HIV-tat induces formation of an LRP-PSD-95-NMDAR-nNOS complex that promotes apoptosis in neurons and astrocytes

Eliseo Eugenin, Jessie E. King, Avindra Nath, Tina M. Calderon, R. Suzanne Zukin, Michael V L Bennett, Joan W. Berman

Research output: Contribution to journalArticle

141 Citations (Scopus)

Abstract

HIV infection of the central nervous system can result in neurologic dysfunction with devastating consequences in AIDS patients. NeuroAIDS is characterized by neuronal injury and loss, yet there is no evidence that HIV can infect neurons. Here we show that the HIV-encoded protein tat triggers formation of a macromolecular complex involving the low-density lipoprotein receptor-related protein (LRP), postsynaptic density protein-95 (PSD-95), N-methyl-D-aspartic acid (NMDA) receptors, and neuronal nitric oxide synthase (nNOS) at the neuronal plasma membrane, and that this complex leads to apoptosis in neurons negative as well as positive for NMDA receptors and also in astrocytes. Blockade of LRP-mediated tat uptake, NMDA receptor activation, or neuronal nitric oxide synthase significantly reduces ensuing neuronal apoptosis, suggesting that formation of this complex is an early step in tat toxicity. We also show that the inflammatory chemokine, CCL2, protects against tat toxicity and inhibits formation of the complex. These findings implicate the complex in HIV-induced neuronal apoptosis and suggest therapeutic targets for intervention in the pathogenesis of NeuroAIDS.

Original languageEnglish (US)
Pages (from-to)3438-3443
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number9
DOIs
StatePublished - Feb 27 2007
Externally publishedYes

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Lipoprotein Receptors
Nitric Oxide Synthase Type I
N-Methylaspartate
Astrocytes
HIV
Apoptosis
Neurons
Human Immunodeficiency Virus tat Gene Products
LDL-Receptor Related Proteins
tat Gene Products
Macromolecular Substances
Proteins
Chemokine CCL2
LDL Receptors
Neurologic Manifestations
HIV Infections
Acquired Immunodeficiency Syndrome
Central Nervous System
Cell Membrane
Wounds and Injuries

Keywords

  • Dementia
  • Excitotoxicity
  • Glutamate
  • HIV-1
  • NeuroAIDS

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

HIV-tat induces formation of an LRP-PSD-95-NMDAR-nNOS complex that promotes apoptosis in neurons and astrocytes. / Eugenin, Eliseo; King, Jessie E.; Nath, Avindra; Calderon, Tina M.; Zukin, R. Suzanne; Bennett, Michael V L; Berman, Joan W.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 9, 27.02.2007, p. 3438-3443.

Research output: Contribution to journalArticle

Eugenin, Eliseo ; King, Jessie E. ; Nath, Avindra ; Calderon, Tina M. ; Zukin, R. Suzanne ; Bennett, Michael V L ; Berman, Joan W. / HIV-tat induces formation of an LRP-PSD-95-NMDAR-nNOS complex that promotes apoptosis in neurons and astrocytes. In: Proceedings of the National Academy of Sciences of the United States of America. 2007 ; Vol. 104, No. 9. pp. 3438-3443.
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