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

Neurological disorders develop in most people infected with human immunodef iciency virus type 1 (HIV-1). However, the underlying mechanisms remain lar gely unknown. Here we report that binding of HIV-1 transactivator (Tat) pro tein to low-density lipoprotein receptor-related protein (LRP) promoted eff icient uptake of Tat into neurons. LRP-mediated uptake of Tat was followed by translocation to the neuronal nucleus. Furthermore, the binding of Tat t o LRP resulted in substantial inhibition of neuronal binding, uptake and de gradation of physiological ligands for LRP, including alpha (2)-macroglobul in, apolipoprotein E4, amyloid precursor protein and amyloid beta -protein. In a model of macaques infected with a chimeric strain of simian-human imm unodeficiency virus, increased staining of amyloid precursor protein was as sociated 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 o f neuronal genes.