Viral Trafficking pathways of JC virus to the brain in progressive multifocal leukoencephalopathy

Abstract

Progressive multifocal leukoencephalopathy (PML) is a highly fatal, demyelinating disease of the brain caused by lytic infection of oligodendrocytes with the JC polyomavirus (JCPyV). Emergence of PML is considered rare and is always associated with an underlying deficit in immune surveillance. In accordance, the majority of PML cases are detected in patients with HIV-induced severe immunodeficiencies. Fortunately, the introduction of cART significantly reduced the incidence of PML in HIV-infected patients. In 2005, however, a surprising increase in PML cases was observed with the use of monoclonal antibodies, including natalizumab and rituximab. As these therapies modulate the immune system rather than suppressing it, questions were raised regarding the conventional route of JCPyV pathogenesis. Owing to the lack of both animal models, and sufficient in vitro models to sustain effective replication of JCPyV, the mechanisms of JC virus infection remain largely uncertain and current understanding in pathogenesis is obtained from human autopsy material. In particular, transport of JCPyV through the blood brain barrier is a challenging concept and requires critical analysis. This review summarizes the current understanding of JCPyV pathogenesis, and revisits commonly accepted mechanisms of JCPyV trafficking to the brain.