Abstract
John Cunningham virus (JCV), the etiological agent of progressive multifocal leukoencephalopathy (PML), contains a hyper-variable non-coding control region usually detected in urine of healthy individuals as archetype form and in the brain and cerebrospinal fluid (CSF) of PML patients as rearranged form. We report a case of HIV-related PML with clinical, immunological and virological data longitudinally collected. On admission (t0), after 8-week treatment with a rescue highly active antiretroviral therapy (HAART), the patient showed a CSF-JCV load of 16,732 gEq/ml, undetectable HIV-RNA and an increase of CD4+ cell count. Brain magnetic resonance imaging (MRI) showed PML-compatible lesions without contrast enhancement. We considered PML-immune reconstitution inflammatory syndrome as plausible because of the sudden onset of neurological symptoms after the effective HAART. An experimental JCV treatment with mefloquine and mirtazapine was added to steroid boli. Two weeks later (t1), motor function worsened and MRI showed expanded lesions with cytotoxic oedema. CSF JCV-DNA increased (26,263 gEq/ml) and JCV viremia was detected. After 4 weeks (t2), JCV was detected only in CSF (37,719 gEq/ml), and 8 weeks after admission (t3), JC viral load decreased in CSF and JCV viremia reappeared. The patient showed high level of immune activation both in peripheral blood and CSF. He died 4 weeks later. Considering disease progression, combined therapy failure and immune hyper-activation, we finally classified the case as classical PML. The archetype variant found in CSF at t0/t3 and a rearranged sequence detected at t1/t2 suggest that PML can develop from an archetype virus and that the appearance of rearranged genotypes contribute to faster disease progression.
Highlights
Progressive multifocal leukoencephalopathy (PML) is a fatal brain demyelinating disorder caused by the human polyomavirus JC (JCV), resulting from lytic infection of oligodendrocytes (Padgett et al 1971)
The highly active antiretroviral therapy (HAART) era evidenced progressive multifocal leukoencephalopathy (PML) cases observed in patients with restored CD4+ T cells count, shortly after HAART initiation and defined as PML-immune reconstitution inflammatory syndrome (IRIS) (Falcò et al 2008)
It is still debated whether John Cunningham virus (JCV) primary infection is triggered by archetype strain and non-coding control region (NCCR) rearrangement occurs during immunosuppression conditions (Fedele et al 2003), or JCV rearranged form is required for initial infection in tonsil tissue (Sabath and Major 2002)
Summary
Progressive multifocal leukoencephalopathy (PML) is a fatal brain demyelinating disorder caused by the human polyomavirus JC (JCV), resulting from lytic infection of oligodendrocytes (Padgett et al 1971). The patient showed high level of immune activation both in peripheral blood and CSF. JCV NCCR rearranged variant showing duplications, tandem repeats, insertions and deletions is usually found in the blood, brain and cerebrospinal fluid (CSF) of PML individuals (Tan et al 2010).
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