All human populations harbor latent inapparent infection with many or all of the eight known human herpesviruses. Both acute and chronic herpesvirus infections are particularly serious problems encountered clinically in immunosuppressed cancer and organ transplant patients, as well as in AIDS patients. However, they can also trigger a variety of tumors, lymphoproliferative and angiogenic diseases in immunocompetent patients.
The focus of our laboratory research is aimed at understanding how the different classes of herpesviruses usurp control of transcription, DNA replication, cell cycle and other nuclear processes of their host cells and how they also block or evade apoptotic and immune responses in both the lytic and latent state. The large genomes (up to 200 genes) of the three representative herpesviruses that we study encode a series of well defined cascade-like pathways of gene expression that are switched on or off depending on appropriate activated or differentiated states of the host neuronal cells (HSV), myeloid precursor cells (CMV) or vascular endothelial cells (KSHV). Each pathway is driven by complex promoter enhancer domains that control expression of a set of key triggering nuclear IE transactivator proteins.
In addition to acting as specific DNA-binding transcription factors that redirect certain cellular factors towards viral transcription, the IE lytic cycle trigger proteins are highly pleomorphic and carry out numerous as yet poorly understood functions associated with RNA nuclear shuttling, engaging histone acetylase and deacetylase complexes, altering SUMO and ubiquitin modulated cell cycle protein stability and degradation pathways, affecting chromatin structure, replacing components of the cellular DNA synthesis machinery with viral encoded proteins and blocking cell cycle progression. In contrast, in the latent state, the viral lytic cycle triggers are repressed, the viral genomes are maintained as episomes and the cells may become immortalized or display "converted" phenotypes.
In addition, recently discovered "captured" cellular genes encoded by KSHV, including cytokines, chemokine receptors and Cyc- D have become modified by a process of "molecular piracy" to play key roles in the pathogenesis of Kaposi's sarcoma.
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