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Uptake of HIV-1 Tat protein mediated by low-density lipoprotein receptor-related protein disrupts the neuronal metabolic balance of the receptor ligands

Abstract

Neurological disorders develop in most people infected with human immunodeficiency virus type 1 (HIV-1). However, the underlying mechanisms remain largely unknown. Here we report that binding of HIV-1 transactivator (Tat) protein to low-density lipoprotein receptor-related protein (LRP) promoted efficient uptake of Tat into neurons. LRP-mediated uptake of Tat was followed by translocation to the neuronal nucleus. Furthermore, the binding of Tat to LRP resulted in substantial inhibition of neuronal binding, uptake and degradation of physiological ligands for LRP, including α2-macroglobulin, apolipoprotein E4, amyloid precursor protein and amyloid β-protein. In a model of macaques infected with a chimeric strain of simian–human immunodeficiency virus, increased staining of amyloid precursor protein was associated with Tat expression in the brains of simian–human immunodeficiency virus-infected macaques with encephalitis. These results indicate that HIV-1 Tat may mediate HIV-1-induced neuropathology through a pathway involving disruption of the metabolic balance of LRP ligands and direct activation of neuronal genes.

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Acknowledgements

We thank C. Herrmann for advice on the GST–Tat protein purification, and H. Broxmeyer, S. Spinola, J. Blum, Y.-C. Yang, A. Srivastava and G. Alkhatib for critical reading of the manuscript. This work was supported by grants from Indiana University School of Medicine and the Ralph W. and Grace M. Showalter Trust Foundation, and funds from Department of Microbiology and Immunology and Walther Oncology Center at Indiana University School of Medicine, and the grant NS39253 (to AN).

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Correspondence to Johnny J. He.

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Further reading

Figure 1: Interaction of Tat with neurons.
Figure 2: Specific interaction of Tat and LRP.
Figure 3: Neuronal uptake of Tat mediated by LRP.
Figure 4: Competitive inhibition of interaction between LRP and LRP ligands by Tat.
Figure 5: Immunostaining for APP and Tat in the brains of SHIV-infected macaques.