Progressive multifocal leukoencephalopathy and the spectrum of JC virus-related disease

Abstract

Progressive multifocal leukoencephalopathy (PML) is a devastating CNS infection caused by JC virus (JCV), a polyomavirus that commonly establishes persistent, asymptomatic infection in the general population. Emerging evidence that PML can be ameliorated with novel immunotherapeutic approaches calls for reassessment of PML pathophysiology and clinical course. PML results from JCV reactivation in the setting of impaired cellular immunity, and no antiviral therapies are available, so survival depends on reversal of the underlying immunosuppression. Antiretroviral therapies greatly reduce the risk of HIV-related PML, but many modern treatments for cancers, organ transplantation and chronic inflammatory disease cause immunosuppression that can be difficult to reverse. These treatments — most notably natalizumab for multiple sclerosis — have led to a surge of iatrogenic PML. The spectrum of presentations of JCV-related disease has evolved over time and may challenge current diagnostic criteria. Immunotherapeutic interventions, such as use of checkpoint inhibitors and adoptive T cell transfer, have shown promise but caution is needed in the management of immune reconstitution inflammatory syndrome, an exuberant immune response that can contribute to morbidity and death. Many people who survive PML are left with neurological sequelae and some with persistent, low-level viral replication in the CNS. As the number of people who survive PML increases, this lack of viral clearance could create challenges in the subsequent management of some underlying diseases. In this Review, Cortese et al. provide an overview of the pathobiology and evolving presentations of progressive multifocal leukoencephalopathy and other diseases caused by JC virus, and discuss emerging immunotherapeutic approaches that could increase survival. Progressive multifocal leukoencephalopathy (PML) is a rare, debilitating and often fatal disease of the CNS caused by JC virus (JCV). JCV establishes asymptomatic, lifelong persistent or latent infection in immune competent hosts, but impairment of cellular immunity can lead to reactivation of JCV and PML. PML most commonly occurs in patients with HIV infection or lymphoproliferative disease and in patients who are receiving natalizumab for treatment of multiple sclerosis. The clinical phenotype of PML varies and is shaped primarily by the host immune response; changes in the treatment of underlying diseases associated with PML have changed phenotypes over time. Other clinical manifestations of JCV infection have been described, including granule cell neuronopathy. Survival of PML depends on reversal of the underlying immunosuppression; emerging immunotherapeutic strategies include use of checkpoint inhibitors and adoptive T cell transfer.