Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) is etiologically associated with Kaposi's sarcoma (KS), a multi-focal angioproliferative disease and with primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). In KS endothelial cells, KSHV is detected in a latent form and expresses the latency-associated nuclear antigen (LANA or ORF73), ORF72 (v-cyclin), K13 (v-FLIP) and Kaposin (K12) genes. A sub-population (<1%) of inflammatory and spindle cells display lytic KSHV replication. In vitro KSHV infection leads to latent infection and thus provides a good in vitro model for studying viral and host factors involved in the establishment and maintenance of latency. In vitro infection of primary human microvascular endothelial cells (HMVEC-d) and fibroblast cells (HFF) is characterized by the induction of pre-existing host signal cascades, sustained expression of latency- associated ORF73, ORF72 and K13 genes, transient expance of KSHV latent gene expression in endothelial cells. KSHV infection of HMVEC-d and HFF cells induced a strong up-regulation of COX-2 gene, an angiogenic stress response gene. Our studies demonstrate that this is also associated with the release of COX-2's stable inflammatory metabolite PGE2. More excitingly, we show that KSHV-induced COX- 2/PGE2 plays roles in the continued expression of latent ORF73 gene expression. From these studies, we hypothesize that KSHV utilizes COX-2 and other host cell genes for its advantage in the establishment of latent infection and immune-modulation. To test this hypothesis, we have formulated two major specific aims.
In Specific aim 1, we will define the molecular mechanisms underlying the transcriptional and post-transcriptional regulation of COX-2 in KSHV infected cells and its role in successful KSHV infection, inflammation, angiogenesis and tumorigenesis.
In Specific aim 2, we will decipher the mechanism of COX-2/PGE2 mediated maintenance of argets that can be used as therapeutic agents in the treatment of KSHV associated neoplasia and the prevention of KS lesion development.
Kaposi's sarcoma-associated herpesvirus is associated with a leading vascular tumor of HIV infected-patients called Kaposi's sarcoma (KS), a lymphoma called body cavity-based lymphoma and some forms of severe lymph node enlargement, called Castleman's disease. Our research is directed towards finding a better understanding of the driving forces behind the KS development which in turn would lead to better treatment of KSHV infection and for the prevention of KS lesion. ? ? ? ????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????
