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

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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.

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.

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References

  • Akay C, Cooper M, Odeleye A, Jensen BK, White MG et al (2014) Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system. J Neuro-Oncol 20:39–53

    CAS  Google Scholar 

  • Akay C, Lindl KA, Shyam N, Nabet B, Goenaga-Vazquez Y et al (2012) Activation status of integrated stress response pathways in neurones and astrocytes of HIV-associated neurocognitive disorders (HAND) cortex. Neuropathol Appl Neurobiol 38:175–200

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bae M, Patel N, Xu H, Lee M, Tominaga-Yamanaka K, Nath A, Geiger J, Gorospe M, Mattson MP, Haughey NJ (2014) Activation of TRPML1 clears intraneuronal Abeta in preclinical models of HIV infection. J Neurosci 34:11485–11503

    PubMed  PubMed Central  Google Scholar 

  • Bansal R, Warrington AE, Gard AL, Ranscht B, Pfeiffer SE (1989) Multiple and novel specificities of monoclonal antibodies O1, O4, and R-mAb used in the analysis of oligodendrocyte development. J Neurosci Res 24:548–557

    CAS  PubMed  Google Scholar 

  • Baracskay KL, Kidd GJ, Miller RH, Trapp BD (2007) NG2-positive cells generate A2B5-positive oligodendrocyte precursor cells. Glia 55:1001–1010

    PubMed  Google Scholar 

  • Beyer BA, Fang M, Sadrian B, Montenegro-Burke JR, Plaisted WC, Kok BPC, Saez E, Kondo T, Siuzdak G, Lairson LL (2018) Metabolomics-based discovery of a metabolite that enhances oligodendrocyte maturation. Nat Chem Biol 14:22–28

    CAS  PubMed  Google Scholar 

  • Borjabad A, Brooks AI, Volsky DJ (2010) Gene expression profiles of HIV-1-infected glia and brain: toward better understanding of the role of astrocytes in HIV-1-associated neurocognitive disorders. J NeuroImmune Pharmacol 5:44–62

    PubMed  Google Scholar 

  • Brandmann M, Tulpule K, Schmidt MM, Dringen R (2012) The antiretroviral protease inhibitors indinavir and nelfinavir stimulate Mrp1-mediated GSH export from cultured brain astrocytes. J Neurochem 120:78–92

    CAS  PubMed  Google Scholar 

  • Chandra S, Mondal D, Agrawal KC (2009) HIV-1 protease inhibitor induced oxidative stress suppresses glucose stimulated insulin release: protection with thymoquinone. Exp Biol Med (Maywood) 234:442–453

    CAS  Google Scholar 

  • Chen X, Hui L, Geiger NH, Haughey NJ, Geiger JD (2013) Endolysosome involvement in HIV-1 transactivator protein-induced neuronal amyloid beta production. Neurobiol Aging 34:2370–2378

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chew LJ, King WC, Kennedy A, Gallo V (2005) Interferon-gamma inhibits cell cycle exit in differentiating oligodendrocyte progenitor cells. Glia 52:127–143

    PubMed  Google Scholar 

  • Correa DG, Zimmermann N, Doring TM, Wilner NV, Leite SC et al (2015) Diffusion tensor MR imaging of white matter integrity in HIV-positive patients with planning deficit. Neuroradiology 57:475–482

    PubMed  Google Scholar 

  • Dai J, Bercury KK, Macklin WB (2014) Interaction of mTOR and Erk1/2 signaling to regulate oligodendrocyte differentiation. Glia 62:2096–2109

    PubMed  PubMed Central  Google Scholar 

  • Ellis RJ, Marquie-Beck J, Delaney P, Alexander T, Clifford DB et al (2008) Human immunodeficiency virus protease inhibitors and risk for peripheral neuropathy. Ann Neurol 64:566–572

    CAS  PubMed  PubMed Central  Google Scholar 

  • Eisenbarth GS, Walsh FS, Nirenberg M (1979) Monoclonal antibody to a plasma membrane antigen of neurons. Proc. Natl. Acad. Sci. 76 (10):4913-4917

