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Protease Inhibitors, Saquinavir and Darunavir, Inhibit Oligodendrocyte Maturation: Implications for Lysosomal Stress

  • Lindsay Festa
  • Lindsay M. Roth
  • Brigid K. Jensen
  • Jonathan D. Geiger
  • Kelly L. Jordan-SciuttoEmail author
  • Judith B. GrinspanEmail author
ORIGINAL ARTICLE

Abstract

Despite the introduction of antiretroviral (ARV) therapy (ART), approximately 30–50% of people living with human immunodeficiency virus-1 (HIV-1) will develop a spectrum of measurable neurocognitive dysfunction, collectively called HIV-associated neurocognitive disorder (HAND). While the clinical manifestations of HAND have changed with the advent of ART, certain pathological features have endured, including white matter alterations and dysfunction. The persistence of white matter alterations in the post-ART era suggests that ARV drugs themselves may contribute to HAND pathology. Our group has previously demonstrated that two ARV compounds from the protease inhibitor (PI) class, ritonavir and lopinavir, inhibit oligodendrocyte maturation and myelin protein production. We hypothesized that other members of the PI class, saquinavir and darunavir, could also negatively impact oligodendrocyte differentiation. Here we demonstrate that treating primary rat oligodendrocyte precursor cells with therapeutically relevant concentrations of either ARV drug results in a concentration-dependent inhibition of oligodendrocyte maturation in vitro. Furthermore, we show that acidifying endolysosomal pH via a mucolipin transient receptor potential channel 1 (TRPML1) agonist provides protection against saquinavir- and darunavir-induced inhibition of oligodendrocyte maturation. Moreover, our findings suggest, for the first time, an imperative role of proper endolysosomal pH in regulating OL differentation, and that therapeutic targeting of endolysosomes may provide protection against ARV-induced oligodendrocyte dysregulation.

Graphical Abstract

Treatment of primary rat oligodendrocyte precursor cells with therapeutically relevant concentrations of either antiretroviral compound of the protease inhibitor class, darunavir or saquinavir, results in a concentration-dependent inhibition of oligodendrocyte maturation in vitro. Additionally, in darunavir or saquinavir-treated cultures we observed a concentration-dependent decrease in the number of acidic lysosomes, via immunostaining with LysoTracker Red, compared with vehicle-treated cultures. Finally, we showed that acidifying endolysosomal pH via a mucolipin transient receptor potential channel 1 (TRPML1) agonist provides protection against saquinavir- or darunavir-induced inhibition of oligodendrocyte maturation. Our findings suggest, for the first time, a critical role of proper endolysosomal pH in regulating OL differentation, and that therapeutic targeting of endolysosomes may provide protection against antiretroviral-induced oligodendrocyte dysregulation.

Keywords

Antiretroviral therapy Oligodendrocyte White matter Endolysosome 

Notes

Acknowledgments

We thank the NIH AIDS reagent program for their generous donation of ARVs and the laboratory of Michael Robinson at The Children’s Hospital of Philadelphia for the use of the Odyssey Infrared Imaging System.

Funding

This project was supported by the following grants: RO1 MH098742 (KJS and JBG), R21 MH118121 (JBG and KJS), NIH F31 NS079192 (BKJ), T32 NS007180 (BKJ,), T32 GM008076 (LMR), P30GM100329, U54GM115458, R01MH100972, R01MH105329, 2R01NS065957 and 2R01DA032444 (JDG) and the Cellular Neuroscience Core of the Institutional Intellectual and Developmental Disabilities Research Core of the Children’s Hospital of Philadelphia (HD26979).

Compliance with Ethical Standards

Conflict of Interest

The authors declare no competing financial interests.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Lindsay Festa
    • 1
  • Lindsay M. Roth
    • 1
    • 2
  • Brigid K. Jensen
    • 3
  • Jonathan D. Geiger
    • 4
  • Kelly L. Jordan-Sciutto
    • 1
    Email author
  • Judith B. Grinspan
    • 2
    Email author
  1. 1.Department of Pathology, School of Dental MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  2. 2.Department of NeurologyThe Children’s Hospital of PhiladelphiaPhiladelphiaUSA
  3. 3.Vickie and Jack Farber Institute for Neuroscience, Jefferson Weinberg ALS CenterThomas Jefferson UniversityPhiladelphiaUSA
  4. 4.Department of Biomedical Sciences, School of Medicine and Health SciencesUniversity of North DakotaGrand ForksUSA

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