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Am J Pathol. 2017 Jan;187(1):91-109. doi: 10.1016/j.ajpath.2016.09.006.

HIV Protease Inhibitors Alter Amyloid Precursor Protein Processing via β-Site Amyloid Precursor Protein Cleaving Enzyme-1 Translational Up-Regulation.

Author information

1
Department of Pharmacology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
2
Department of Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
3
Department of Psychology, Temple University, Philadelphia, Pennsylvania.
4
Department of Pathology, University of Texas Medical Branch, Galveston, Texas.
5
Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
6
Richard T. Johnson Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
7
Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
8
Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
9
Department of Psychiatry, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
10
Department of Neurology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
11
Department of Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: jordank@upenn.edu.

Abstract

Mounting evidence implicates antiretroviral (ARV) drugs as potential contributors to the persistence and evolution of clinical and pathological presentation of HIV-associated neurocognitive disorders in the post-ARV era. Based on their ability to induce endoplasmic reticulum (ER) stress in various cell types, we hypothesized that ARV-mediated ER stress in the central nervous system resulted in chronic dysregulation of the unfolded protein response and altered amyloid precursor protein (APP) processing. We used in vitro and in vivo models to show that HIV protease inhibitor (PI) class ARVs induced neuronal damage and ER stress, leading to PKR-like ER kinase-dependent phosphorylation of the eukaryotic translation initiation factor 2α and enhanced translation of β-site APP cleaving enzyme-1 (BACE1). In addition, PIs induced β-amyloid production, indicative of increased BACE1-mediated APP processing, in rodent neuroglial cultures and human APP-expressing Chinese hamster ovary cells. Inhibition of BACE1 activity protected against neuronal damage. Finally, ARVs administered to mice and SIV-infected macaques resulted in neuronal damage and BACE1 up-regulation in the central nervous system. These findings implicate a subset of PIs as potential mediators of neurodegeneration in HIV-associated neurocognitive disorders.

PMID:
27993242
PMCID:
PMC5225305
DOI:
10.1016/j.ajpath.2016.09.006
[Indexed for MEDLINE]
Free PMC Article

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