Molecular regulation of JC virus tropism: insights into potential therapeutic targets for progressive multifocal leukoencephalopathy

Abstract

Progressive multifocal leukoencephalopathy (PML) is a growing concern for patients undergoing immune modulatory therapies for treatment of autoimmune diseases such as multiple sclerosis. Currently, there are no drugs approved for the treatment of PML that have been demonstrated in the patient to effectively and reproducibly alter the course of disease progression. The human polyoma virus JC is the causative agent of PML. JC virus (JCV) dissemination is tightly controlled by regulation of viral gene expression from the promoter by cellular transcription factors expressed in cells permissive for infection. JCV infection likely occurs during childhood, and latent virus containing PML-associated promoter sequences is maintained in lymphoid cells within the bone marrow. Because development of PML is tightly linked to suppression and or modulation of the immune system as in development of hematological malignancies, AIDS, and monoclonal antibody treatments, further scrutiny of the course of JCV infection in immune cells will be essential to our understanding of development of PML and identification of new therapeutic targets.

Fig. 1

Model of JC virus dissemination throughout host tissue. Lytic infection (orange—DNA replication, protein expression, progeny virus) occurs at widest points of the hour glass at the probable initial site of infection in the respiratory tract and the terminal site of infection in the brain. Establishment of and reactivation from latency (yellow—DNA replication, protein expression) occurs within the peripheral blood in the B cell compartment. Latency (white—maintenance of viral DNA) occurs at the center of the hour glass in lymphocyte precursors within the bone marrow

Fig. 2

Host transcription factor binding sites present in JC virus archetype and prototype regulatory region sequences. The circular map represents the 5.1-kb circular double-stranded DNA genome of JC virus. Early (large T antigen and small t antigen) and late genes (agnoprotein, VP1, VP2, and VP3) are separated by the noncoding viral regulatory region that contains the origin of DNA replication (ORI) and enhancer sequences (gray). The noncoding regulatory regions from the nonpathogenic archetype and PML-associated prototype variants of JC virus are represented in the late orientation for transcription. The origin of DNA replication (ORI), enhancer regions (gray), TATA boxes, and transcription factor binding sites are labeled on each regulatory region diagram. The following cellular transcription factor binding sites are represented: AP-1, NF-1, NFκB, Oct-6, Spi-B, YB-1/Purα