Human papovavirus, JCV, is associated with the human demyelinating disorder progressive multifocal leukoencephalopathy. In tissue culture, the virus is largely restricted to growth in primary human fetal glial cells. In this study, we demonstrate two levels of regulation of the viral host range. Expression of early JCV mRNA, which encodes the essential viral protein, large tumor antigen (T-antigen), depends on recognition of the early enhancer/promoter elements by tissue- specific factors found in both human and rodent glial cells. In the presence of JCV T-antigen, viral DNA replication requires a species-specific factor, presumably a component of DNA polymerase, which is found in a wide range of primate cells. We further demonstrated that simian virus 40 T-antigen has sufficient homology to efficiently substitute for the analogous JCV protein in initiating viral DNA replication. We have used primer extension and S1 analysis to localize the 5'-termini of JC virus (JCV) early RNAs in infected primary human glial cells at various times postinfection and in stable JCV-transformed hamster fetal glial cells. At early times postinfection (days 1-5), two early transcripts are initiated at nucleotides 5122 and 5082. A major shift in 5'-ends at later times results in the synthesis of a new series of early mRNAs beginning upstream at nucleotide 35 and downstream at nucleotides 5047, 5037, ad 5012. In the transformed hamster cells, however, only on RNA species was detected, starting at nucleotide 5122. The mechanism underlying the shift in the initiation site of JCV early RNAs during a lytic infection remains unclear but appears analogous to that which occurs in the SV40 lytic cycle. Since the shift occurs during DNA replication, when T-antigen is at maximal levels, it is possible that T-antigen binding to JCV DNA and/or alterations in chromatin structure contribute to this event.

Agency
National Institute of Health (NIH)
Institute
Division of Cancer Epidemiology And Genetics (NCI)
Type
Intramural Research (Z01)
Project #
1Z01CP005391-06
Application #
3916808
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Cancer Epidemiology and Genetics
Department
Type
DUNS #
City
State
Country
United States
Zip Code