  • Everall I, Vaida F, Khanlou N, Lazzaretto D, Achim C et al (2009) Cliniconeuropathologic correlates of human immunodeficiency virus in the era of antiretroviral therapy. J Neuro-Oncol 15:360–370

    CAS  Google Scholar 

  • Everall IP, Hansen LA, Masliah E (2005) The shifting patterns of HIV encephalitis neuropathology. Neurotox Res 8:51–61

    CAS  PubMed  Google Scholar 

  • Fauci AS, Marston HD (2015) Ending the HIV-AIDS pandemic--follow the science. N Engl J Med 373:2197–2199

    PubMed  Google Scholar 

  • Feigenson K, Reid M, See J, Crenshaw EB 3rd, Grinspan JB (2009) Wnt signaling is sufficient to perturb oligodendrocyte maturation. Mol Cell Neurosci 42:255–265

    CAS  PubMed  Google Scholar 

  • Feigenson K, Reid M, See J, Crenshaw IE, Grinspan JB (2011) Canonical Wnt signalling requires the BMP pathway to inhibit oligodendrocyte maturation. ASN Neuro 3:e00061

    PubMed  PubMed Central  Google Scholar 

  • Fields J, Dumaop W, Eleuteri S, Campos S, Serger E et al (2015) HIV-1 tat alters neuronal autophagy by modulating autophagosome fusion to the lysosome: implications for HIV-associated neurocognitive disorders. J Neurosci 35:1921–1938

    CAS  PubMed  PubMed Central  Google Scholar 

  • French HM, Reid M, Mamontov P, Simmons RA, Grinspan JB (2009) Oxidative stress disrupts oligodendrocyte maturation. J Neurosci Res 87:3076–3087

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gannon PJ, Akay-Espinoza C, Yee AC, Briand LA, Erickson MA, Gelman BB, Gao Y, Haughey NJ, Zink MC, Clements JE, Kim NS, van de Walle G, Jensen BK, Vassar R, Pierce RC, Gill AJ, Kolson DL, Diehl JA, Mankowski JL, Jordan-Sciutto KL (2017) HIV protease inhibitors Alter amyloid precursor protein processing via beta-site amyloid precursor protein cleaving Enzyme-1 translational up-regulation. Am J Pathol 187:91–109

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gavrieli Y, Sherman Y, Ben-Sasson SA (1992) Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol 119:493–501

    CAS  PubMed  Google Scholar 

  • Gongvatana A, Cohen RA, Correia S, Devlin KN, Miles J et al (2011) Clinical contributors to cerebral white matter integrity in HIV-infected individuals. J Neuro-Oncol 17:477–486

    Google Scholar 

  • Hart IK, Richardson WD, Heldin CH, Westermark B, Raff MC (1989) PDGF receptors on cells of the oligodendrocyte-type-2 astrocyte (O-2A) cell lineage. Development 105:595–603

    CAS  PubMed  Google Scholar 

  • Heaton RK, Clifford DB, Franklin DR Jr, Woods SP, Ake C et al (2010) HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER study. Neurology 75:2087–2096

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hoare J, Fouche JP, Spottiswoode B, Joska JA, Schoeman R et al (2010) White matter correlates of apathy in HIV-positive subjects: a diffusion tensor imaging study. J Neuropsychiatry Clin Neurosci 22:313–320

    PubMed  Google Scholar 

  • Hui L, Ye Y, Soliman ML, Lakpa KL, Miller NM et al (2019) Antiretroviral drugs promote Amyloidogenesis by De-acidifying Endolysosomes. J NeuroImmune Pharmacol

  • Hussien Y, Cavener DR, Popko B (2014) Genetic inactivation of PERK signaling in mouse oligodendrocytes: normal developmental myelination with increased susceptibility to inflammatory demyelination. Glia 62:680–691

    PubMed  PubMed Central  Google Scholar 

  • Jensen BK, Monnerie H, Mannell MV, Gannon PJ, Espinoza CA, Erickson MA, Bruce-Keller AJ, Gelman BB, Briand LA, Pierce RC, Jordan-Sciutto KL, Grinspan JB (2015) Altered Oligodendrocyte maturation and myelin maintenance: the role of Antiretrovirals in HIV-associated neurocognitive disorders. J Neuropathol Exp Neurol 74:1093–1118

