Kaposi?s sarcoma-associated herpesvirus (KSHV) is large DNA virus, which is the etiological agent of several AIDS-related malignancies such as Kaposi?s sarcoma, primary effusion lymphoma, and aggressive forms of multicentric Castleman?s disease. Lytic replication of KSHV is critical for both KSHV-induced tumorigenesis and dissemination of the virus. Recent studies have shown that following replication in the oral epithelial cells, KSHV can be transmitted into endothelial and B cells where the virus establishes latency resulting persistent infection of the host. Infected oral epithelial cells also serve as the source of new viral particles shedding into the saliva, which mediates the viral transmission in the population. Despite the medical and biological importance of oral KSHV infection, it is still largely unknown what viral and host factors play a role in the regulation of lytic KSHV infection of oral epithelial cells. KSHV is unique among human viruses that it encodes four viral interferon regulatory factors that are homologous to cellular IRFs. These viral proteins have been shown to regulate many different immune-related pathways and can enhance cell growth and cell survival. While many of these vIRF functions are linked to the cytoplasmic functions of vIRFs, the nuclear role of vIRFs in gene regulation, especially in oral epithelial cells, that may promote lytic KSHV infection is still poorly understood. To reveal the role of vIRFs in viral and cellular gene regulation, we have identified the host target genes of each vIRF in primary human gingival epithelial cells and revealed a highly specialized function for each vIRF. In addition, we performed a protein complex purification of vIRF1 from KSHV-infected cells and discovered that vIRF1 can interact with several host epigenetic factors involved in DNA binding, histone acetylation or histone methylation. Based on our preliminary data, the goal of this proposal is (Aim 1) to identify the direct target genes of vIRFs and test their role in lytic KSHV infection, and (Aim 2) to investigate the gene regulatory mechanisms mediated by vIRF1 and its associated host epigenetic factors, which can be critical for facilitating lytic replication of KSHV. Since many of the vIRF1-regulated host genes encode factors that are known to be de-regulated in other viral infections as well, we envision that the investigation of epigenetic mechanisms and host gene targets of vIRF1 during KSHV infection can provide novel targets for future development of new antiviral therapies.
Lytic replication of Kaposi?s sarcoma-associated herpesvirus (KSHV) in the oral cavity is critical for both KSHV- induced tumorigenesis and dissemination of the virus. The goal of our study is to evaluate the genome-wide role of the viral interferon regulatory factors of KSHV in order to identify their key targets controlling host-pathogen interactions at the cellular level during oral infection, which is the very first step during infection of humans. We expect that our results can facilitate the future development of novel antiviral approaches, which could ultimately eliminate KSHV transmissions.
