JCPyV T-Antigen Activation of the Anti-Apoptotic Survivin Promoter-Its Role in the Development of Progressive Multifocal Leukoencephalopathy.

Luis Del Valle,Amanda Parker-Struckhoff,Sergio Piña-Oviedo,Thersa Sweet,Georgina Perez-Liz

doi:10.3390/v12111253

Abstract

Progressive Multifocal Leukoencephalopathy (PML) is a fatal demyelinating disease of the CNS, resulting from the lytic infection of oligodendrocytes by the human neurotropic polyomavirus JC (JCPyV), typically associated with severe immunocompromised states and, in recent years, with the use of immunotherapies. Apoptosis is a homeostatic mechanism to dispose of senescent or damaged cells, including virally infected cells, triggered in the vast majority of viral infections of the brain. Previously, we showed upregulation of the normally dormant anti-apoptotic protein Survivin in cases of PML, which—in vitro—resulted in protection from apoptosis in JCPyV-infected primary cultures of astrocytes and oligodendrocytes. In the present study, we first demonstrate the absence of apoptotic DNA fragmentation and the lack of caspase activity in 16 cases of PML. We also identified the viral protein large T-Antigen as being responsible for the activation of the Survivin promoter. Chromatin Immunoprecipitation assay shows a direct binding between T-Antigen and the Survivin promoter DNA. Finally, we have identified the specific region of T-Antigen, spanning from amino acids 266 and 688, which binds to Survivin and translocates it to the nucleus, providing evidence of a mechanism that results in the efficient replication of JCPyV and a potential target for novel therapies.

Highlights

The human neurotropic virus JC (JCPyV), a member of the Polyomaviridiae family of DNA viruses, which includes BKPyV, SV40 and the Merkel cell polyomavirus (MCPyV) [1], is the well-established opportunistic etiological agent of the fatal, demyelinating disease of the brainProgressive Multifocal Leukoencephalopathy (PML)
We showed the presence of Survivin in the nuclei of JCPyV-infected oligodendrocytes and in the cytoplasm of JCPyV-infected astrocytes, while both phenotypes of glial cells outside plaques of demyelination remained negative
Expression of T-Antigen is frequently observed in early lesions of PML in the nucleus of oligodendrocytes and in the cytoplasm and nucleus of bizarre astrocytes; in late lesions, T-Antigen is less frequently observed, but the detection of capsid proteins with an anti-VP1 antibody is a reliable indicator of active JCPyV

Summary

Introduction

The human neurotropic virus JC (JCPyV), a member of the Polyomaviridiae family of DNA viruses, which includes BKPyV, SV40 and the Merkel cell polyomavirus (MCPyV) [1], is the well-established opportunistic etiological agent of the fatal, demyelinating disease of the brainProgressive Multifocal Leukoencephalopathy (PML). The human neurotropic virus JC (JCPyV), a member of the Polyomaviridiae family of DNA viruses, which includes BKPyV, SV40 and the Merkel cell polyomavirus (MCPyV) [1], is the well-established opportunistic etiological agent of the fatal, demyelinating disease of the brain. PML consists of areas of severe demyelination with multiple foamy macrophages, microglial nodules, perivascular cuffing of lymphocytes, both findings of any CNS viral infection, and the pathognomonic cells of the disease: enlarged oligodendrocytes harboring intra-nuclear inclusion eosinophilic bodies and bizarre atypical astrocytes, reminiscent of malignant glial cells [7]. JCPyV is a small (38–40 nm), non-enveloped virus with a double-stranded DNA and a circular genome of 5130 nucleotides that can be divided into three regions: a non-coding regulatory region that controls the initiation of replication and viral transcription, which is located between an early and a late transcriptional region. The early region contains the codifying sequences for the large and small

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