Preventing HIV-1 Tat-induced neuronal apoptosis using antioxidant enzymes: mechanistic and therapeutic implications.
HIV-1 proteins, especially gp120 and Tat, elicit reactive oxygen species (ROS) and cause neuron apoptosis. We used antioxidant enzymes, Cu/Zn superoxide dismutase (SOD1) and glutathione peroxidase (GPx1) to study signaling and neuroprotection from Tat-induced apoptosis. SOD1 converts superoxide to peroxide; GPx1 converts peroxide to water. Primary human neurons were transduced with SV40-derived vectors carrying SOD1 and GPx1, then HIV-1 Tat protein was added. Both SV(SOD1) and SV(GPx1) delivered substantial transgene expression. Tat decreased endogenous cellular, but not transduced, SOD1 and GPx1. Tat rapidly increased neuron [Ca(2+)](i), which effect was not altered by SV(SOD1) or SV(GPx1). However, both vectors together blocked Tat-induced [Ca(2+)](i) fluxes. Similarly, neither SV(SOD1) nor SV(GPx1) protected neurons from Tat-induced apoptosis, but both vectors together did. Tat therefore activates multiple signaling pathways, in one of which superoxide acts as an intermediate while the other utilizes peroxide. Gene delivery to protect neurons from Tat must therefore target both.
Agrawal
Lokesh
L
Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Room 251, 1020 Locust Street, Philadelphia, PA 19107, USA.
Louboutin
Jean-Pierre
JP
Strayer
David S
DS
D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D016166:Free Radical Scavengers / Q000378:metabolism / Q000494:pharmacology*; D015696:Gene Products, tat / Q000633:toxicity*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D015658:HIV Infections / Q000503:physiopathology / Q000628:therapy / Q000821:virology*; D015497:HIV-1 / Q000737:chemistry / Q000472:pathogenicity*; D006801:Humans; D009474:Neurons / Q000473:pathology / Q000821:virology; D013539:Simian virus 40 / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D014774:Virulence; D054322:tat Gene Products, Human Immunodeficiency Virus
D016166:Free Radical Scavengers; D015696:Gene Products, tat; D054322:tat Gene Products, Human Immunodeficiency Virus; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D002118:Calcium