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(American Journal of Pathology. 2005;167:695-704.)
© 2005 American Society for Investigative Pathology

Characterization of Cell Death Pathways in Human Immunodeficiency Virus-Associated Encephalitis

Roberta Nardacci^*, Andrea Antinori^*, Luigi Maria Larocca, Vincenzo Arena, Alessandra Amendola^*, Jean-Luc Perfettini, Guido Kroemer and Mauro Piacentini^*

From the National Institute for Infectious Diseases, Lazzaro Spallanzani,^* Rome, Italy; the Institute of Pathological Anatomy, Catholic University of Rome, School of Medicine, Rome, Italy; the Department of Biology, University of Rome "Tor Vergata," Rome, Italy; and CNRS-UMR8125, Institut Gustave Roussy, Villejuif, France

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 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.

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