Evidence for Virus-specific immune response imbalance in HIV associated leukoencephalopathies

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, virological and immunological parameters of AIDS-related leukoencephalopathies, a longitudinal survey has been taken. HIV+ HAART treated patients were subjected to MRI examination. Virological 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 RealTime PCR. MCP-1 was quantified in CSF by EIAs. The immunological evaluation consisted of measurement, by flow cytometry, of PBMC production of TNFalpha, IFNgamma, IL-2 and MCP-1, previous and after JCV HLA-restricted peptides stimulation. Statistical evaluation was done by Student’s test and by Pearson’s analysis. Results: MRI examination of 75 eligible patients revealed: 22 MRI+ (8 JCV+ PML, 12 NDLE and 2 with other neurological diseases, OND) and 41 MRI- patients (30 without neurological symptoms and 11 OND) 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 ln copies/ml) than in NDLE patients (8,53 ln 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 three 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 OND MRI+ patients. In PML patients median JCV DNA in CSF load was 12,29 ln copies/ml. IFNgamma 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 IFNgamma 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.