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

Ying Liu, Melina Jones, Cynthia M. Hingtgen, Guojun Bu, Nick Laribee, Rudolph E. Tanzi, Robert D. Moir, Avindra Nath, Johnny J. He

Research output: Contribution to journalArticle

312 Scopus citations

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.

Original languageEnglish
Pages (from-to)1380-1387
Number of pages8
JournalNature Medicine
Volume6
Issue number12
DOIs
StatePublished - 1 Dec 2000

Fingerprint Dive into the research topics of 'Uptake of HIV-1 Tat protein mediated by low-density lipoprotein receptor-related protein disrupts the neuronal metabolic balance of the receptor ligands'. Together they form a unique fingerprint.

  • Cite this