Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with several proliferative disorders, including Kaposi's sarcoma (KS). KS became the most common neoplasm associated with untreated human immunodeficiency virus (HIV) infection. KS lesions are characterized by proliferation of spindle-like endothelial cells, inflammation, and neoangiogenesis. KSHV promotes a global shutoff of cellular gene expression during lytic replication cycle by inducing mRNA turnover of host cellular genes. This global shutoff is mediated by a viral factor, SOX (shutoff and exonuclease) with a novel RNA turnover activity that is unique to KSHV in addition to its DNase activity. Previous experiments have demonstrated SOX expression is initiated at approximately 8 h post lytic activation, concordantly with the onset of host shutoff. It was also demonstrated that SOX induces mRNA turnover of many cellular genes as a dominant effector of KSHV-induced host shutoff. While most of cellular mRNAs are subjected to SOX-mediated host shutoff, some cellular mRNAs, e.g. IL-6 mRNA, escape host shutoff and up-regulated during the KSHV lytic cycle. Hence it will be important to examine the mechanism of SOX-mediated mRNA turnover that leads to shutoff of host cellular genes, while some cellular genes (including IL-6) escape SOX-mediated host shutoff.
The specific aims of the proposed research are: to develop an in vitro mRNA turnover system to characterize the mechanism by which KSHV SOX mediates host shutoff;to map and characterize the stability element that is essential and sufficient to lead to escape of the IL-6 mRNA;and to identify the proteins that bind to the stability element within the IL-6 mRNA and characterize the mechanism leading to escape of the IL-6 mRNA from host shutoff during lytic infection. The result of the proposed experiments should significantly increase the understanding of the molecular mechanism that SOX viral factor plays in host shutoff during the lytic phage of KSHV and hence may provide an insight to improve the clinical treatment of KS.
My project involves two objectives to study the mechanisms of which Kaposi's sarcoma-associated herpesvirus (KSHV, or HHV8) selective global downregulation of host genes, although Interleukin-6 (IL-6) is a prominent gene that evades this process. KSHV is the most recently discovered human herpesvirus, (2, 9), and is the etiologic agent of Kaposi's sarcoma (KS) and two rare B cell lymphoproliferative diseases, pleural effusion lymphoma (PEL) and multicentric Castleman's disease (MCD) (9). Since the AIDS epidemic Kaposi's sarcoma (KS) emerged as the most common AIDS-associated cancer (1), the proposed study is anticipated to provide key insights into both the normal regulation of critical B cell growth factors, as well as pinpoint mechanisms by which KSHV interfaces with these pathways to promote disease.
|Hutin, Stephanie; Lee, Yeon; Glaunsinger, Britt A (2013) An RNA element in human interleukin 6 confers escape from degradation by the gammaherpesvirus SOX protein. J Virol 87:4672-82|