Host-Immune Interactions in JC Virus Reactivation and Development of Progressive Multifocal Leukoencephalopathy (PML)

Abstract

With the advent of immunomodulatory therapies and the HIV epidemic, the impact of JC Virus (JCV) on the public health system has grown significantly due to the increased incidence of Progressive Multifocal Leukoencephalopathy (PML). Currently, there are no pharmaceutical agents targeting JCV infection for the treatment and the prevention of viral reactivation leading to the development of PML. As JCV primarily reactivates in immunocompromised patients, it is proposed that the immune system (mainly the cellular-immunity component) plays a key role in the regulation of JCV to prevent productive infection and PML development. However, the exact mechanism of JCV immune regulation and reactivation is not well understood. Likewise, the impact of host factors on JCV regulation and reactivation is another understudied area. Here we discuss the current literature on host factor-mediated and immune factor-mediated regulation of JCV gene expression with the purpose of developing a model of the factors that are bypassed during JCV reactivation, and thus are potential targets for the development of therapeutic interventions to suppress PML initiation. Graphical Abstract.

Keywords: Diagnosis; Immunosuppression; JC virus; PML; Reactivation; Therapy.

Fig. 1.

Organization of JC virus (JCV) genome. JCV genome is a double-stranded circular DNA genome which contains a bidirectional non-coding control region (NCCR, yellow), which separates the early (red) and late (green) coding regions. Prior to DNA replication, the early coding region of JCV is transcribed, resulting in expression of the JCV regulatory T-antigen proteins, including large T-antigen, small t-antigen, and the T-prime splice variants, which are expressed following the alternative splicing of the early viral transcript. After early coding region transcription, both DNA replication of the genome as well as transcription of the late coding region of JCV occur simultaneously. The late coding region of JCV encodes the viral capsid proteins, VP1, VP2, and VP3, as wells as the small regulatory agnoprotein. Positions of nucleotides on circular viral genome are numbered relative to the Mad-1 reference strain (GenBank # NC-001699). Orange color on circular viral genome depicts the overlapping region for early and late transcripts.