HIV-tat induces formation of an LRP-PSD-95- NMDAR-nNOS complex that promotes apoptosis in neurons and astrocytes.
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.
Eugenin
Eliseo A
EA
Department of Pathology and Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
King
Jessie E
JE
Nath
Avindra
A
Calderon
Tina M
TM
Zukin
R Suzanne
RS
Bennett
Michael V L
MV
Berman
Joan W
JW
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001253:Astrocytes / Q000502:physiology*; D015153:Blotting, Western; D018932:Chemokine CCL2 / Q000378:metabolism / Q000494:pharmacology; D000076122:Disks Large Homolog 4 Protein; D004591:Electrophoresis, Polyacrylamide Gel; D005333:Fetus; D015696:Gene Products, tat / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D020287:In Situ Nick-End Labeling; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D026502:LDL-Receptor Related Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D018613:Microscopy, Confocal; D046912:Multiprotein Complexes / Q000378:metabolism*; D009474:Neurons / Q000502:physiology*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D018709:Statistics, Nonparametric; D054322:tat Gene Products, Human Immunodeficiency Virus
C111835:CCL2 protein, human; D018932:Chemokine CCL2; C501444:DLG4 protein, human; D000076122:Disks Large Homolog 4 Protein; D015696:Gene Products, tat; D047908:Intracellular Signaling Peptides and Proteins; D026502:LDL-Receptor Related Proteins; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D016194:Receptors, N-Methyl-D-Aspartate; D054322:tat Gene Products, Human Immunodeficiency Virus; D052248:Nitric Oxide Synthase Type I