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 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 alpha2-macroglobulin, apolipoprotein E4, amyloid precursor protein and amyloid beta-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.
Liu
Y
Y
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Jones
M
M
Hingtgen
C M
CM
Bu
G
G
Laribee
N
N
Tanzi
R E
RE
Moir
R D
RD
Nath
A
A
He
J J
JJ
D015526:AIDS Dementia Complex / Q000209:etiology*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000378:metabolism; D001479:Basal Ganglia / Q000473:pathology; D001692:Biological Transport; D001921:Brain / Q000166:cytology / Q000473:pathology; D016466:CHO Cells; D006224:Cricetinae; D004705:Endocytosis; D005333:Fetus; D015696:Gene Products, tat / Q000378:metabolism*; D005865:Gestational Age; D015497:HIV-1; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008251:Macaca; D009474:Neurons / Q000378:metabolism*; D016716:PC12 Cells; D051381:Rats; D011971:Receptors, Immunologic / Q000378:metabolism*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000473:pathology; D000511:alpha-Macroglobulins / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus
D016564:Amyloid beta-Protein Precursor; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D015696:Gene Products, tat; D019812:Heparan Sulfate Proteoglycans; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D011971:Receptors, Immunologic; D000511:alpha-Macroglobulins; D054322:tat Gene Products, Human Immunodeficiency Virus