Antiretroviral therapy (ART) has led to significant decrease in incidence of the most severe forms of HIV associated neurocognitive disorder (HAND); however, the level of less severe forms of cognitive, behavioral and motor dysfunction have been reported to persist in 30-50% of patients. HIV-associated neuropathology has shifted from a rapidly progressing encephalitic condition to a prolonged neurodegenerative disease with pathologic features including astrogliosis, microgliosis and dendritic damage. However, white matter changes remain a common feature of HAND in the pre- and post-ART era. Intriguingly, a recent transcriptome analysis has shown that genes associated with oligodendrocyte differentiation and myelin production are down regulated in untreated patients with HAND as well as in patients with HAND treated with ART. These findings indicate that HIV and ART may disrupt myelin development and maintenance. However, the effects of ART compounds alone or in combination with HIV-infected cells on the oligodendrocytes and their precursor cells have not been studied. We hypothesize, that ART compounds alter oligodendrocyte differentiation, function, and survival, contributing to the persistence of HAND in the post-ART era. To this end, we have demonstrated that 2 antiretroviral compounds (ARV), one nucleoside reverse transcriptase inhibitor (NRTI), AZT, and one protease inhibitor (PI), ritonavir, alter oligodendrocyte morphology and decrease oligodendrocyte survival in a dose dependent manner in vitro. Further, at subtoxic concentrations, both AZT and ritonavir disrupt maturation of oligodendrocyte precursors (OPCs) in vitro induce oxidative damage and induce the endogenous antioxidant response as indicated by upregulation of heme oxygenase 1 (HO1). Oxidative stress has been shown to alter oligodendrocyte survival and differentiation in both perinatal white matter injury and Multiple Sclerosis models. A recent study has shown that a fumaric acid ester (FAE) with antioxidant properties is efficacious in MS clinical trials. Given th presence of oxidative stress in the CNS of patients with HAND, including those on ART we propose to test the hypothesis that HIV-infected macrophages (HIVMDM) and ARV compounds induce oxidative stress altering oligodendrocyte differentiation, function, and survival in vitro ad in vivo. To test this we will: a) determine the contribution of HIVMDM and ARVs to the development and maintenance of mature oligodendrocytes, b) determine the role of HIVMDM- and ARV-induced oxidative stress in blocking oligodendrocyte differentiation and myelination, c) determine the effect of ARV-induced oxidative stress on oligodendrocytes in vivo, and d) determine the state of oligodendrocyte damage and stress in the context of lentiviral-infection and ART in primates.

Public Health Relevance

Despite the advent of antiretroviral therapy, HIV positive patients continue to have changes in the white matter of the brain. The cell type responsible for forming and maintaining white matter is the oligodendrocyte. Our study will assess the effects of HIV -infection and antiretroviral therapy on changes in white matter in HIV- positive patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
4R01MH098742-05
Application #
9085413
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Joseph, Jeymohan
Project Start
2012-07-16
Project End
2017-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
5
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Dentistry/Oral Hygn
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Stern, Anna L; Lee, Rebecca N; Panvelker, Nina et al. (2018) Differential Effects of Antiretroviral Drugs on Neurons In Vitro: Roles for Oxidative Stress and Integrated Stress Response. J Neuroimmune Pharmacol 13:64-76
Stern, Anna L; Ghura, Shivesh; Gannon, Patrick J et al. (2018) BACE1 Mediates HIV-Associated and Excitotoxic Neuronal Damage Through an APP-Dependent Mechanism. J Neurosci 38:4288-4300
Gannon, Patrick J; Akay-Espinoza, Cagla; Yee, Alan C et al. (2017) HIV Protease Inhibitors Alter Amyloid Precursor Protein Processing via ?-Site Amyloid Precursor Protein Cleaving Enzyme-1 Translational Up-Regulation. Am J Pathol 187:91-109
Monnerie, Hubert; Romer, Micah; Jensen, Brigid K et al. (2017) Reduced sterol regulatory element-binding protein (SREBP) processing through site-1 protease (S1P) inhibition alters oligodendrocyte differentiation in vitro. J Neurochem 140:53-67
Jensen, Brigid K; Monnerie, Hubert; Mannell, Maggie V et al. (2015) Altered Oligodendrocyte Maturation and Myelin Maintenance: The Role of Antiretrovirals in HIV-Associated Neurocognitive Disorders. J Neuropathol Exp Neurol 74:1093-118
Grinspan, Judith B (2015) Bone Morphogenetic Proteins: Inhibitors of Myelination in Development and Disease. Vitam Horm 99:195-222
Akay, Cagla; Cooper, Michael; Odeleye, Akinleye et al. (2014) Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system. J Neurovirol 20:39-53
Akay, C; Lindl, K A; Shyam, N 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