Reactivation of latent varicella zoster virus (VZV) from dorsal root ganglia at all levels of the neuraxis produces serious neurological disease. In latently infected ganglia from normal humans, we have shown that low levels of VZV DNA are present in a circular form, that VZV genes 21, 29, 62 and 63 are transcribed, and that VZV gene 63 is translated. The fact that the VZV gene transcribed during latency include those immediate- early (IE) genes with either proven (gene 62) or implied (gene 63) regulatory functions and genes with putative DNA binding capacity (VZV genes 21 and 29) provides the ratione for our hypothesis that proteins encoded by VZV genes transcribed during latency inhibit virus replication. Synthesis of virus proteins and assembly of infectious virions are complex events that depend on coordinated gene activity and differ during productive infection and latency. For example, IE62 (the product of VZV gene 62) is a potent transactivator of many VZV genes associated with productive infection. While the function of IE63 (the product of VZV gene 63) is still uncertain, it may also function to regulate VZV gene expression and might be pivotal to the programmed switch from IE to early virus gene usage. During latency, however, the transactivation of VZV genes of IE62 or IE63 is modified. For example, in the presence of IE62 and IE63, the promoters for VZV genes 20, 21, 28, and 29 are active, while in latently infected ganglia where genes 62 and 63 are transcribed, the promoters for VZV genes 20 and 28 are silent. Thus, we will examine the hypothesis that IE62 and IE63 transactivation is regulated by VZV gene 21 and 29 proteins. Since the model relies on the translation of the transcripts detected during latency, we will search for proteins encoded by VZV genes 63, 62, 21 and 29 in the same latently infected human ganglionic cell. We will determine whether the VZV gene 21 protein forms a complex with VZV gene 29 protein, and whether this complex can inhibit VZV gene transactivation induced by IE62 or IE63. We will assay VZV replication, virus gene transcription, and virus promoter activity in cell lines expressing VZV genes 21 and 29. Our accumulated data on VZV gene expression in the human ganglia during latency have been assembled into a testable model designed to determine the interaction of these virus proteins. Such information will provide a rationale for future hypotheses about VZV reactivation, a cause of considerable morbidity, and occasional mortality, especially in elderly and immunocompromised humans.

Project Start
2000-12-01
Project End
2001-11-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
13
Fiscal Year
2001
Total Cost
$242,910
Indirect Cost
Name
University of Colorado Denver
Department
Type
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
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