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 multi focal leukoencephalopathy (PML) is a demyelinating disease of the CNS that generally affects patients exhibiting an immunocompromised condit ion due to various illnesses. The human polyomavirus, JCV, which infec ts greater than 70% of the adult population is the etiological agent o f this disease. infection with JCV occurs during childhood and the vir us remains in the latent state with no apparent clinical signals. Howe ver, under immunocompromised conditions, the virus enters the lytic cy cle, and upon cytolytic destruction of glial cells, causes PML. To und erstand the molecular mechanism underlying immune regulation of JCV re plication, we have developed a cell culture system and have investigat ed the effect of soluble factors from T-cell cultures on replication o f JCV DNA in glial cells. Our data demonstrate that replication of JCV DNA in the presence of PMA-stimulated T-cell supernatant is substanti ally 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 fr action enriched in 30- to 100-kDa proteins reduced the level of viral DNA replication during the early phase of the lytic cycle, These obser vations suggest that regulatory factors which are secreted by immune c ells may modulate the level of JCV DNA replication in glial cells. The importance of these observations in reactivation of JCV in immunocomp romised individuals and development of PML is discussed. (C) 1996 Acad emic Press, Inc.