Characterization of the K1 Protein of Kaposi Sarcoma-associated Herpesvirus and Development of a Novel Vaccine for Protection Against Rhadinovirus Infection Public Deposited

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  • March 20, 2019
  • Wen, Kwun Wah
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
  • Kaposi sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD). KS is the most common malignancy in HIV/AIDS patients worldwide and can lead to significant mortality. There is no cure or vaccine for KSHV infection. KSHV encodes several oncogenic/transforming proteins that are implicated in KSHV-associated malignancies. Our work is directed towards understanding the functional role of the KSHV K1 protein, which has been shown to activate signaling in B lymphocytes as well as to transform cells. We used tandem affinity purification (TAP) to identify the cellular interacting proteins of K1 and study the mechanisms by which K1 activates signal transduction pathways, inhibits apoptosis, and induces cellular transformation. The functional consequences of the interactions of K1 with its cellular binding partners were investigated with respect to the regulation of K1 expression and its anti-apoptotic function, using pharmacological inhibitors and RNA interference (RNAi). This study thus identified cellular targets essential for K1 function and may also aid in the identification of therapeutic targets that can be used in the treatment of KSHV-associated cancers. In addition, we examined the role of K1 in the viral lifecycle. We took advantage of a highly related virus, rhesus rhadinovirus (RRV), which is the simian relative of KSHV. Unlike KSHV, RRV grows to high titers in vitro making it a good model to study lytic replication and viral spread. RRV encodes a gene named R1, which is functionally homologous to the KSHV K1 gene. We constructed a RRVΔR1/GFPcc recombinant virus to analyze the contribution of R1 during de novo infection, latency, and reactivation of RRV. Furthermore, we attempted to develop a novel vaccine for protection against rhadinovirus infection in primates using the RRV model system. The latency-associated nuclear antigen (LANA) is critical for the establishment and maintenance of both KSHV and RRV latency. We generated a recombinant virus deleted for RRV LANA, named RRVΔLANA/GFP, and found that this virus was highly lytic and unable to establish latency. A future goal of this aim will be to evaluate the RRVΔLANA/GFP as a vaccine candidate in rhesus macaques.
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  • In Copyright
  • "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Microbiology and Immunology."
  • Damania, Blossom
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  • Chapel Hill, NC
  • Open access

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