Role of FOXK subfamily in KSHV infection

Project Summary Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic gammaherpesvirus with a biphasic lifecycle associated with several diseases such as Kaposi's sarcoma and primary effusion lymphoma (PEL). It is primarily spread through saliva making the oral cavity a critical site for initial infection. KSHV encodes an

immediate early virion-associated tegument protein that is vital for efficient lytic reactivation and virus production. Following up on a proteomics study of KSHV factors in uninfected cells, our coimmunoprecipitation and imaging analysis in primary effusion lymphoma (PEL) cells during lytic reactivation of KSHV demonstrated

that an immediate early protein of KSHV interacts with host transcription factors, FOXK1 and FOXK2. FOXK1 and FOXK2 belong to the Forkhead family of transcription factors. FOXK1 and FOXK2 are unique as they are the only Forkhead proteins which carry a Forkhead-associated (FHA) domain. FOXK proteins are ubiquitously

expressed and play a key role in cellular processes such as cell cycle regulation, cancer development, and autophagy regulation. Their role in KSHV infection is not well understood though. Preliminary data from this proposal supports a pro-viral role for these host transcription factors during KSHV's lytic cycle. The purpose of

this project is to dissect the importance of the interaction between the immediate early KSHV tegument protein and FOXK proteins and identify novel targets genome-wide of the immediate early KSHV tegument protein during reactivation and de novo infection. A combination of genome-wide studies coupled with KSHV mutants

will be used to analyze how the FOXK and immediate early tegument proteins affects KSHV infection. In summary, I predict that this novel host-pathogen interaction might be engaged by KSHV, in order to promote its lytic cycle in the oral cavity and beyond, thus by understanding the mechanism, we could uncover future

therapeutic targets. The completion of this project will provide in-depth training in epigenetics, virology and genomics approaches. These skills will be enhanced in the outstanding research environment provided by the Oral Biology department at the University of Florida College of Dentistry.