Background:  Effective antiviral therapy for progressive multifocal leukoencephalopathy (PML) among HIV patients has not yet been found. Although HAART may maintain or restore cellular immunity, PML remains a serious cause of neurologic morbidity, with a 50% fatality rate. PML may also arise amid the setting of immune reconstitution inflammatory syndrome. An apparent limitation of HAART is its inability to inhibit replication of polyomavirus JC (JCV), the causative agent of PML. We previously demonstrated induction of genes associated with interferon (IFN) antiviral response pathway in primary human fetal glial (PHFG) cells, specifically at later stages of JCV replication. The objective of this study was to analyze specific viral events required to induce IFN-stimulated genes, and to assess the potential antiviral effects of IFN-α and -β on JCV replication.

Methods:  PHFG cells were infected with 50 hemagglutination units (HAU) of JCV (Mad1) or UV-inactivated JCV, and cells were grown in the continuous presence of 100 units/mL of IFN-α or -β. To assess antiviral efficacy of IFN, at days 3, 5, 8, and 15 post-inoculation, JCV T antigen DNA and mRNA transcripts, and IFN-stimulated gene mRNA transcripts were analyzed by quantitative real time polymerase chain reaction (RT-PCR) and RT-PCR, and T antigen protein expression was quantitated by Western blotting.

Results:  Treatment with both, IFN- α and -β resulted in significant induction of IFN-stimulated genes in PHFG cells at all time points. Productive JCV replication was essential for the induction of IFN-stimulated genes in PHFG cells. JCV replication at days 5, 8, and 15 was significantly inhibited in the presence of IFN- α and -β. Effect of IFN on JCV replication was reversed in the presence of neutralizing anti-IFN antibody. Furthermore, IFN-ß was found to have more potent effect on blocking JCV infection.

Conclusions:  Our in vitro data demonstrate direct antiviral effect of IFN on JCV replication. It suggests that IFN-α and -β may be useful as adjunct therapies to manage patients with PML. Since IFN cannot cross the blood–brain barrier, to achieve its direct antiviral effect, intrathecal administration of IFN warrants consideration of clinical trials in humans.