Characterization of cell death pathways in human immunodeficiency virus-associated encephalitis.
Human immunodeficiency virus (HIV)-associated dementia is a neurodegenerative syndrome characterized by cognitive decline, personality change, and motor deficits. HIV-associated encephalitis (HAE), the neuropathology responsible for HIV-associated dementia, involves the formation of multinucleated giant cells or syncytia. In this article we describe the apoptotic pathways activated in the brains of HAE-affected patients. Approximately 50% of multinuclear giant cells exhibited apoptotic DNA fragmentation as detected by the terminal dUTP nick-end labeling technique. In addition, the presence of syncytia in the frontal cortex of approximately 35% of HAE patients correlated with the number of cells expressing the HIV-1 protein p24. Histochemical and immunohistochemical analyses revealed that HAE-associated syncytia underwent apoptosis through a mitochondrial pathway previously delineated for HIV-1 envelope-elicited syncytia in vitro. We observed over-expression of the mammalian target of rapamycin (mTOR), a kinase that mediates activation of the pro-apoptotic transcription factor p53, and p53-dependent up-regulation of two effectors of mitochondrial apoptosis, namely the BH3-only proteins Puma and transglutaminase type 2 (TG2). Interestingly, although mTOR activation and Puma induction were observed in dying syncytia and neurons, IkB phosphorylation and TG2 up-regulation were only found in syncytia. These findings provide substantial new information on the cell death mechanisms that regulate HAE, suggesting an important pathogenetic role of syncytia in the disease.
Nardacci
Roberta
R
National Institute for Infectious Diseases, University of Rome, 00149 Rome, Italy.
Antinori
Andrea
A
Larocca
Luigi Maria
LM
Arena
Vincenzo
V
Amendola
Alessandra
A
Perfettini
Jean-Luc
JL
Kroemer
Guido
G
Piacentini
Mauro
M
D000163:Acquired Immunodeficiency Syndrome; D000328:Adult; D017209:Apoptosis; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D016923:Cell Death; D004660:Encephalitis / Q000473:pathology / Q000503:physiopathology* / Q000821:virology*; D005260:Female; D015726:Giant Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D012720:Severity of Illness Index; D058570:TOR Serine-Threonine Kinases
D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases