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Ellis, Laura Christine

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Ellis

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Laura Christine

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Ellis, Laura Christine

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2013 - 20142

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Author's Publications: search.filters.isAuthorOfPublication.ccf812ad-e371-4352-b7d3-612b2b815597

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    Agnogene Deletion in a Novel Pathogenic JC Virus Isolate Impairs VP1 Expression and Virion Production
    (Public Library of Science, 2013) Ellis, Laura Christine; Norton, Elizabeth; Dang, Xin; Koralnik, Igor J.
    Infection of glial cells by the human polyomavirus JC (JCV) causes progressive multifocal leukoencephalopathy (PML). JCV Encephalopathy (JCVE) is a newly identified disease characterized by JCV infection of cortical pyramidal neurons. The virus JCVCPN associated with JCVE contains a unique 143 base pair deletion in the agnogene. Contrary to most JCV brain isolates, JCVCPN has an archetype-like regulatory region (RR) usually found in kidney strains. This provided us with the unique opportunity to determine for the first time how each of these regions contributed to the phenotype of JCVCPN. We characterized the replication of JCVCPN compared to the prototype virus JCVMad-1 in kidney, glial and neuronal cell lines. We found that JCVCPN is capable of replicating viral DNA in all cell lines tested, but is unable to establish persistent infection seen with JCVMad-1. JCVCPN does not have an increased ability to replicate in the neuronal cell line tested. To determine whether this phenotype results from the archetype-like RR or the agnogene deletion, we generated chimeric viruses between JCVCPN of JCVMad-1. We found that the deletion in the agnogene is the predominant cause of the inability of the virus to maintain a persistent infection, with the introduction of a full length agnogene, either with or without agnoprotein expression, rescues the replication of JCVCPN. Studying this naturally occurring pathogenic variant of JCV provides a valuable tool for understanding the functions of the agnogene and RR form in JCV replication.
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    Investigating the roles of the JC virus agnogene and regulatory region using a naturally occurring, pathogenic viral isolate
    (2014-06-06) Ellis, Laura Christine; Koralnik, Igor J.; DeCaprio, James; Kaye, Ken; Munger, Karl; Bullock, Peter
    Progressive Multifocal Leukoencephalopathy (PML) is caused by lytic infection of oligodendrocytes by JC Virus (JCV). JCV Encephalopathy (JCVE) is a newly identified disease characterized by JCV infection of cortical pyramidal neurons. JCVCPN was isolated from the brain of a JCVE patient. JCVCPN contains a unique 143 base pair deletion in the agnogene and has an archetype-like regulatory region (RR), of the type typically found in the kidneys. In this dissertation, we studied the JCVCPN virus to better understand the role of the agnogene and the RR in JCV replication. We used kidney, glial and neuronal cell lines to compare the replication of JCVCPN to the prototype virus JCVMad-1. JCVCPN was able to replicate viral DNA in all cell lines tested, but was unable to establish the high level of infection seen with JCVMad-1. Levels of VP1 capsid protein were undetectable in JCVCPN transfected cells, and few infectious virions were produced. JCVCPN did not have a replication advantage in the neuronal cell line tested. To determine if the agnogene deletion or the archetype-like RR was responsible for the observed phenotype of JCVCPN, we generated a series of chimeric viruses between JCVCPN and JCVMad-1. We found that the phenotype of JCVCPN was due predominantly to the deletion in the agnogene, in particular the loss of the DNA and not the lack of a full length agnoprotein. To further study the role of the agnogene DNA in JCV replication, we introduced a series of small agnogene deletions into a virus with a start codon mutation which prevents agnoprotein expression. We characterized the replication of these additional mutants and found that nucleotides 376-396 are crucial for the expression of VP1 capsid protein. Previous studies have provided evidence for the binding of host cell proteins to the agnogene DNA. We used DNA-Immunoprecipitations with the agnogene to identify candidate binding proteins, but were unable to confirm any candidate proteins as binding specifically to the JCV agnogene. Studying this naturally occurring pathogenic variant of JCV provided a valuable tool for understanding the functions of the agnogene and RR form in JCV replication.