Role of Cyclooxygenase-2 and PGE2 in KSHV pathogenesis

Rosalind Franklin Univ Of Medicine & Sci, North Chicago IL

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Abstract

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE 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. 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