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Differential Effects of Antiretroviral Drugs on Neurons In Vitro: Roles for Oxidative Stress and Integrated Stress Response

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Abstract

Mounting evidence suggests that antiretroviral drugs may contribute to the persistence of HIV-associated neurocognitive disorders (HAND), which impact 30%–50% of HIV-infected patients in the post-antiretroviral era. We previously reported that two first generation HIV protease inhibitors, ritonavir and saquinavir, induced oxidative stress, with subsequent neuronal death in vitro, which was reversed by augmentation of the endogenous antioxidant response by monomethyl fumarate. We herein determined whether two newer-generation PIs, darunavir and lopinavir, were deleterious to neurons in vitro. Further, we expanded our assessment to include three integrase strand transfer inhibitors, raltegravir, dolutegravir, and elvitegravir. We found that only lopinavir and elvitegravir were neurotoxic to primary rat neuroglial cultures as determined by the loss of microtubule-associated protein 2 (MAP2). Intriguingly, lopinavir but not elvitegravir led to oxidative stress and induced the endogenous antioxidant response (EAR). Furthermore, neurotoxicity of lopinavir was blocked by pharmacological augmentation of the endogenous antioxidant heme oxygenase-1 (HO-1), expanding our previous finding that protease inhibitor-induced neurotoxicity was mediated by oxidative stress. Conversely, elvitegravir but not lopinavir led to increased eIF2α phosphorylation, indicating the activation of a common adaptive pathway termed the integrated stress response (ISR), and elvitegravir-mediated neurotoxicity was partially alleviated by the ISR inhibitor trans-ISRIB, suggesting ISR as a promoter of elvitegravir-associated neurotoxicity. Overall, we found that neurotoxicity was induced only by a subset of protease inhibitors and integrase strand transfer inhibitors, providing evidence for class- and drug-specific neurotoxic effects of antiretroviral drugs. Future in vivo studies will be critical to confirm the neurotoxicity profiles of these drugs for incorporation of these findings into patient management. The EAR and ISR pathways are potential access points for the development of adjunctive therapies to complement antiretroviral therapies and limit their contribution to HAND persistence.

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Acknowledgments

We thank Margaret Maronski for her help in the preparation of primary rat cortical neuroglial cultures, Ping Lin for her technical assistance, the NIH AIDS reagent program for their generous donation of ARVs, and Dr. Sarah Ratcliffe for her help with statistical analysis.

Funding

We thank the NIH for the following funding sources: R01MH109382, R01MH106967, R01MH098742 (K.J-S). The following reagents were obtained through the AIDS Reagent Program, Division of AIDS, NIAID, NIH: lopinavir, darunavir, and raltegravir.

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  1. Department of Pathology, School of Dental Medicine, University of Pennsylvania, 240 S. 40th St. Rm. 312 Levy Building, Philadelphia, PA, 19104-6030, USA

    Anna L. Stern, Rebecca N. Lee, Nina Panvelker, Jiean Li, Jenna Harowitz, Kelly L. Jordan-Sciutto & Cagla Akay-Espinoza

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  1. Anna L. Stern
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Correspondence to Cagla Akay-Espinoza.

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Financial support was provided by NIH grants MH098742, MH106967, and MH109382.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. This article does not contain any studies with human participants performed by any of the authors.

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Stern, A.L., Lee, R.N., Panvelker, N. et al. Differential Effects of Antiretroviral Drugs on Neurons In Vitro: Roles for Oxidative Stress and Integrated Stress Response. J Neuroimmune Pharmacol 13, 64–76 (2018). https://doi.org/10.1007/s11481-017-9761-6

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