SEQUENCES WITHIN THE EARLY AND LATE PROMOTERS OF ARCHETYPE JC VIRUS RESTRICT VIRAL-DNA REPLICATION AND INFECTIVITY

Two forms of JC virus (JCV) have been isolated from its human host, an archetype found in kidney tissue and urine of nonimmunocompromised in dividuals and a rearranged type detected in lymphocytes and brain tiss ue of patients with and without progressive multifocal leukoencephalop athy. To investigate the hypothesis that alterations to the archetype transcriptional control region yield rearranged forms of the virus exh ibiting new tissue tropic and pathogenic potentials, attempts were mad e to propagate archetype JCV in human renal and glial cell cultures. A lthough rearranged forms of JCV multiplied in these cells, archetype J CV failed to do so, Through the use of chimeric and mutant viral genom es, and a cell line that constitutively expresses viral T protein, we demonstrated that archetype's inactivity relative to that of rearrange d forms was due to differences in the promoter-enhancer and not in the protein coding regions or origin of DNA replication. Additional analy ses revealed that the absence of a large tandem duplication and the pr esence of a 23- and a 66-base pair sequence in the archetype transcrip tional control region were responsible for this restricted lyric behav ior. We discuss the possibility that deletion and duplication events w ithin the archetype promoter-enhancer might yield more active viral va riants via the loss of a negative, or the creation of a positive, tran scriptional control signal(s). (C) 1996 Academic Press, Inc.