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Background:  HAART has changed the AIDS scenario, but neurological disorders including PML and JC virus (JCV)-negative leukoencephalopathy are still a problem.

Methods:  To investigate clinical, virologic, and immunologic parameters of AIDS-related leukoencephalopathies, a longitudinal survey has been taken. HIV⁺ HAART-treated patients were subjected to MRI examination. Virologic studies were carried out in cerebrospinal fluid (CSF) to verify the presence of JCV and other neurotropic viruses (HSV1/2, VZV, EBV, HCMV, HHV6, HHV8) and HIV and JCV viral loads were determined in CSF by real-time PCR. MCP-1 was quantified in CSF by EIA. The immunologic evaluation consisted of measurement, by flow cytometry, of PBMC production of TNF-α, IFN-γ, IL-2, and MCP-1, previous and after JCV HLA-restricted peptides stimulation. Differences were analyzed by Student’s test and correlation by Pearson’s analysis.

Results:  MRI examinations of 75 eligible patients revealed:  22 MRI⁺ (8 JCV⁺ PML, 12 NDLE, and 2 with other neurological diseases) and 41 MRI patients (30 without neurological symptoms and 11 with other neurological diseases) were enrolled in the study, together with 27 healthy subjects, as control. Median plasma HIV load was significantly higher (p < 0.05) in PML patients (11,12 log copies/mL) than in NDLE patients (8,53 log copies/mL), whereas median CSF HIV load was similar in the three groups. MCP-1 and HIV RNA in CSF were positively correlated in the 3 groups (PML:  r = 0.11 p = 0.89; NDLE r = 0.399 p = 0.199; OND:  r = 0.260; p = 0.391). No viruses were found in CSF of NDLE patients, whereas VZV and EBV were found in CSF of 2 MRI⁺ patients with other neurological diseases. In PML patients median JCV DNA in CSF load was 12,29 log copies/mL. IFN-γ was produced, after stimulation, in a significantly (p < 0.05) higher number of CD4⁺ cells of NDLE (0.60%) and PML (0.51%) patients, than of healthy subjects (0.01%); likewise, the IFN-γ a production by CD8⁺ cells was higher (p < 0.05) in NDLE patients (0.59%) than in healthy subjects (0.03%). No other significant differences in cytokines and chemokines production among patients and controls were found.

Conclusions:  No virus has been found in NDLE samples, however, the JCV-specific immune response observed in PML and in NDLE patients suggests that, also in NDLE, JCV could play a role yet to be defined. The finding of an increased cytotoxic activity indicates that an immune mediated mechanism is probably relevant in NDLE pathogenesis.

Keywords: Leukoencephalopathy; JC virus; HLA-restricted peptides