Studies on Viral Enhancer for Latency-Lytic Switch

Abstract Kaposi’s sarcoma-associated herpesvirus (KSHV), also known as Human Herpesvirus 8 (HHV-8), is the etiologic agent of three AIDS-associated malignancies: Kaposi sarcoma (KS), a plasmablastic variant of multicentric Castleman disease (MCD), and primary effusion lymphoma (PEL). Although their incidence in HIV+ patients has decreased since the introduction of antiretroviral therapy, KS remains the most common HIV-associated malignancy. Concerningly, nearly one-third of patients who develop KS have well-controlled HIV infection, and it is estimated that the incidence of KS may increase as the life expectancy of HIV+ patients increases. Although less common than KS, MCD and PEL do not have standardized treatments and both exhibit poor prognosis. A current area of research focus is to better understand the KSHV gene regulation to identify new drug targets to control KSHV replication and associated neoplasms. Amounts of nuclear enzymes and transcriptional factors are limited in the cell nucleus and cannot support all of cellular transcription at the same time, the nuclear architecture including chromatin structure must allow for these molecules to be located at the proper time and place for coordinated gene expression to occur. Alterations in this organization could thus lead to a variety of diseases, including cancer. The principles underlying this process are still poorly understood. We previously revealed (i) a 3D KSHV genomic structural and (ii) identified key cellular proteins that play essential roles in both establishing/maintaining latency and induction of lytic replication. The 3D structure modeling and recruitment sites of these key enzymes suggested to us an important role for evolutionally maintaining multiple copies of terminal repeat sequences in the function of concentrating specific protein near KSHV inducible promoters. Accordingly, we hypothesize that having large copies of terminal repeat sequence foster an increase in the local concentration of LANA, and the 3D KSHV genomic structure is designed to allow locally-concentrated LANA complexes to regulate viral lytic gene promoters located in unique region. We will focus on function of terminal repeat sequence in regulation of lytic gene promoters.