KSHV is a human oncogenic gammaherpesvirus which induces oncogenesis in infected cells. In the; HIV positive immunocompromised patients, pleural effusion lymphoma (PELs), Kaposi's sarcoma (KS) and Multicentric Castleman's Disease (MCD) are common. The associated human malignancy is a major contributor to increased mortality in developing countries in this population of HIV positive patients. This study will explore the mechanisms by which KiSHV encoded LANA interacts with the cellular transcription regulator RBP-Jk during the early stages of de novo infection of human primary B cells. We will determine the role ofthe LANA and RBP-Jk complex during early infection where the regulatory functions of this complex is likely to play a critical role in establishment of latency. We will determine the epigenetic state of the RBP-Jk and LANA binding sites during the early infection and establishment of latency and determine how LANA modulates the DNA damage proteins DNA-PK, ATM, ATR and regulate early infection. We will determine the requirement for the latent antigen LANA in establishment and maintenance of KSHV latency specifically as it relates to modification of LANA and its interacting partner RBP-Jk the cellular transcription regulator. In this application we will focus; on the early events during primary B cell infection and the requirements needed for successful establishment of latency. Studies in our lab has demonstrated that LANA is in fact phosphorylated but we do not yet understand the precise need for phosphorylation as a perquisite for second site phosphorylation, or ubiquitination of LANA. We will undertake the broad aim to identify the cellular targets regulated as it relates to the phosphorylation, acetylation and ubiquitination of LANA. Specific mutations in the major latency sites on the KSHV genome will be used along with the wild type molecules and these will be further tested in assays including transcription, cell growth and proliferation. These studies will further our understanding of KSHV latency mechanisms and provide insights for therapeutic potential by targeting the pathways activated in these cells.
KSHV is a human pathogen. It is associated with at least 3 proliferative diseases in humans including pleural effusion lymphomas. In the proposed studies in project #1 we will focus on the regulation of viral and cellular sites important for this regulation and how this may be linked to the successful establishment of latent infection. This will provide clues for targeted therapeutic development for the associated malignancies.
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