Evidence that the soluble factors secreted by activated immune cells suppress replication of human neurotropic JC virus DNA in glial cells.

Coordination of the immune response to viral infection and disease in the brain is believed to involve bidirectional interaction between the immune system and the central nervous system (CNS). Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the CNS that generally affects patients exhibiting an immunocompromised condition due to various illnesses. The human polyomavirus, JCV, which infects greater than 70% of the adult population is the etiological agent of this disease. Infection with JCV occurs during childhood and the virus remains in the latent state with no apparent clinical signals. However, under immunocompromised conditions, the virus enters the lytic cycle, and upon cytolytic destruction of glial cells, causes PML. To understand the molecular mechanism underlying immune regulation of JCV replication, we have developed a cell culture system and have investigated the effect of soluble factors from T-cell cultures on replication of JCV DNA in glial cells. Our data demonstrate that replication of JCV DNA in the presence of PMA-stimulated T-cell supernatant is substantially decreased in transfected glial cells. Heat-inactivation and size-fractionation studies revealed participation of a heat labile factor(s) which loses its maximum activity at 60 degrees and ranges between 30 and 100 kDa in size. The unfractionated T-cell supernatant and the fraction enriched in 30- to 100-kDa proteins reduced the level of viral DNA replication during the early phase of the lytic cycle. These observations suggest that regulatory factors which are secreted by immune cells may modulate the level of JCV DNA replication in glial cells. The importance of these observations in reactivation of JCV in immunocompromised individuals and development of PML is discussed.