Role of vFLIP K13 in Bone Marrow Failure Syndrome Associated with Infection by Hu

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DESCRIPTION (provided by applicant): Bone-marrow suppression is frequently seen in association with infection by human viruses, including the cytomegalovirus, Epstein-Barr virus, human herpes virus 6 and hepatitis B virus, and is an important cause of morbidity and mortality among post-transplant patients. Human herpes virus 8 (HHV8), also known as Kaposi's sarcoma associated herpes virus (KSHV), has been previously linked to the occurrence of Kaposi's sarcoma, primary effusion lymphoma and multicentric Castleman's disease. Recent studies have also linked infection with HHV-8 to bone marrow failure in solid-organ and stem cell transplant recipients. However, the exact mechanism of action of HHV8 in the pathogenesis of marrow failure is has not been characterized. We have discovered that K13, an HHV8-encoded vFLIP (viral FLICE inhibitory protein) is a strong activator of the NF-kB pathway, which has been previously linked to hematopoietic suppression. We have further demonstrated that K13 can upregulate the expression of cytokines with marrow suppressive properties. Thus, we believe that K13 may play a pivotal role in the pathogenesis of HHV8-associated marrow suppression and presents an ideal candidate for development of molecularly targeted therapies against this disorder. The primary goal of this application is to test the above hypotheses using in vitro and in vivo assays. In aim 1, we will express K13 in the marrow of transgenic mice and study its effect on hematopoieses. In aim 2, we will study the effect of K13 on the growth and proliferation of hematopoietic stem cells and progenitor cells. Finally, in aim 3, we will test the ability of inhibitors of K13-induced NF-?B activation and their downstream target genes to reverse its suppressive effect on hematopoieses. We believe that collectively these studies will not only lead to a better understanding of viral-induced marrow failure syndromes but will also provide the framework for future clinical evaluation of NF-kB inhibitors in these disorders. Bone marrow failure is frequently observed in patients undergoing bone marrow and solid-organ transplants. This study will lead to a better understanding of the mechanism(s) by which infection with viruses leads to bone marrow failure in transplant patients and provide new treatment strategies.