Fifty Years of JC Polyomavirus: A Brief Overview and Remaining Questions

Abstract

In the fifty years since the discovery of JC polyomavirus (JCPyV), the body of research representing our collective knowledge on this virus has grown substantially. As the causative agent of progressive multifocal leukoencephalopathy (PML), an often fatal central nervous system disease, JCPyV remains enigmatic in its ability to live a dual lifestyle. In most individuals, JCPyV reproduces benignly in renal tissues, but in a subset of immunocompromised individuals, JCPyV undergoes rearrangement and begins lytic infection of the central nervous system, subsequently becoming highly debilitating-and in many cases, deadly. Understanding the mechanisms allowing this process to occur is vital to the development of new and more effective diagnosis and treatment options for those at risk of developing PML. Here, we discuss the current state of affairs with regards to JCPyV and PML; first summarizing the history of PML as a disease and then discussing current treatment options and the viral biology of JCPyV as we understand it. We highlight the foundational research published in recent years on PML and JCPyV and attempt to outline which next steps are most necessary to reduce the disease burden of PML in populations at risk.

Keywords: HIV/AIDS; JC polyomavirus; autoimmune disease; multiple sclerosis; polyomavirus; progressive multifocal leukoencephalopathy.

Figure 1

JCPyV genome undergoes rearrangement in progressive multifocal leukoencephalopathy (PML). Left panel: Archetype JCPyV develops a persistent infection in the kidneys and is generally asymptomatic. PML-type JCPyV is a rearranged form with one or more deletions or duplications of genomic block sequence in the non-coding control region (NCCR) (shown above in expanded form as a deletion of blocks b and d and a duplication of blocks a, c and e) and is found in the brain, cerebrospinal fluid (CSF) and blood. Right panel: Early genes include large T and small t antigens and are transcribed first. Late genes include structural proteins and additional regulatory proteins. Early and late genes are separated by the NCCR and are transcribed in opposite directions. ORI—origin of replication; NCCR—non-coding control region; T—T antigen and splice variants. Agno: JCPyV agnoprotein. Adapted from [30] and [126].

Figure 2

JCPyV cellular entry may occur through multiple pathways. JCPyV initially binds to LSTc receptors before transient interaction with 5-HT₂ receptors which facilitate internalization through clathrin-mediated endocytosis. JCPyV then switches from a Rab5+ early endosome to a caveolin-1+ late endosome before entering the endoplasmic reticulum (ER) where the virus is uncoated. JCPyV exits the ER into the cytosol before entering the nucleus for replication. Alternatively, JCPyV may bind to the cell within an extracellular vesicle. Here, the vesicle is internalized through micropinocytosis or clathrin-mediated endocytosis before trafficking to the ER. Adapted from [30] and [126].

Figure 3

Model of JCPyV CNS entry by choroid plexus. Evidence suggests JCPyV may utilize extracellular vesicles (EVs) in entry of the CNS. A model proposed by O’Hara et al. theorizes JCPyV may pass into the stroma from the bloodstream as either free virions or enclosed in capsules. JCPyV is then able to infect choroid plexus epithelial (CPE) cells which package and release the virions in EVs into the CSF. JCPyV-containing EVs then enter the brain parenchyma and infect glial cells without necessitating the use of the LSTc cellular entry receptor. Adapted from [194].