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Histone deacetylase inhibitors modulate human polyomavirus JC replication

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Title:Histone deacetylase inhibitors modulate human polyomavirus JC replication
Authors:Fisher, Michellei Chiemi
Contributors:Nerurkar, Vivek R. (advisor)
Biomed Science (Tropical Medicine) (department)
Molecular biology
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Date Issued:2019
Publisher:University of Hawai'i at Manoa
Abstract:The human polyomavirus JC (JCPyV) is the causative agent of progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the brain. Although archetype JCPyV exists as an asymptomatic infection in the healthy population, PML occurs almost exclusively in individuals with immunodeficiencies or on immunomodulatory medication. When immune function is perturbed, the mechanisms which maintain viral latency are disrupted and can lead to the development of PML. Therefore, an important question in understanding PML pathogenesis are the molecular mechanisms which maintain JCPyV latency. The JCPyV genome incorporates host-derived histones and closely resembles host chromatin structure, therefore we hypothesize it is subject to epigenetic regulation. Histone deacetylase inhibitors (HDACi) have been demonstrated to increase rearranged JCPyV replication in a transfection model and are candidates for latency reversal agents in HIV treatment. The potential for these HDACi to reactivate HIV suggests the possibility of reactivating other viruses as well. The objective of this study is to characterize the effects of histone deacetylase inhibitors (HDACis) on archetype JCPyV infection, replication, and rearrangement in vitro and in vivo. Here, we demonstrate that HDACi, Trichostatin A, treatment of primary human brain cortical astrocytes and renal proximal tubule epithelial cells increases both early and late archetype JCPyV replication in a cell-specific manner. Further, we demonstrate in patients treated with HDACi, panobinostat, statistically higher increase in archetype JCPyV genome copy number in urine, which was abrogated after treatment. To our knowledge, this is the first study to show the effect of HDACi on archetype JCPyV replication in an in vitro infection model and the first to investigate JCPyV viruria during HDACi treatment. Taken together, these findings suggest that HDACi modulate archetype JCPyV replication. This study emphasizes the need to understand the effects of these global HDACi on other viruses to improve risk stratification for latency reactivation agent treatments. These findings will open new therapeutic strategies for treatment of PML aimed at preventing viral replication and maintaining JCPyV in a latent state.
Description:M.S. Thesis. Ph.D. Thesis. University of Hawaiʻi at Mānoa 2019
Pages/Duration:104 pages
Rights:All UHM dissertations and theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission from the copyright owner.
Appears in Collections: M.S. - Biomedical Sciences (Tropical Medicine)

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