Tags

Type your tag names separated by a space and hit enter

Antioxidant enzyme gene delivery to protect from HIV-1 gp120-induced neuronal apoptosis.
Gene Ther. 2006 Dec; 13(23):1645-56.GT

Abstract

Human immunodeficiency virus-1 (HIV-1) infection in the central nervous system (CNS) may lead to neuronal loss and progressively deteriorating CNS function: HIV-1 gene products, especially gp120, induce free radical-mediated apoptosis. Reactive oxygen species (ROS), are among the potential mediators of these effects. Neurons readily form ROS after gp120 exposure, and so might be protected from ROS-mediated injury by antioxidant enzymes such as Cu/Zn-superoxide dismutase (SOD1) and/or glutathione peroxidase (GPx1). Both enzymes detoxify oxygen free radicals. As they are highly efficient gene delivery vehicles for neurons, recombinant SV40-derived vectors were used for these studies. Cultured mature neurons derived from NT2 cells and primary fetal neurons were transduced with rSV40 vectors carrying human SOD1 and/or GPx1 cDNAs, then exposed to gp120. Apoptosis was measured by terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay. Transduction efficiency of both neuron populations was >95%, as assayed by immunostaining. Transgene expression was also ascertained by Western blotting and direct assays of enzyme activity. Gp120 induced apoptosis in a high percentage of unprotected NT2-N. Transduction with SV(SOD1) and SV(GPx1) before gp120 challenge reduced neuronal apoptosis by >90%. Even greater protection was seen in cells treated with both vectors in sequence. Given singly or in combination, they protect neuronal cells from HIV-1-gp120 induced apoptosis. We tested whether rSV40 s can deliver antioxidant enzymes to the CNS in vivo: intracerebral injection of SV(SOD1) or SV(GPx1) into the caudate putamen of rat brain yielded excellent transgene expression in neurons. In vivo transduction using SV(SOD1) also protected neurons from subsequent gp120-induced apoptosis after injection of both into the caudate putamen of rat brain. Thus, SOD1 and GPx1 can be delivered by SV40 vectors in vitro or in vivo. This approach may merit consideration for therapies in HIV-1-induced encephalopathy.

Authors+Show Affiliations

Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA. lokesh.agrawal@jefferson.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

16871233

Citation

Agrawal, L, et al. "Antioxidant Enzyme Gene Delivery to Protect From HIV-1 Gp120-induced Neuronal Apoptosis." Gene Therapy, vol. 13, no. 23, 2006, pp. 1645-56.
Agrawal L, Louboutin JP, Reyes BA, et al. Antioxidant enzyme gene delivery to protect from HIV-1 gp120-induced neuronal apoptosis. Gene Ther. 2006;13(23):1645-56.
Agrawal, L., Louboutin, J. P., Reyes, B. A., Van Bockstaele, E. J., & Strayer, D. S. (2006). Antioxidant enzyme gene delivery to protect from HIV-1 gp120-induced neuronal apoptosis. Gene Therapy, 13(23), 1645-56.
Agrawal L, et al. Antioxidant Enzyme Gene Delivery to Protect From HIV-1 Gp120-induced Neuronal Apoptosis. Gene Ther. 2006;13(23):1645-56. PubMed PMID: 16871233.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Antioxidant enzyme gene delivery to protect from HIV-1 gp120-induced neuronal apoptosis. AU - Agrawal,L, AU - Louboutin,J-P, AU - Reyes,B A S, AU - Van Bockstaele,E J, AU - Strayer,D S, Y1 - 2006/07/27/ PY - 2006/7/28/pubmed PY - 2007/5/22/medline PY - 2006/7/28/entrez SP - 1645 EP - 56 JF - Gene therapy JO - Gene Ther VL - 13 IS - 23 N2 - Human immunodeficiency virus-1 (HIV-1) infection in the central nervous system (CNS) may lead to neuronal loss and progressively deteriorating CNS function: HIV-1 gene products, especially gp120, induce free radical-mediated apoptosis. Reactive oxygen species (ROS), are among the potential mediators of these effects. Neurons readily form ROS after gp120 exposure, and so might be protected from ROS-mediated injury by antioxidant enzymes such as Cu/Zn-superoxide dismutase (SOD1) and/or glutathione peroxidase (GPx1). Both enzymes detoxify oxygen free radicals. As they are highly efficient gene delivery vehicles for neurons, recombinant SV40-derived vectors were used for these studies. Cultured mature neurons derived from NT2 cells and primary fetal neurons were transduced with rSV40 vectors carrying human SOD1 and/or GPx1 cDNAs, then exposed to gp120. Apoptosis was measured by terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay. Transduction efficiency of both neuron populations was >95%, as assayed by immunostaining. Transgene expression was also ascertained by Western blotting and direct assays of enzyme activity. Gp120 induced apoptosis in a high percentage of unprotected NT2-N. Transduction with SV(SOD1) and SV(GPx1) before gp120 challenge reduced neuronal apoptosis by >90%. Even greater protection was seen in cells treated with both vectors in sequence. Given singly or in combination, they protect neuronal cells from HIV-1-gp120 induced apoptosis. We tested whether rSV40 s can deliver antioxidant enzymes to the CNS in vivo: intracerebral injection of SV(SOD1) or SV(GPx1) into the caudate putamen of rat brain yielded excellent transgene expression in neurons. In vivo transduction using SV(SOD1) also protected neurons from subsequent gp120-induced apoptosis after injection of both into the caudate putamen of rat brain. Thus, SOD1 and GPx1 can be delivered by SV40 vectors in vitro or in vivo. This approach may merit consideration for therapies in HIV-1-induced encephalopathy. SN - 0969-7128 UR - https://www.unboundmedicine.com/medline/citation/16871233/Antioxidant_enzyme_gene_delivery_to_protect_from_HIV_1_gp120_induced_neuronal_apoptosis_ L2 - https://doi.org/10.1038/sj.gt.3302821 DB - PRIME DP - Unbound Medicine ER -