This study is proposed as a proof of principle: that gene delivery to the central nervous system can mitigate the harmful effects of HIV and HIV gene products on the brain. HIV encephalopathy is a potentially devastating complication of AIDS. There is no current therapy for CNS HIV infection: conventional antiretroviral drugs penetrate the brain poorly and anti-HIV CNS gene therapy has not been reported. Transgenes are currently available that are highly potent inhibitors of HIV entry and replication. Further, HIV envelope glycoprotein, gp120, has been implicated in neuron cell death via oxidant-related mechanisms in HIV encephalopathy. We have confirmed that gp120 causes apoptosis in human neurons, and that providing these cells with antioxidant enzymes, such as catalase protects them from apoptosis induced by HIV proteins. We submit that tools are now available to test gene delivery for the first time to address this problem, and propose to use gene delivery techniques to test the following hypothesis - Anti-oxidant and anti-HIV transgenes can protect cns cells from HIV and neural apoptosis caused by HIV gene products. To test this hypothesis, we will use as tools gene delivery vehicles derived from Tag-deleted SV40 (rSV40s). These vectors efficiently transduce key CNS cell targets for HIV and neurotoxicity induced by HIV, i.e., microglia, neurons, and monocyte-derived macrophages (MDM). We propose 4 aims: 1. Identify longitudinally optimal transgenes individually and in combination to inhibit HIV in CNS cells 2. Assess CNS and peripheral routes of administration to deliver rSV40s to the brain most effectively 3. Measure the ability of anti-CCR5 genes delivered in vivo to reduce MDM and microglial CCR5 gene delivery in vitro and in vivo to apoptosis-induced products. Despite the frequency and severity of CNS HIV infection, people with HIV encephalopathy have few treatment options. We propose to address this therapeutic challenge using gene delivery to the CNS, both to protect the brain from HIV infection and to mitigate HIV-induced CNS dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH070287-01A1
Application #
6798491
Study Section
Special Emphasis Panel (ZRG1-AARR-B (01))
Program Officer
Kopnisky, Kathy Lynn
Project Start
2004-04-01
Project End
2009-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
1
Fiscal Year
2004
Total Cost
$392,500
Indirect Cost
Name
Thomas Jefferson University
Department
Pathology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Louboutin, Jean-Pierre; Strayer, David S (2013) Relationship between the chemokine receptor CCR5 and microglia in neurological disorders: consequences of targeting CCR5 on neuroinflammation, neuronal death and regeneration in a model of epilepsy. CNS Neurol Disord Drug Targets 12:815-29
Louboutin, Jean-Pierre; Marusich, Elena; Gao, Ehre et al. (2012) Ethanol protects from injury due to ischemia and reperfusion by increasing vascularity via vascular endothelial growth factor. Alcohol 46:441-54
Louboutin, J-P; Agrawal, L; Reyes, B A S et al. (2012) Gene delivery of antioxidant enzymes inhibits human immunodeficiency virus type 1 gp120-induced expression of caspases. Neuroscience 214:68-77
Louboutin, Jean-Pierre; Strayer, David S (2012) Blood-brain barrier abnormalities caused by HIV-1 gp120: mechanistic and therapeutic implications. ScientificWorldJournal 2012:482575
Agrawal, Lokesh; Louboutin, Jean-Pierre; Reyes, Beverly A S et al. (2012) HIV-1 Tat neurotoxicity: a model of acute and chronic exposure, and neuroprotection by gene delivery of antioxidant enzymes. Neurobiol Dis 45:657-70
Louboutin, J-P; Reyes, B A S; Agrawal, L et al. (2012) Intracisternal rSV40 administration provides effective pan-CNS transgene expression. Gene Ther 19:114-8
Louboutin, Jean-Pierre; Reyes, Beverly A S; Agrawal, Lokesh et al. (2011) HIV-1 gp120 upregulates matrix metalloproteinases and their inhibitors in a rat model of HIV encephalopathy. Eur J Neurosci 34:2015-23
Louboutin, Jean-Pierre; Chekmasova, Alena; Marusich, Elena et al. (2011) Role of CCR5 and its ligands in the control of vascular inflammation and leukocyte recruitment required for acute excitotoxic seizure induction and neural damage. FASEB J 25:737-53
Louboutin, J-P; Chekmasova, A A; Reyes, B A S et al. (2011) Bone marrow-derived cells migrate to line the vessels of the CNS: opportunities for gene delivery to CNS vasculature. Neuroscience 195:215-23
Louboutin, J-P; Marusich, E; Fisher-Perkins, J et al. (2011) Gene transfer to the rhesus monkey brain using SV40-derived vectors is durable and safe. Gene Ther 18:682-91

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