HUMAN CYTOMEGALOVIRUS INDUCES JC VIRUS-DNA REPLICATION IN HUMAN FIBROBLASTS

JC virus, a human papovavirus, is the causative agent of the demyelina ting brain disease progressive multifocal leucoencephalopathy (PML). P ML is a rare but fatal disease which develops as a complication of sev ere immunosuppression. Latent JC virus is harbored by many asymptomati c carriers and is transiently reactivated from the latent state upon i mmunosuppression. JC virus has a very restricted host range, with huma n glial cells being the only tissue in which it can replicate at reaso nable efficiency. Evidence that latent human cytomegalovirus is harbor ed in the kidney similar to latent JC virus led to the speculation tha t during episodes of impaired immunocompetence, cytomegalovirus might serve as helper virus for JC virus replication in otherwise nonpermiss ive cells. We show here that cytomegalovirus infection indeed leads to considerable JC virus DNA replication in cultured human fibroblasts t hat are nonpermissive for the replication of JC virus alone. Cytomegal ovirus-mediated JC virus replication is dependent on the JC virus orig in of replication and T antigen. Ganciclovir-induced inhibition of cyt omegalovirus replication is associated with a concomitant inhibition o f JC virus replication. These results suggest that reactivation of cyt omegalovirus during episodes of immunosuppression might lead to activa tion of latent JC virus, which would enhance the probability of subseq uent PML development. Ganciclovir-induced repression of both cytomegal ovirus and JC virus replication may form the rational basis for the de velopment of an approach toward treatment or prevention of PML.