Research Abstract

Our laboratory investigates the link between viruses and human malignancy. Our work focuses on Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8), which is linked with Kaposi's sarcoma, primary effusion lymphomas and multicentric Castleman's disease, a lymphoproliferative disorder. Our goal is to gain a better understanding of the molecular mechanisms by which KSHV exerts tumorigenic effects, in order to develop therapeutic and preventive strategies for these disorders.

KSHV infection in tumor cells is primarily latent. In latently infected cells, KSHV persists as a multiple copy plasmid (episome). In order to persist in proliferating cells, KSHV episomes must replicate and efficiently segregate to progeny cells. The KSHV latency-associated nuclear antigen (LANA) is expressed in KSHV infected tumor cells. We have shown that LANA colocalizes with KSHV episomes on chromosomes of KSHV infected cells. In addition, LANA is necessary and sufficient to mediate persistence of episomal DNA containing a specific KSHV sequence. These data are consistent with a model in which LANA tethers KSHV episomes to chromosomes during mitosis to ensure efficient segregation of KSHV DNA to progeny cells. LANA also has important regulatory effects on transcription. We are currently investigating the molecular mechanisms by which LANA exerts these functions.