Upregulation of Reactive Oxygen Species During The Retrovirus Life Cycle and Their Roles In A Mutant of Moloney Murine Leukemia Virus, Ts1-Mediated Neurodegeneration

<p>Viral invasion of the central nervous system (CNS) and development of neurological symptoms is a characteristic of many retroviruses. The mechanism by which retrovirus infection causes neurological dysfunction has yet to be fully elucidated. Given the complexity of the retrovirus-mediated neuropathogenesis, studies using small animal models are extremely valuable. Our laboratory has used a mutant moloney murine leukemia retrovirus, <em>ts</em>1-mediated neurodegneration. We hypothesize that astrocytes play an important role in <em>ts</em>1-induced neurodegeneration since they are retroviral reservoirs and supporting cells for neurons. It has been shown that <em>ts</em>1 is able to infect astrocytes <em>in vivo</em> and <em>in vitro</em>. Astrocytes, the dominant cell population in the CNS, extend their end feet to endothelial cells and neuronal synapse to provide neuronal support. Signs of oxidative stress in the <em>ts</em>1-infected CNS have been well-documented from previous studies.</p> <p>After viral infection, retroviral DNA is generated from its RNA genome and integrated into the host genome. In this study, we identified the life cycle of <em>ts</em>1 in the infected astrocytes. During the infection, we observed reactive oxygen species (ROS) upregulations: one at low levels during the early infection phase and another at high levels during the late infection phase. Initially we hypothesized that p53 might play an important role in <em>ts</em>1-mediated astrocytic cell death. Subsequently, we found that p53 is unlikely to be involved in the <em>ts</em>1-mediated astrocytic cell death. Instead, p53 phosphorylation was increased by the early ROS upregulation via ATM, the protein encoded by the ataxia-telangiectasia (A-T) mutated gene. The early upregulation of p53 delayed viral gene expression by suppressing expression of the catalytic subunit of NADPH oxidase (NOX). We further demonstrated that the ROS upregulation induced by NOX activation plays an important role in establishing retroviral genome into the host. Inhibition of NOX decreased viral replication and delayed the onset of pathological symptoms in <em>ts</em>1-infected mice. These observations lead us to conclude that suppression of NOX not only prevents the establishment of the retrovirus but also decreases oxidative stress in the CNS. This study provides us with new perspectives on the retrovirus-host cell interaction and sheds light on retrovirus-induced neurodegeneration as a result of the astrocyte-neuron interaction.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2011

Author dc:creator

• KIM, SOO JIN

Contributors dc:contributor

• Paul K.Y. Wong
• David Johnson
• Dean Tang

• Reactive Oxygen Sepcies
• Retrovirus
• p53
• NADPH oxidase
• Neurodegeneration
• Astrocyte
• Biology
• Molecular and Cellular Neuroscience
• Nervous System Diseases
• Other Immunology and Infectious Disease
• Virology
• Virus Diseases

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/170

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1200