New Insights on Human Polyomavirus JC and Pathogenesis of Progressive Multifocal Leukoencephalopathy

Abstract

John Cunningham virus (JCV) is a member of the Polyomaviridae family. It was first isolated from the brain of a patient with Hodgkin disease in 1971, and since then the etiological agent of the progressive multifocal leukoencephalopathy (PML) was considered. Until the human immunodeficiency virus (HIV) pandemic, PML was rare: in fact HIV-induced immunodeficiency is the most common predisposing factor accounting for 85% of all instances of PML. This data led to intense research on JCV infection and resulted in better understanding of epidemiology and clinic-pathologic spectrum. Recently, cases of PML have been observed after the introduction of monoclonal antibodies, such as natalizumab, rituximab, efalizumab, and infliximab, in the treatment of autoimmune disease, underlining the important role of host immunity in PML pathogenesis. In this review current understanding of the JCV infection and the new findings relating to the pathogenesis of PML has been comprehensively revised, focusing our attention on the interaction between the cellular and viral molecular pathways implicated in the JCV infection and the modulating role of host immune surveillance in the viral reactivation from a latent state.

Clinical and Radiological Characterization of Progressive Multifocal Leukoencephalopathy in HIV-Infected Patients: A Retrospective Analysis and Review of the Literature

“…33,34 However, this immunomodulating effect is associated with an increased risk of PML lesions, depending on the duration of exposure to the drug, anti-JCV antibody serology status, and prior or current administration of immunosuppressive therapies. [35][36][37] In April 2014, there were 454 cases of natalizumabassociated PML documented in more than 123 000 treated patients with an overall survival rate of 77%. 38 Indeed, an adequate and frequent clinical monitoring, including serological tests and radiological evaluation, are of extreme importance in the follow-up of these patients in order to prevent and enable early detection of PML lesions.…”

CD49d antisense drug ATL1102 reduces disease activity in patients with relapsing-remitting MS

“…This also extends to ascertaining the profile of ATL1102 with respect to the risk of PML. Natalizumab increases the release of CD341 hematopoietic stem/progenitor cells and CD191 pre B cells and CD201 B cells into the blood, which carry latent low copy JC virus, 30,31 including in individuals who are seronegative. 31 Latent JC virus activation is theorized to involve B-cell differentiation, including B-cell DNA-binding protein Spi-B, which increases JCV transcription.…”

“…31 Latent JC virus activation is theorized to involve B-cell differentiation, including B-cell DNA-binding protein Spi-B, which increases JCV transcription. 30 Natalizumab has a long half-life in the blood (6 days), and a broad VLA-4 antagonist effect, and can impair JC virus immunosurveillance, leading to PML. 4,30 Preliminary data have shown ATL1102 treatment increases CD341 RNA 50% at week 8 vs baseline, though its effects at the CD341 cell level need to be explored 14 (appendix e-2).…”

“…30 Natalizumab has a long half-life in the blood (6 days), and a broad VLA-4 antagonist effect, and can impair JC virus immunosurveillance, leading to PML. 4,30 Preliminary data have shown ATL1102 treatment increases CD341 RNA 50% at week 8 vs baseline, though its effects at the CD341 cell level need to be explored 14 (appendix e-2). The reduction of CD191 (pre) B cells with ATL1102 treatment suggests that release of lymphoid precursors into the blood may be low or they do not survive, potentially reducing the pool of cells that may carry latent virus.…”

“…Natalizumab binding to VLA-4 induces intracellular signaling-associated proinflammatory effects, leading to poor outcomes in patients with PML following treatment suspension. 30,32 The short ATL1102 half-life in plasma of 4.8 hours 14 potentially limits exposure of circulating leukocytes to drug, which may better preserve blood leukocyte VLA-4-mediated immunosurveillance and therefore be at less risk of causing PML. IFN-b1 treatment of RRMS reduces blood mononuclear cell CD49d RNA 33 and VLA-4 expression on CD81 lymphocytes 34 and CD41CD45RO1 primed memory T cells, while preserving other blood leukocyte VLA-4 function.…”