A case of HIV-associated progressive multifocal leukoencephalopathy: longitudinal studyof JCV NCCR arrangement in serial CSF samples

Progressive multifocal leukoencephalopathy (PML) is a subacute demyelinating disease of the brain caused by the JC virus (JCV). The viral genome contains a non-coding control region (NCCR) that regulates JCV replication. In the urine of healthy people NCCR has a linear arrangement designed as archetype (CY strain). In brain and cerebrospinal fluid (CSF) of PML patients NCCR shows deletions and enhancements. A 51-year-old black man with HIV-1 infection was admitted to our ward because of gait ataxia and dysarthria. Diagnosis of HIV infection was made in 2004; nadir of lymphocyte T CD4 (CD4) count was 4 cells/μl (1%); the patient experienced multiple treatment failures; HIV genotyping test showed a subtype B virus, with resistance mutations for PI, NRTI, NNRTI, INI and a CXCR4 tropism. Two months before the onset of symptoms a salvage treatment with boosted tipranavir, raltegravir, enfuvirtide, tenofovir/emtricitabine was started. At this time HIV-RNA was 2527 copies/ml and CD4 count was 9 cell/ μl (2%). After two months HIV-RNA was undetectable and CD4 count was 23 cells/ μl (3,8%). On admission physical examination showed a positive Romberg’s sign, gait ataxia, dysarthria and the Kurtzke Expanded Disability Status Scale (EDSS) score was 2,5. HIV-RNA was still undetectable, CD4 count was 18 cells/ μl (4%). Brain MRI showed multiple hyperintense white matter lesions on T2- weighted and fluid-attenuated inversion-recovery (FLAIR) imaging, in the temporal, cerebellar, ponto-bulbar regions. Diffusion-weighted imaging (DWI) showed signal hyperintensities. No contrast enhancement was seen. Real time polymerase chain reaction (Q-PCR) for JCV in the CSF was positive with a viral load of 16.700 gEq/mL. HIV-RNA in CSF was undetectable. Two weeks after admission motor function worsened and EDSS score was 6,5. A new MRI showed further extension of the lesions previously described, with cytotoxic edema. CSF examination was repeated, with JCVDNA viral load of 20.600 gEq/mL. An additional CSF sample was collected 4 weeks after admission, with JCV-DNA viral load of 26.000 gEq/mL. Patient showed high level of immune activation both in peripheral blood and CSF. Regarding the monitoring for JCV reactivation, at the time of first CSF sampling, the patient was negative for the viral load in plasma and urine. Concerning NCCR analysis, the viral variant archetype CY was found in CSF, in PBMCs and in the cells of the rectal swab. In the second and third CSF samples, the JCV NCCR analysis showed the presence of a rearranged sequence, with a duplication of the box C containing the binding site for the HIV-tat protein. In this case we observed a rearrangement of the JCV NCCR from the first to the second CSF sample, with a pattern suggestive for interactions between JCV and HIV-tat protein. Neurological deterioration coincided with JCV NCCR rearrangement.