably to intra-CP vector administration.…”

Section: Antioxidant Therapeutic Approaches In Handmentioning

confidence: 99%

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Role of Oxidative Stress in HIV-1-Associated Neurocognitive Disorder and Protection by Gene Delivery of Antioxidant Enzymes

Louboutin

Strayer

2014

Antioxidants

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HIV encephalopathy covers a range of HIV-1-related brain dysfunction. In the Central Nervous System (CNS), it is largely impervious to Highly Active AntiRetroviral Therapy (HAART). As survival with chronic HIV-1 infection improves, the number of people harboring the virus in their CNS increases. Neurodegenerative and neuroinflammatory changes may continue despite the use of HAART. Neurons themselves are rarely infected by HIV-1, but HIV-1 infects resident microglia, periventricular macrophages, leading to increased production of cytokines and to release of HIV-1 proteins, the most likely neurotoxins, among which are the envelope glycoprotein gp120 and HIV-1 trans-acting protein Tat. Gp120 and Tat induce oxidative stress in the brain, leading to neuronal apoptosis/death. We review here the role of oxidative stress in animal models of HIV-1 Associated Neurocognitive Disorder (HAND) and in patients with HAND. Different therapeutic approaches, including clinical trials, have been used to mitigate oxidative stress in HAND. We used SV40 vectors for gene delivery of antioxidant enzymes, Cu/Zn superoxide dismutase (SOD1), or glutathione peroxidase (GPx1) into the rat caudate putamen (CP). Intracerebral injection of SV (SOD1) or SV (GPx1) protects neurons from apoptosis caused by subsequent inoculation of gp120 and Tat at the same location. Vector administration into the lateral ventricle or cisterna magna protects from intra-CP gp120-induced neurotoxicity comparably to intra-CP vector administration. These models should provide a better understanding of the pathogenesis of HIV-1 in the brain as well as offer new therapeutic avenues.

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Section: Antioxidant Therapeutic Approaches In Handmentioning

confidence: 99%

“…Cerebral ischemia triggers both the intrinsic and extrinsic pathways of apoptosis [ 55 , 59 ]. Mounting evidence suggests the involvement of caspases in the disease process associated with neurodegenerative diseases such AD [ 115 ] and amyotrophic lateral sclerosis (ALS) [ 114 ].…”

Section: Antioxidant Therapeutic Approaches In Handmentioning

confidence: 99%

Role of Oxidative Stress in HIV-1-Associated Neurocognitive Disorder and Protection by Gene Delivery of Antioxidant Enzymes

Louboutin

Strayer

2014

Antioxidants

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“…Vector administration into the lateral ventricle (LV) or the cisterna magna, particularly if preceded by mannitol i.p., protects from intra-CP gp120-induced neurotoxicity comparably to intra-CP vector administration [31, 70]. …”

Section: Gp120 In Vivo Induces Oxidative Stress In Endothelial Celmentioning

confidence: 99%

“…Intracerebral injection of rSV40s carrying cDNAs for these antioxidant enzymes significantly protected neurons from apoptosis and other consequences of subsequent injection of HIV-1 gp120 at the same location [ 18 , 25 , 31 , 69 ]. Vector administration into the lateral ventricle (LV) or the cisterna magna, particularly if preceded by mannitol i.p., protects from intra-CP gp120-induced neurotoxicity comparably to intra-CP vector administration [ 31 , 70 ].…”

Section: Gp120 In Vivo Induces Oxidative Stressmentioning

confidence: 99%

Blood-Brain Barrier Abnormalities Caused by HIV-1 gp120: Mechanistic and Therapeutic Implications