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jensen BK, Roth LM, Grinspan JB, Jordan-Sciutto KL (2019) White matter loss and oligodendrocyte dysfunction in HIV: a consequence of the infection, the antiretroviral therapy or both? Brain Res 1724:146397

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lagathu C, Eustace B, Prot M, Frantz D, Gu Y, Bastard JP, Maachi M, Azoulay S, Briggs M, Caron M, Capeau J (2007) Some HIV antiretrovirals increase oxidative stress and alter chemokine, cytokine or adiponectin production in human adipocytes and macrophages. Antivir Ther 12:489–500

    CAS  PubMed  Google Scholar 

  • Langford TD, Letendre SL, Larrea GJ, Masliah E (2003) Changing patterns in the neuropathogenesis of HIV during the HAART era. Brain Pathol 13:195–210

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lindl KA, Akay C, Wang Y, White MG, Jordan-Sciutto KL (2007) Expression of the endoplasmic reticulum stress response marker, BiP, in the central nervous system of HIV-positive individuals. Neuropathol Appl Neurobiol 33:658–669

    CAS  PubMed  Google Scholar 

  • Manda KR, Banerjee A, Banks WA, Ercal N (2011) Highly active antiretroviral therapy drug combination induces oxidative stress and mitochondrial dysfunction in immortalized human blood-brain barrier endothelial cells. Free Radic Biol Med 50:801–810

    CAS  PubMed  Google Scholar 

  • McCarthy KD, de Vellis J (1980) Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue. J Cell Biol 85:890–902

    CAS  PubMed  Google Scholar 

  • Meireles AM, Shen K, Zoupi L, Iyer H, Bouchard EL et al (2018) The Lysosomal transcription factor TFEB represses myelination downstream of the rag-Ragulator complex. Dev Cell 47(319–330):e315

    Google Scholar 

  • Miller RH (2002) Regulation of oligodendrocyte development in the vertebrate CNS. Prog Neurobiol 67:451–467

    CAS  PubMed  Google Scholar 

  • Muller-Oehring EM, Schulte T, Rosenbloom MJ, Pfefferbaum A, Sullivan EV (2010) Callosal degradation in HIV-1 infection predicts hierarchical perception: a DTI study. Neuropsychologia 48:1133–1143

    PubMed  Google Scholar 

  • Nishiyama A, Lin XH, Giese N, Heldin CH, Stallcup WB (1996) Co-localization of NG2 proteoglycan and PDGF alpha-receptor on O2A progenitor cells in the developing rat brain. J Neurosci Res 43:299–314

    CAS  PubMed  Google Scholar 

  • Raff MC, Abney ER, Cohen J, Lindsay R, Noble M (1983) Two types of astrocytes in cultures of developing rat white matter: differences in morphology, surface gangliosides, and growth characteristics. J Neurosci 3:1289–1300

    CAS  PubMed  PubMed Central  Google Scholar 

  • Raff MC, Mirsky R, Fields KL, Lisak RP, Dorfman SH et al (1978) Galactocerebroside is a specific cell-surface antigenic marker for oligodendrocytes in culture. Nature 274:813–816

    CAS  PubMed  Google Scholar 

  • Ranscht B, Clapshaw PA, Price J, Noble M, Seifert W (1982) Development of oligodendrocytes and Schwann cells studied with a monoclonal antibody against galactocerebroside. Proc Natl Acad Sci U S A 79:2709–2713

    CAS  PubMed  PubMed Central  Google Scholar 

  • Reid MV, Murray KA, Marsh ED, Golden JA, Simmons RA, Grinspan JB (2012) Delayed myelination in an intrauterine growth retardation model is mediated by oxidative stress upregulating bone morphogenetic protein 4. J Neuropathol Exp Neurol 71:640–653

    CAS  PubMed  PubMed Central  Google Scholar 

  • Romero-Ramirez L, Nieto-Sampedro M, Barreda-Manso MA (2017) Integrated stress response as a therapeutic target for CNS injuries. Biomed Res Int 2017:6953156

