HIV-associated progressive multifocal leukoencephalopathy: longitudinal study of JC virus non-coding control region rearrangements and host immunity

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.

5-HT 2 Receptors Facilitate JC Polyomavirus Entry

“…In fact, several 5-HT 2 receptor inhibitors, both selective and nonselective, are approved for use by the FDA and commonly used to treat neurological disorders (70,71). To our knowledge, only mirtazapine has been administered in patients with PML, often with positive outcomes in delaying the progression of the disease (42)(43)(44)(45)72), but in other cases, no effect was observed (44,46). The use of mirtazapine is most successful if administered early at the onset of PML symptoms (44).…”

“…In the clinical setting, mirtazapine has been administered to indi-viduals diagnosed with PML, either alone or in combination with other drugs, and in several cases, it has been shown to delay the progression of this fatal disease when given at the onset of PML symptoms (42)(43)(44)(45). In contrast, other reports have shown no effect on degeneration (44,46). Thus, the roles of the 5-HT receptors in JCPyV infection remained unclear.…”

Prospective Study of Human Polyomaviruses and Risk of Cutaneous Squamous Cell Carcinoma in the United States

“…Available studies on repeated measures of seroreactivity against PyVs have primarily been conducted among special populations such as organ transplant recipients (13, 61), pregnant women (20), and heavily immunosuppressed patients (e.g., HIV-infected individuals (62, 63), or multiple sclerosis patients treated with natalizumab (17–19, 64–66)), with evidence of greater seroinstability over time, possible due to their condition or immunotherapy. A nested case-control study of non-Hodgkin's lymphoma found only 1 change in JC serostatus and 3 changes in BK serostatus over a period of 15 years out of 94 controls (67).…”

Progressive multifocal leukoencephalopathy in common variable immunodeficiency: mitigated course under mirtazapine and mefloquine

“…PML treatment with mirtazapine or mefloquine was mainly described in patients with HIV, organ transplant, dermatomyositis, polycythemia vera, sarcoidosis, systemic lupus erythematosus, and idiopathic CD4+ T lymphocytopenia (Loyaga-Rendon et al 2013;Delgado-Alvarado et al 2013;Hohlfeld et al 2012;Verma et al 2007;Vulliemoz et al 2006;Beppu et al 2012;Naito et al 2012;Clifford et al 2013;Cettomai and McArthur 2009). Combined treatment with mefloquine and mirtazapine has been reported in PML cases in the context of HIV infection, multiple sclerosis (MS) (Gheuens et al 2011;Iannetta et al 2013;Moenster and Jett 2012;Schröder et al 2010), and in one seemingly immunocompetent PML patient (Christakis et al 2013). One case series compared the effect of mirtazapine to mirtazapine and mefloquine in 34 HIV-negative patients with PML (Gheuens et al 2011), including nine patients who had hematological disorders including Waldenstrom macroglobulinemia, common variable immunodeficiency (CVID), and idiopathic CD4+ or CD8+ T lymphocytopenia.…”