Abstract
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.
Highlights
The human polyomavirus JC (JCV) has a circular double stranded DNA genome which can be divided into 3 regions
Our studies determined that JCV Cortical Pyramidal Neuron 1 (JCVCPN1).1 and JCVCPN1.2 are phenotypically equivalent in our cell cultures model
JCVCPN was isolated from the brain of the first patient to be diagnosed with JCV Encephalopathy (JCVE), a novel syndrome characterized by infection of cortical pyramidal neurons
Summary
The human polyomavirus JC (JCV) has a circular double stranded DNA genome which can be divided into 3 regions. The early coding region encodes the regulatory proteins small t antigen and large T antigen (T Ag). The late coding region encodes the VP1, VP2 and VP3 structural proteins, and the agnoprotein [1]. The regulatory region (RR) contains the origin of replication, as well as the early and late promoters [2,3]. While the coding regions are well conserved, the RR is hypervariable, with different sequences being isolated from individuals [1]. Archetype RR, which has one 98-bp element and contains a 23-bp and a 66-bp insert, is generally found in the kidneys or urine of healthy and immunosuppressed individuals [4]. RRs from the brain or CSF of PML patients are generally of the rearranged type, containing two 98-bp tandem repeats with additional mutations, insertions and deletions [1,2]
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