    PubMed  PubMed Central  Google Scholar 

  • Saylor D, Dickens AM, Sacktor N, Haughey N, Slusher B et al (2016) HIV-associated neurocognitive disorder - pathogenesis and prospects for treatment. Nat Rev Neurol 12:309

    PubMed  PubMed Central  Google Scholar 

  • See J, Zhang X, Eraydin N, Mun SB, Mamontov P, Golden JA, Grinspan JB (2004) Oligodendrocyte maturation is inhibited by bone morphogenetic protein. Mol Cell Neurosci 26:481–492

    CAS  PubMed  Google Scholar 

  • Settembre C, Fraldi A, Medina DL, Ballabio A (2013) Signals from the lysosome: a control Centre for cellular clearance and energy metabolism. Nat Rev Mol Cell Biol 14:283–296

    CAS  PubMed  PubMed Central  Google Scholar 

  • Stern AL, Ghura S, Gannon PJ, Akay-Espinoza C, Phan JM, Yee AC, Vassar R, Gelman BB, Kolson DL, Jordan-Sciutto KL (2018) BACE1 mediates HIV-associated and Excitotoxic neuronal damage through an APP-dependent mechanism. J Neurosci 38:4288–4300

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tate DF, Conley J, Paul RH, Coop K, Zhang S, Zhou W, Laidlaw DH, Taylor LE, Flanigan T, Navia B, Cohen R, Tashima K (2010) Quantitative diffusion tensor imaging tractography metrics are associated with cognitive performance among HIV-infected patients. Brain Imaging Behav 4:68–79

    PubMed  PubMed Central  Google Scholar 

  • Tate DF, Sampat M, Harezlak J, Fiecas M, Hogan J et al (2011) Regional areas and widths of the midsagittal corpus callosum among HIV-infected patients on stable antiretroviral therapies. J Neuro-Oncol 17:368–379

    Google Scholar 

  • Touzet O, Philips A (2010) Resveratrol protects against protease inhibitor-induced reactive oxygen species production, reticulum stress and lipid raft perturbation. AIDS 24:1437–1447

    CAS  PubMed  Google Scholar 

  • Vermeir M, Lachau-Durand S, Mannens G, Cuyckens F, van Hoof B et al (2009) Absorption, metabolism, and excretion of darunavir, a new protease inhibitor, administered alone and with low-dose ritonavir in healthy subjects. Drug Metab Dispos 37:809–820

    CAS  PubMed  Google Scholar 

  • Way SW, Popko B (2016) Harnessing the integrated stress response for the treatment of multiple sclerosis. Lancet Neurol 15:434–443

    PubMed  PubMed Central  Google Scholar 

  • WHO, 2016 Clinical Guidelines: Antiretroviral Therapy, pp. 97 & 151

  • Yu T, Lieberman AP (2013) Npc1 acting in neurons and glia is essential for the formation and maintenance of CNS myelin. PLoS Genet 9:e1003462

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR et al (2014) An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci 34:11929–11947

    CAS  PubMed  PubMed Central  Google Scholar 

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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).

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  1. Lindsay Festa and Lindsay M. Roth contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, School of Dental Medicine, University of Pennsylvania, 240 S 40th St, Philadelphia, PA, 19104, USA

    Lindsay Festa, Lindsay M. Roth & Kelly L. Jordan-Sciutto

  2. Department of Neurology, The Children’s Hospital of Philadelphia, 516D Abramson Center, 3615 Civic Center Blvd, Philadelphia, PA, 19104-6030, USA

    Lindsay M. Roth & Judith B. Grinspan

  3. Vickie and Jack Farber Institute for Neuroscience, Jefferson Weinberg ALS Center, Thomas Jefferson University, 900 Walnut St, Philadelphia, PA, 19107, USA

    Brigid K. Jensen

  4. Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, 504 Hamline Street, Grand Forks, ND, 58203, USA

    Jonathan D. Geiger

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Festa, L., Roth, L.M., K. Jensen, B. et al. Protease Inhibitors, Saquinavir and Darunavir, Inhibit Oligodendrocyte Maturation: Implications for Lysosomal Stress. J Neuroimmune Pharmacol 16, 169–180 (2021). https://doi.org/10.1007/s11481-019-09893-8

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