SUMMARY Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease caused by the John Cunningham virus (JCV). While it is known to cause lytic infection in oligodendrocytes, many questions remain as to how this virus remains asymptomatic and dormant during initial infection throughout childhood and throughout most of the population’s adulthood. JCV becomes neurotropic under very specific conditions such as autoimmune disease and the use of disease-modifying therapies, which are commonly monoclonal antibody drugs designed to suppress some part of the adaptive immune system. This paper addresses how JCV crosses the blood brain barrier, what host and viral genetics enable neurotropism and virulence and how monoclonal antibody drugs aid in the reactivation of the virus. Based on the current literature, the rearrangement of the non-coding control region and VP1 capsid protein are key determinants of whether the virus becomes neurotropic. Host immune factors such as permissive alleles and overexpression of Spi-B, a ubiquitous transcription factor, can also lead to immune evasion and increased viral replication by JCV. A model is proposed wherein JCV use B cells as a “Trojan Horse” to cross the blood brain barrier. Co-infection with Epstein-Barr virus (EBV) can result in B cell fusion with oligodendrocytes and transmission of JCV. Finally, disease-modifying therapies play a role by primarily supressing the immune system and upregulating the migration of leukocytes, allowing the mobilization of JCV-infected cells to the blood brain barrier. Future studies should further elucidate the roles that Spi-B, hematopoietic stem cells and EBV coinfection play in transmission, pathogenesis, and genetic rearrangement of JCV.
Crossing Barriers: How JC Virus Crosses the Blood Brain Barrier and Induces Progressive Multifocal Leukoencephalopathy in Patients on Disease-Modifying Therapies.
Fall 2017 / Winter 2018