The fatal CNS demyelinating disease progressive multifocal leukoencephalopathy (PML) is caused by the productive infection of glial cells with the human neurotropic polyomavirus, JC (JCV). JCV infects most people early in life and then remains in a latent state where JCV gene expression and replication cannot be detected. However, in the context of severe immunosuppression, especially HIV-1/AIDS, JCV becomes reactivated leadings to PML. In regard to reactivation, our working hypothesis is that JCV gene expression is switched on in glial cells of the brain by the action of proinflammatory cytokines. This application is a competitive renewal of our R01 entitled "Cytokine Regulation of JC Virus Latency and Reactivation", in which we have pursued this hypothesis. We have observed that transcription from both the early and late JCV promoters is positively regulated by NF-?B and negatively regulated by C/EBP?, which act at a common element (KB) in the JCV control region. The activities of both of these transcription factors are modulated by extracellular cytokines and both JCV promoters are activated by cytokines, e.g., TNF-? and IL-1? through the KB element. TNF-? and its receptor were found to be abundant in clinical samples of HIV-1/PML lesions. In these studies, we also made two novel and interesting observations. Firstly, we found that a third transcription factor NFAT4, which is activated by cytokines and calcium signaling via calcineurin, can bind and stimulate the JCV KB element in cooperation with NF-?B and is also negatively regulated by C/EBP?. Secondly, epigenetic events involving protein acetylation are involved in this process, since histone deacetylase inhibitors potently stimulate JCV early and late transcription and mutation analysis has implicated the KB element in this effect. In the light of our new findings, we have now extended our hypothesis and propose that, in addition to NF-?B and C/EBP?, the transcription factor NFAT4 and epigenetic control by protein acetylation are also involved in viral reactivation. We now propose a comprehensive experimental analysis of the roles of these factors in determining JCV latency/reactivation and its response to the status of extracellular cytokines. Through these studies, we hope to gain a better understanding of the molecular mechanisms involved in JCV latency and reactivation to cause PML and this may open new therapeutic avenues to this disease.
Progressive multifocal leukoencephalopathy (PML) is a deadly disease of the central nervous system that is caused by a virus called JCV, which is only able to grow when the immune system is impaired. Mostly, this disease afflicts people with HIV/AIDS. The goal of this proposal is to understand the reasons why the virus begins to grow in these patients so as to allow the development of new therapies.
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