Human Cytomegalovirus (HCMV) represents the major infectious cause of birth defects, as well as an important pathogen for immuno-compromised individuals. The virus owes its evolutionary success and clinical importance to its ability to establish a latent infection and is able to reactivate, presenting significant clinical problems to immuno-compromised individuals, certain transplant patients and also neonates.
The balance between the lyric and latent status is controlled by both host and viral factors and among them, the HCMV immediate early protein IE1. Viruses, which fail to express functional IE1 enter the lytic cycle inefficiently and instead can be maintained in a quiescent state in the cell. Upon HCMV infection, distinct nuclear domains known as ND10 are disrupted at early times and the regulatory protein IE1 is necessary and sufficient for this effect. It has been proposed that IE1 potentially play a role in maintenance of the latent state of HCMV DNA and that its activity might be involved in viral gene expression or repression pathways. Considering that the environment of parental viral genomes in the nucleus and their interactions with viral and cellular proteins are important in transcriptional activation or silencing, it is particularly interesting t hat several HCMV transcripts are preferentially found in association with ND10 and a number of ND10 proteins or proteins with which they interact, have been implicated in repression.
The proposed project intends to investigate the localisation and dynamics of lytic and quiescent viral genomes in the cell and explore the involvement of IE1 in the molecular and cellular events that take place during reactivation of HCMV gene expression. Parental HCMV genomes will be visualised by using engineered HCMV amplicon plasmids, taking the advantage of auto-fluorescent fusion proteins along with the specific Tetracycline Repressor/Operator interaction
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