A. Research In Cytomegaloviruses (CMV). My studies have been focused on CMV gene regulation at the very early time of infection. During the immediate early (IE) stage of CMV infection, the cell uses widely different cellular proteins, in its defensive arsenal, such as nuclear domains 10 (ND10) components (Daxx, PML and SP100), nuclear suppressors (HDAC), apoptotic pathway molecules. These proteins suppress major immediate early promoter (MIEP) activity. Viruses have also evolved molecular anti-defense mechanisms. For example, CMV gene products IE2 can shut off cellular activities so that the virus can usurp cellular machineries for viral gene expression and DNA replication; IE1 disperses PML bodies and represses HDAC activity. We have recently mapped out a small domain of IE1 be responsible for murine CMV to disperse ND10. MIE gene products (IE1 and IE2 for HCMV or IE3 for MCMV) are then responsible for activation of early gene. IE3 of MCMV (homology of IE2 of HCMV) is a suppressor of MIEP and activator of early gene (e.g. 112-113 gene). IE3’s suppressive effects on MIEP can be eliminated by 112-113 gene products. IE3 can also interact with HDAC to reduce the HDAC activity, which play a role in activating early gene promoter. We very recently mapped out a small motif in 112-113 gene promoter region, and it is called IE3BAM that is essential for IE3 to activate 112-113 gene expression. We also found that IE3 activates 112-113 gene promoter via interaction with TBP to stabilize TFIID complexes. These studies will advance our understanding of the mechanisms of CMV latency and reactivation and may lead to the development of new therapies to prevent CMV-caused disease.

B. Research In Kaposi’s Sarcoma Associated Herpesvirus (KSHV). KSHV (also known as Human herpesvirus 8) has been determined to be the most frequent cause of malignancies in AIDS patients. It is associated primarily with Kaposi’s sarcoma and primary effusion lymphoma (PEL), as well as with multicentric Castleman’s disease (MCD). The switch from the latent to the lytic stage is important both in maintenance of malignancy and viral infection. Therefore, strategies for the treatment of KSHV-related malignancies need to both prevent cellular proliferation and block viral production. Only a few genes can be expressed during latency, and these gene products tether KSHV DNA episomes with chromosomes in order to keep KSHV in its latent state. Several chemicals, including 12-O-Tetradecanoyl-phorbol-13-acetate (TPA), sodium butyrate (NaB), and 5-azacytidin e (5-AC), can reactivate KSHV from latency in cell cultures. RTA (also called ORF50) gene expression is the switch point from latency to the lytic cycle because RTA is essential and sufficient for the reactivation of KSHV, but the pathological mechanism of the reactivation of KSHV is poorly understood. Prior studies on the reactivation of KSHV using chemical inducers implied that epigenetic modification, especially chromatin remodeling by acetylation, is critical for transactivators to access lytic gene promoters. Our studies also indicate that another KSHV-encoded protein, K-bZIP, is critical in reactivation of KSHV. We mapped out that the leucine zipper domain is essential for K-bZIP to interact with HDAC and reduce HDAC activity, which function play a role in viral replication.