Grants and Contracts Details
Kaposi's sarcoma associated herpesvirus (KSHV)/human herpesvirus 8 (HHV8) has been consistently identified in Kaposi's sarcoma (KS), body cavity based lymphoma (SCSl) and multicentric Castleman's disease (MCD). There is compelling evidence indicating that KSHV is the etiological agent of these diseases. KS is a multifocal vascular neoplasm with an endothelial origin. KS is one of the most common cancers in patients with acquired immune deficiency syndrome (AIDS) and represents 9% of all the cancer in men in Africa. SCSl or primary effusion lymphoma (PEL) is also an AIDS-associated malignancy with a very poor clinical outcome. MCD is a disorder of abnormal proliferation of lymphoid tissues and MCD in HIV-positive patients is associated with a high risk of lymphoma development. KSHV k9 open reading frame encodes the first identified viral interferon regulatory factor, vIRF-1. Searing sequence homology to cellular interferon factors, vIRF-1 functions as a potent suppressor against host interferon-mediated anti-viral immune responses. In addition, vIRF-1 is able to induce cell transformation. vIRF-1 transformed cells exhibit deregulated growth control and form tumors in mice. The proposed study aims to understand the oncogenic role of KSHV vIRF-1 in the development of KS. We hypothesize that vIRF-1 contributes to KSHV-associated tumorigenesis by inhibiting p53 tumor suppressor associated cell growth control and by blocking interferonmediated anti-viral and anti-tumor activities. Using human T4 endothelial cell line as a model, we plan to investigate three areas. First, we will study the transforming activity of vIRF-1 in endothelial cells. We will study the activity of p53 tumor suppressor in the presence of vIRF-1 as well as the effect of vIRF-1 on p53-mediated cell cycle arrest and apoptosis. We will also examine effects of vIRF-1 on the proliferation and morphology of the endothelial cells. Second, we will identify cellular targets of vIRF-1. We will use microarray to study the gene expression profile of endothelial cells in the presence of vi RF-1. Our goal is to identify cellular pathways involved in vIRF-1 induced cell transformation. Finally, based on our previous data that vIRF-1 inhibits host defense mechanism against viral infection and regulates viral gene expression, we will study the role of vIRF-1 in maintaining persistent viral infection. We will apply siRNA technology to specifically block vIRF-1 expression in KSHV infected cells and examine the role of vIRF-1 in viral replication and maintenance of persistent infection. This study will elucidate the molecular mechanisms used by vIRF-1 in facilitating tumor development and repressing host immune responses. The findings should increase our understanding of KSHV associated pathogenesis, suggest a viral gene for therapeutic target, and allow us to successfully compete for NIH/NCI funds.
|Effective start/end date||6/1/04 → 5/31/05|
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