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

Departments of *Pathology and
^‡Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461; and
^†The Johns Hopkins Medical Center, Baltimore, MD 21224

Contributed by Michael V. L. Bennett, January 3, 2007 (received for review December 11, 2006)

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.

Footnotes

^§To whom correspondence should be addressed at:
Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461.
E-mail: berman{at}aecom.yu.edu
Author contributions: E.A.E., J.E.K., A.N., T.M.C., and J.W.B. designed research; E.A.E., J.E.K., and J.W.B. performed research; A.N. contributed new reagents/analytic tools; E.A.E., J.E.K., R.S.Z., M.V.L.B., and J.W.B. analyzed data; and E.A.E., J.E.K., T.M.C., R.S.Z., M.V.L.B., and J.W.B. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0611699104/DC1.
Abbreviations:

NMDAR,

N-methyl-d-aspartic acid receptor;

nNOS,

neuronal nitric oxide synthase;

iNOS,

inducible NOS;

CoIP,

coimmunoprecipitation;

NPA,

Nω-propyl-l-arginine.