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The Journal of Neuroscience, November 19, 2008, 28(47):12190-12198; doi:10.1523/JNEUROSCI.3019-08.2008

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Neurobiology of Disease
NMDA Receptor Activation by HIV-Tat Protein Is Clade Dependent

Wenxue Li,¹ Yan Huang,¹ Rollie Reid,¹ Joseph Steiner,¹ Tanya Malpica-Llanos,¹ Thomas A. Darden,³ Susarla K. Shankar,⁴ Anita Mahadevan,⁴ Parthasarthy Satishchandra,⁵ and Avindra Nath^1,2

Departments of ¹Neurology and ²Neuroscience, Johns Hopkins University, Baltimore, Maryland 21287, ³Laboratory of Structural Biology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, and Departments of ⁴Neuropathology and ⁵Neurology, National Institute of Mental Health and Neurosciences, Bangalore 560029, India

Correspondence should be addressed to Dr. Avindra Nath, Department of Neurology, Johns Hopkins University, 509 Pathology, 600 North Wolfe Street, Baltimore, MD 21287. Email: anath1{at}jhmi.edu

In countries infected with HIV clade B, some patients develop a rapidly progressive dementia that if untreated results in death. In regions of the world infected with HIV clade C, only milder forms of cognitive impairment have been recognized. HIV-infected macrophages are the principal mediators of dementia. HIV clade C, however, efficiently infects macrophages and HIV-infected macrophages are found in the brains of clade C-infected patients. HIV-infected macrophages release Tat protein, which may act directly on neurons to cause toxicity. We found that Tat released from Tat-expressing cells was at least 1000-fold more toxic than recombinant Tat protein. We determined whether Tat could interact with NMDA receptors and whether these interactions are clade dependent. It is demonstrated that Tat binds directly to the NMDA receptor leading to excitotoxicity. The Cys 30-Cys 31 motif in Tat is critical for exciting the NMDA receptor and the Cys31Ser mutation found in clade C Tat has a significantly attenuated neurotoxic response. Through molecular modeling and site-directed mutagenesis, we predict that Cys 31 disrupts the disulfide bond between Cys 744 and Cys 798 on the NR1 subunit of the NMDA receptor by directly interacting with Cys 744 leading to a free thiol group on Cys 798 and subsequent persistent activation of the NMDA receptor.

Key words: injury; NMDA receptor; neuron; neuronal death; nitric oxide; neurotoxicity

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Received June 30, 2008; revised Aug. 17, 2008; accepted Sept. 22, 2008.

Correspondence should be addressed to Dr. Avindra Nath, Department of Neurology, Johns Hopkins University, 509 Pathology, 600 North Wolfe Street, Baltimore, MD 21287. Email: anath1{at}jhmi.edu

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