The mechanisms underlying human immunodeficiency virus (HIV)-mediated cell death in the central nervous system (CMS) are not well defined, but evidence suggests that oxidative stress plays a critical role in neuropathogenesis in HIV-associated dementia (HAD). Several mouse models of HAD have been developed, but few are suitable to the study of oxidative stress and cell death pathways in HAD. In our model of HAD, FVB/N mice are infected with a mutant of the Moloney murine leukemia virus, called te1, which causes progressive neuroimmunodegeneration that is in many ways similar to that of HAD. As in HAD, glial cells are infected by te1, but neurons are not, although neuronal loss is the most severe pathological feature in the CMS. Work in our lab has focused on the role of oxidative stress in the death of te1 -infected astrocytes, and on prevention of neurodegeneration (ND) via antioxidant treatment. We hypothesize that te1 -mediated oxidative stress causes astrocyte dysfunction, that dysfunctional astrocytes are unable to support nearby neurons, and that neurons die as a result. In support of this idea, we have demonstrated that reactive oxygen species (ROS) accumulate in te1-infected astrocytes. Treatment with an antioxidant called GVT (a-luminol) decreases ROS accumulation and prevents cell death in te1-infected astrocytes and in CNS of te1-infected mice. We have also shown that p53 phosphorylation occurs in astrocytes and neurons of te1 -infected mice, and that death of these cells may involve activation of p53-dependent cell death pathways. Further, te1- infected astrocytes respond to ROS increases via activation of ataxia telangiectasia mutated (ATM), extracellular signal-regulated kinases (ERK), and mammalian target of rapamycin (mTOR). All these three kinases have been shown to be able to phosphorylate p53. In te1 -infected astrocytes, the p53-target proapoptotic factors PUMA, Bax, and cell cycle inhibitor p21 are upregulated, and the antiapoptotic factors Bcl-2 and Bcl-xL decrease. All of these events are known to occur in HAD. We hypothesize that similar cell death mechanisms contribute to te1 -associated ND and HAD. Our goal is therefore to understand the mechanisms underlying astrocyte dysfunction and neuronal death in te1 -mediated ND. We will focus on three specific aims: 1) to determine how p53 contributes to oxidative stress;2) to confirm that neurons are damaged by oxidative stress through pathways shared by astrocytes;and 3) to determine whether antioxidants and thiol-repleting agents provide protection for astrocytes and neurons. Our studies may identify new targets for treatment of HAD and of other neurodegenerative diseases associated with oxidative stress, p53 activation and the mitochondrial death pathway.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS043984-08
Application #
7761722
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Wong, May
Project Start
2002-06-18
Project End
2011-07-31
Budget Start
2010-02-01
Budget End
2011-07-31
Support Year
8
Fiscal Year
2010
Total Cost
$404,989
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Organized Research Units
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Kim, Soo Jin; Wong, Paul K Y (2015) p53 as a retrovirus-induced oxidative stress modulator. J Gen Virol 96:144-9
Kim, Soo Jin; Wong, Paul K Y (2013) ROS upregulation during the early phase of retroviral infection plays an important role in viral establishment in the host cell. J Gen Virol 94:2309-17
Reddy, Pichili Vijaya Bhaskar; Lungu, Gina; Kuang, Xianghong et al. (2010) Neuroprotective effects of the drug GVT (monosodium luminol) are mediated by the stabilization of Nrf2 in astrocytes. Neurochem Int 56:780-8
Lungu, G; Kuang, X; Stoica, G et al. (2010) Monosodium luminol upregulates the expression of Bcl-2 and VEGF in retrovirus-infected mice through downregulation of corresponding miRNAs. Acta Virol 54:27-32
Kuang, Xianghong; Hu, Wenhui; Yan, Mingshan et al. (2010) Phenylbutyric acid suppresses protein accumulation-mediated ER stress in retrovirus-infected astrocytes and delays onset of paralysis in infected mice. Neurochem Int 57:738-48
Scofield, Virginia L; Yan, Mingshan; Kuang, Xianghong et al. (2009) The drug monosodium luminol (GVT) preserves crypt-villus epithelial organization and allows survival of intestinal T cells in mice infected with the ts1 retrovirus. Immunol Lett 122:150-8
Kuang, Xianghong; Scofield, Virginia L; Yan, Mingshan et al. (2009) Attenuation of oxidative stress, inflammation and apoptosis by minocycline prevents retrovirus-induced neurodegeneration in mice. Brain Res 1286:174-84
Scofield, Virginia L; Yan, Mingshan; Kuang, Xianghong et al. (2009) The drug monosodium luminol (GVT) preserves thymic epithelial cell cytoarchitecture and allows thymocyte survival in mice infected with the T cell-tropic, cytopathic retrovirus ts1. Immunol Lett 122:159-69
Lungu, Gina F; Stoica, George; Wong, Paul K Y (2008) Down-regulation of Jab1, HIF-1alpha, and VEGF by Moloney murine leukemia virus-ts1 infection: a possible cause of neurodegeneration. J Neurovirol 14:239-51
Stoica, George; Lungu, Gina; Kim, Hun-Taek et al. (2008) Up-regulation of pro-nerve growth factor, neurotrophin receptor p75, and sortilin is associated with retrovirus-induced spongiform encephalomyelopathy. Brain Res 1208:204-16

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