Louboutin

Strayer

2012

The Scientific World Journal

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The blood-brain barrier (BBB) is compromised in many systemic and CNS diseases, including HIV-1 infection of the brain. We studied BBB disruption caused by HIV-1 envelope glycoprotein 120 (gp120) as a model. Exposure to gp120, whether acute [by direct intra-caudate-putamen (CP) injection] or chronic [using SV(gp120), an experimental model of ongoing production of gp120] disrupted the BBB, and led to leakage of vascular contents. Gp120 was directly toxic to brain endothelial cells. Abnormalities of the BBB reflect the activity of matrix metalloproteinases (MMPs). These target laminin and attack the tight junctions between endothelial cells and BBB basal laminae. MMP-2 and MMP-9 were upregulated following gp120-injection. Gp120 reduced laminin and tight junction proteins. Reactive oxygen species (ROS) activate MMPs. Injecting gp120 induced lipid peroxidation. Gene transfer of antioxidant enzymes protected against gp120-induced BBB abnormalities. NMDA upregulates the proform of MMP-9. Using the NMDA receptor (NMDAR-1) inhibitor, memantine, we observed partial protection from gp120-induced BBB injury. Thus, (1) HIV-envelope gp120 disrupts the BBB; (2) this occurs via lesions in brain microvessels, MMP activation and degradation of vascular basement membrane and vascular tight junctions; (3) NMDAR-1 activation plays a role in this BBB injury; and (4) antioxidant gene delivery as well as NMDAR-1 antagonists may protect the BBB.

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“…Moreover, intra-CP SV40-mediated gene delivery of antioxidant enzymes protects against several deleterious consequences following gp120 injection into the CP (Louboutin et al, 2009b, 2010b,c,d). Vector administration into the lateral ventricle (LV) or the cisterna magna, particularly if preceded by mannitol i.p., protects from intra-CP gp120-induced neurotoxicity comparably to intra-CP vector administration (Louboutin et al, 2007a; Louboutin et al, in press). rSV40s were employed in the current study because they transduce cells in G0 with high efficiency; they infect a wide range of cell types from humans and other mammals and deliver genes to nondividing cells efficiently and achieve long-term transgene expression in vitro and in vivo (Strayer, 1999).…”

Section: Discussionmentioning

confidence: 99%

Gene delivery of antioxidant enzymes inhibits human immunodeficiency virus type 1 gp120-induced expression of caspases

et al. 2012

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Caspases are implicated in neuronal death in neurodegenerative and other Central Nervous System (CNS) diseases. In a rat model of HIV-1 associated neurocognitive disorders (HAND), we previously characterized HIV-1 envelope gp120-induced neuronal apoptosis by TUNEL assay. In this model, neuronal apoptosis occurred probably via gp120-induced reactive oxygen species (ROS). Antioxidant gene delivery blunted gp120-related apoptosis. Here, we studied the effect of gp120 on different caspases (3, 6, 8, 9) expression. Caspases production increased in the rat caudate-putamen (CP) 6h after gp120 injection into the same structure. The expression of caspases peaked by 24h. Caspases colocalized mainly with neurons. Prior gene delivery of the antioxidant enzymes Cu/Zn superoxide dismutase (SOD1) or glutathione peroxidase (GPx1) into the CP before injecting gp120 there reduced levels of gp120-induced caspases, recapitulating the effect of antioxidant enzymes on gp120-induced apoptosis observed by TUNEL. Thus, HIV-1 gp120 increased caspases expression in the CP. Prior antioxidant enzyme treatment mitigated production of these caspases, probably by reducing ROS levels.

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Intracisternal rSV40 administration provides effective pan-CNS transgene expression

Cited by 7 publications

References 38 publications

Role of Oxidative Stress in HIV-1-Associated Neurocognitive Disorder and Protection by Gene Delivery of Antioxidant Enzymes

Role of Oxidative Stress in HIV-1-Associated Neurocognitive Disorder and Protection by Gene Delivery of Antioxidant Enzymes

Blood-Brain Barrier Abnormalities Caused by HIV-1 gp120: Mechanistic and Therapeutic Implications

Gene delivery of antioxidant enzymes inhibits human immunodeficiency virus type 1 gp120-induced expression of caspases

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