The basis for modeling progressive multifocal leukoencephalopathy pathogenesis

Abstract

The appearance of progressive multifocal leukoencephalopathy (PML) in association with newer, highly effective biological agents has increased the importance of understanding the mechanisms by which they and other underlying predisposing causes give rise to the disorder. This review attempts to describe what is currently known about the pathogenesis of PML. JC virus is a ubiquitous polyoma virus that infects at least 50% of the human population by adulthood. Despite this high prevalence of infection PML remains exceptionally rare, suggesting the presence of multiple high barriers to its development. Proposed barriers include host, viral, and immunological factors. With respect to host factors, no data is presently available. A viral barrier exists if the initial infection is with the archetype JC virus which requires genetic rearrangement of its promoter region to enable effective replication in oligodendrocytes. Cell-mediated immunity, in particular, JC virus-specific cytotoxic T cells, appears to be the most important recognized immunological barrier but likely not the only one. There remain significant gaps in our understanding of JC virus biology and PML pathogenesis. However, the present state of knowledge provides a framework for the generation of coherent and reasonable hypotheses. A better understanding of these disease mechanisms will improve our ability to both predict and mitigate the risks for the development of PML associated with various predisposing diseases and therapies.