Background:  We studied  the role of immunological, virological, and radiological factors in the clinical outcome of a large group of patients with progressive multifocal leukoencephalopathy (PML).

Methods:  We enrolled 60 patients with PML (73% HIV⁺, 27% HIV^–), 20 HIV⁺ matched controls, and 15 healthy individuals. JC virus (JCV) viral load was measured in peripheral blood mononuclear cells (PBMC), plasma, and urine by quantitative polymerase chain reaction (qPCR) using JCV T-specific primers. JCV-specific CD8⁺ cytotoxic T lymphocytes (CTL) against JCV VP1 protein were analyzed in blood of HLA A*0201⁺ subjects by tetramer staining and in others by ⁵¹Cr release assay.

Results:  HIV⁺/PML and HIV⁺ patients had a CD4 cell count of 263 vs 398 /µL, and a plasma HIV viral load of 1.5 vs 2.2 log₁₀ copies/mL, respectively. JCV DNA was detected in the urine of 48% PML, 61% HIV⁺ and 27% healthy individuals. JCV DNA was detected in blood of 56% PML, 30% HIV⁺, and 0% healthy individuals. JCV detection was significantly increased in plasma of PML vs HIV⁺. (p = 0.024).The mean JC viral load in blood was similar in PML and HIV⁺ and among the 3 study groups in urine. In HLA A*0201⁺ PML there was a positive correlation between the magnitude of JCV VP1 _p100 CTL response and JC viral load in urine (r = 0.92, p = 0.03) or blood (plasma r = 0.63, p = 0.05; PBMC r = 0.76, p = 0.04). Survival at 1 year was 77% for HIV⁺PML and 60% for HIV^-PML patients. Among HIV⁺ PML survival was 83% vs 33% for those with detectable vs undetectable JCV-specific CTL within 1 year of diagnosis, respectively (HR of death 0.22, p = 0.05). Of 52 PML who underwent magnetic resonance imaging (MRI), 14 (27%) had contrast enhancement of PML lesions, and 10 of 60 (17%) PML patients had an immune reconstitution inflammatory syndrome (IRIS). Patients with contrast enhancement and IRIS had increased likelihood of having a CTL response (OR 4.2; p = 0.06 and OR 5.1; p = 0.08), but contrast enhancement and IRIS had no significant effect on survival. One-year survival was worse, 70% vs 92% in HIV⁺ PML patients with CD4 counts <200 than for those >200 (HR of death 5.1, p = 0.03). Treatment with serotonin receptor blockers had no significant influence on survival.

Conclusions:  JCV detection in plasma is significantly more frequent in PML than HIV⁺ patients. The association between JCV-specific CTL and better survival was observed in HIV⁺PML only, where it was a highly significant predictor. Conversely, HIV⁺PML patients with baseline CD4 counts <200 had a worse survival than those with higher CD4 counts. Despite the association of clinical features with JCV-specific CTL (contrast enhancement, IRIS), those cannot be considered as surrogate for the prognostic value of the CTL.