Abstract
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.