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Investigation of Archetype Human Polyomavirus JC Cellular Tropism and Genomic Alterations in JC Virus Pathogenesis.

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Title:Investigation of Archetype Human Polyomavirus JC Cellular Tropism and Genomic Alterations in JC Virus Pathogenesis.
Authors:Lazaga, Nelson
Contributors:Biomedical Sciences (Tropical Medicine) (department)
Date Issued:Aug 2017
Publisher:University of Hawaiʻi at Mānoa
Abstract:The human polyomavirus JC (JCPyV) is the causative agent of the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML). While the archetypal form of the virus is ubiquitous in the healthy human population, it is the rearranged form that is responsible for PML. The archetype form of JCPyV has a conserved noncoding control region (NCCR) that is defined by six designated blocks, A-F. However, the rearranged form has deletions and/or duplications in its NCCR. Although it has been established that the rearranged form of JCPyV is pathogenic, the events leading to the reactivation and/or rearrangement in its NCCR have yet to be determined. Thus, the lack of in vitro and in vivo archetype JCPyV replication models have hindered the understanding of mechanisms underlying the development of PML pathogenesis. In this report, we demonstrate in vitro infection and efficient replication of archetype JCPyV in renal proximal tubule epithelial (RPTE) and human brain microvascular endothelial (HBMVE) cells, limited or no replication in human brain cortical astrocytes (HBCA) and primary human fetal glial (PHFG) cells, and in vitro rearrangement of archetype JCPyV at day 645 in COS-7 cells. In addition, we demonstrate that archetype JCPyV (CY) and rearranged JCPyV (Mad1) can replicate in HBMVE cells, while limited replication was observed when HBMVE cells were transfected with the hybrid JCPyV (CYrM1c). Lastly, we demonstrate in vivo infection of JCPyV in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice. To our knowledge, this is the first study demonstrating the ability for urine-derived archetype JCPyV to rearrange in vitro, to be infectious in naïve primary cells, and to demonstrate JCPyV infection in humanized NSG mice. This study will therefore give insight on cellular conditions involved in urine-derived archetype JCPyV infection, reactivation, and rearrangement, which will impact the development of much-needed therapeutics for PML
Description:Ph.D. Thesis. University of Hawaiʻi at Mānoa 2017.
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: Ph.D. - Biomedical Sciences (Tropical Medicine)

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