Silencing the PTEN gene is protective against neuronal death induced by human immunodeficiency virus type 1 Tat.
Neurons are targets of toxicity induced by the human immunodeficiency virus (HIV)-1 protein Tat (transactivator of transcription). Exposure to Tat increases [Ca(2+)](i) in striatal neurons and activates multiple cell death pathways. In earlier studies the authors showed that Tat activated both caspase-3 and endonuclease-G, a caspase-independent effector of apoptosis, and that Tat-induced neurotoxicity was not attenuated by a caspase-3 inhibitor. Because Tat activates multiple, parallel death pathways, the authors attempted to reduce Tat-induced neurotoxicity by manipulating signaling pathways upstream of mitochondrial apoptotic events. PTEN (phosphatase and tensin homolog deleted on chromosome 10), a negative regulator of Akt/PKB (protein kinase B) phosphorylation, was chosen as a target for silencing. Akt/PKB activity directs multiple downstream pathways mediated by GSK3beta, BAD, forkhead transcription factors, nuclear factor kappa B (NFkappaB), and others, in a manner that promotes proliferation and survival. Striatal neurons were nucleofected with short interfering RNA (siRNA) vectors targeting PTEN, or a negative-control siRNA. Although Tat(1-86) significantly increased the death of neurons transfected with control construct by 72 h, PTEN-silenced neurons were completely protected. These findings indicate that Akt is a critical intermediary in the direct neurotoxicity induced by HIV-1 Tat, and identify Akt regulation as a possible therapeutic strategy for Tat-induced neurotoxicity in HIV encephalitis (HIVE).
Zhao
Tianyong
T
Department of Anatomy and Neurobiology, University of Kentucky College of Medicine, Lexington, Kentucky 40536-0298, USA.
Adams
Mary H
MH
Zou
Shi-Ping
SP
El-Hage
Nazira
N
Hauser
Kurt F
KF
Knapp
Pamela E
PE
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology; D005260:Female; D015696:Gene Products, tat / Q000633:toxicity*; D020868:Gene Silencing; D015658:HIV Infections / Q000503:physiopathology / Q000628:therapy / Q000821:virology*; D015497:HIV-1 / Q000737:chemistry / Q000472:pathogenicity; D006801:Humans; D051379:Mice; D009474:Neurons / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D014774:Virulence; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D054322:tat Gene Products, Human Immunodeficiency Virus; D051059:PTEN Phosphohydrolase