Traffic of JC Virus from Sites of Initial Infection to the Brain: The Path to Progressive Multifocal Leukoencephalopathy

Abstract

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disorder of the human brain caused by infection with the human polyomavirus, JC. Up to 80% of humans express serum antibodies to JC virus (JCV), yet considerably fewer people develop PML-predominantly those under immunosuppressive conditions. Recent research showed JCV infection in multiple tissues throughout the body, suggesting sites for viral latency. These observations allow the proposal of pathways that JCV may use from sites of initial infection to the brain. Results from investigations into cell-surface receptors, intracellular DNA-binding proteins, and variant viral regulatory regions also suggest mechanisms that may regulate cellular susceptibility to JCV infection. Together, these data elucidate how JCV may establish infection in various cell types, persist latently or become reactivated, and ultimately reach the brain to cause PML.

Progressive multifocal leukoencephalopathy in rheumatic diseases: Evolving clinical and pathologic patterns of disease

“…However, binding itself does not appear to be a critical step in establishing productive infection. The ability of JCV to infect CNS glial cells (which correlates well with its pathogenic potential for causing PML) is contingent upon rearrangement of the viral transcription control region (TCR) and upon intracellular DNA binding proteins that direct gene expression from the rearranged TCR (47,51).…”

“…The most likely scenario for the pathogenesis of PML is reactivation of JCV replication in the context of profoundly impaired cell-mediated immunity, with subsequent viremia and entry of virus into the CNS, either cell-associated or cell-free (47). JCV infection causes lysis of oligodendrocytes, which results in demyelination, the proximate cause of the signs and symptoms of PML.…”

“…It remains uncertain whether JCV undergoes rearrangement in vivo, generating TCRs with tandem repeats that are capable of infecting glial cells and causing PML (47). It is also possible that some patients with PML have had a primary infection (94).…”

“…It is also possible that some patients with PML have had a primary infection (94). Sites of viral replication and routes of dissemination to the CNS remain to be definitively established (47). In significant part, the limitation in our understanding arises from the lack of an analogous spontaneous disorder in nonhuman mammals and the absence of an animal model of PML.…”

A prospective, open, non-randomized study on the safety and efficacy of natalizumab (tisabri) in the Russian population of patients with relapsing-remitting multiple sclerosis

“…Данное состояние, преимущественно развивающее-ся у лиц с нарушенным иммунитетом, может при-вести к тяжелой инвалидизации или смертельному исходу [41,42,[44][45][46]. Известно, что риск развития ПМЛ у пациентов, получающих натализумаб, ассо-циирован с наличием антител к JC-вирусу, большей длительностью терапии натализумабом (в особен-ности при его применении на протяжении 2 лет и более) и приемом иммунодепрессантов в анамне-зе.…”