New insights into HIV- related leukoencephalopathies during HAART therapy: data from an Italian longitudinal study

BACKGROUND: HAART has changed the scenario of HIV-related neurological disorders but the incidence of Leukoencephalopathies has not decreased significantly. METHODS: To investigate clinical, virological and immunological parameters of leukoencephalopathies, a longitudinal survey was performed. HIV+ HAART treated patients were subjected to clinical and MRI examination. Virological studies were carried out, every six months, to verify the presence of JCV and herpesviruses and determine HIV and JCV viral loads in CSF. Immunological evaluations consisted of measurement every month, of PBMC production of TNF, IFN, IL-2, previous and after JCV HLA-restricted peptides stimulation. RESULTS: Clinical and MRI examinations were performed on 135 HIV+ patients: 19 MRI+ and 40 MRI- patients (30 without neurological symptoms and 10 with other neurological diseases, OND) were enrolled in the study, together with 27 healthy subjects. At the onset, no virus was found in CSF of 11 patients, classified as possible NDLE, whereas EBV was found in CSF of one OND patient and JCV DNA (mean load:12,29 log copies/ml) in CSF of 8 PML patients. Mean CD4 cells count was 300/l (range: 14-794 cells/l), plasma HIV load was significantly higher in PML than in NDLE patients (9.42 versus 4.78 log copies/ml, p<0.005), CSF HIV load was similar in the groups (5.7 log copies/ml). Stereotactic brain biopsies from two NDLE patients revealed the presence of JCV DNA, that, after seven months, was also found in the CSF. Immunological evaluations showed that IFN production by CD4+ cells, after stimulation, was significantly higher (p<0.05) in NDLE (0.60%) and PML (0.51%), than in healthy subjects (0.01%); IFN production by CD8+ cells was higher (p<0.05) in NDLE (0.59%) than in healthy subjects (0.03%). CONCLUSIONS: Our findings suggest the brain as possible site of latency for JCV and that the onset of the PML pathogenesis could occur earlier than thought. The presence of JCV DNA in CSF does not always correlate with clinical and radiological evolution of PML. Finally, JCV-specific immune response observed in PML and in NDLE indicates these immunological tests as possible surrogate markers for disease evolution and that JCV could play a pathogenic role also in NDLE.