Studies on human polyomavirus infection in association with central nervous system disorders and bone marrow transplantation

Abstract: Human polyomaviruses BK virus (BKV) and JC virus (JCV) do not generally cause diseases in healthy immunocompetent individuals. However both BKV and JCV can establish persistent infections that can be reactivated and associated with serious clinical diseases in some innmunocompromised patients. The present studies have focused on infections with BKV and JCV in patients with central nervous system disorders (CNS) and bone marrow transplant (BMT) patients. In order to screen and follow BKV and JCV infections, a nested PCR specific for both BKV and JCV DNA was developed. This PCR had a sensitivity of 10 genome copies for each virus. Furthermore, previously established serological tests such as a BKV specific alzyme linked immunosorbent assay (EUSA) and a hemagglutination-inhibition assay (HAI) were used to follow BKV infection. Progressive multifocal leukoencephalopathy (PML) is a fatal neurological disease caused by JCV. In recent years most PML cases occur in AIDS patients, and there is a need for an accurate and rapid diagnosis of PML, since other CNS diseases with similar symptoms may be accessible for treatment. Detection of JCV DNA by the nested PCR in the cerebrospinal fluid (CSF) was evaluated as a diagnostic tool for PML. CSF samples from HIV-infected patients and from HIV negative patients in general with innmunological disorders, with PML or other neurological symptoms were included in this study. JCV DNA was detected exclusively in CSF specimens of patients with PML. To exclude that JCV is reactivated in the CNS by other viruses or multiple sclerosis (MS), CSF samples from patients with herpes simplex encephalitis, enteroviral meningitis and MS were examined for the presence of JCV DNA. JCV DNA was not detected in the CSF samples of any of these patients, which further supports that the detection of JCV DNA in the CSF is an efficient marker for PML. To follow if human polyomaviruses contributed to the pathology of Alzheimer's disease or to the development of astrocytomas, the presence of JCV and BKV DNA in the brain or tumor tissue of such patients was examined. There was no evidence that JCV or BKV contributed to either of these conditions. In BMT patients with a late onset of hemorrhagic cystitis (HC) BKV is excreted in the urine. However, not all BMT patients with BK viruria develop HC. To analyze if the presence of BKV DNA in the peripheral circulation was associated with HC in BMT patients, blood samples from both BMT patients with and without HC were examined by PCR. BKV and JCV DNA was found in peripheral blood leukocytes, plasma and serum of patients with and without HC and was subsequentdy not diagnostic for HC. To test if BMT patients encountering a primary BKV infection were at risk for HC development, serum samples from children before and after BMT and their corresponding donors were analyzed for the presence of antibodies against BKV. Primary BKV infection was not dhe major cause of HC, since most children were seropositive before transplantation. However, significandy more patients with HC than without HC exhibited BKV specific serological changes, such as presence of BKV IgM antibodies or HAI titer increase, but these changes occurred mainly late after the onset of HC.