Highly Active Antiretroviral Therapy and Progressive Multifocal Leukoencephalopathy: Effects on Cerebrospinal Fluid Markers of JC Virus Replication and Immune Response

Abstract

Cerebrospinal fluid (CSF) samples were examined from 7 patients infected with human immunodeficiency virus type 1 (HIV-1) who had progressive multifocal leukoencephalopathy (PML). Samples were obtained both before and after 35-365 days of highly active antiretroviral therapy (HAART). By polymerase chain reaction, JC virus (JCV) DNA was found in 6 of 7 patients at baseline but in only 1 patient after HAART. In contrast, in 25 historical control patients from whom sequential CSF specimens were obtained, no reversion from detectable to undetectable JCV DNA was observed. By use of enzyme-linked immunosorbent assay, intrathecal production of antibody to JCV-VP1 was shown in only 1 of 4 HAART recipients at baseline but in 5 of 5 patients after treatment. The neuroradiological picture improved or had stabilized in all patients after 12 months of HAART, and all were alive after a median of 646 days (range, 505-775 days). Prolonged survival after HAART for PML is associated with JCV clearance from CSF. JCV-specific humoral intrathecal immunity may play a role in this response.

Molecular Biology, Epidemiology, and Pathogenesis of Progressive Multifocal Leukoencephalopathy, the JC Virus-Induced Demyelinating Disease of the Human Brain

“…In the era of HAART, HIV patients with PML and low or undetectable JCV copy number have been described with increased frequency (319,320), and HAART treatment is correlated with a reduction in the viral load of JCV in the CSF (108,166). Brain biopsy is sometimes indicated in patients where the CSF cannot be obtained or is inconclusive and the MRI is not characteristic of the disease.…”

Rearranged JC Virus Noncoding Control Regions Found in Progressive Multifocal Leukoencephalopathy Patient Samples Increase Virus Early Gene Expression and Replication Rate

“…The PCR products were compared after 2% Tris-acetate-EDTA-agarose gel electrophoresis to at-NCCR controls and excised for sequence analysis. The sequences were aligned to the CY archetype (55) by the program MultiAlign (10) and arbitrarily divided into sequence blocks Ori, A, B, C, D, E, and F, consisting of 117, 36,23,55,66,18, and 69 bp, respectively (4). Cells and culture.…”

“…Due to the lack of effective antiviral therapy (13), the treatment of PML is based on improving overall immune functions. While this is difficult to achieve in cancer, chemotherapy, and transplantation, prompt antiretroviral therapy in HIV/AIDS patients has significantly improved PML survival, with increasing JCV-specific immune responses and declining intracerebral JCV replication (7,15,23,35,37). In patients diagnosed with PML after treatment with natalizumab for multiple sclerosis or inflammatory bowel disease, the removal of the monoclonal antibody by plasmapheresis has been tried to restore lymphocyte homing to, and the immune surveillance of, JCV replication sites in the central nervous system (38,40,52).…”

JC Virus-Specific Cytotoxic T Lymphocytes in Individuals with Progressive Multifocal Leukoencephalopathy

“…This patient was already on HAART when the diagnostic CSF PCR was performed. It is possible that he indeed had PML but that the JC viral load in the CSF was below the limit of detection at the time he was receiving HAART (8). Alternatively, this cytolytic response might reflect a cross-reactive immune response directed against another polyomavirus, such as a virus that is closely related to JC virus but whose DNA cannot be amplified with the JCV-specific PCR primers.…”