Kaposi's Sarcoma (KS) was the most common tumor in Aids patients in this country before the wide spread use of highly active antiretroviral therapy. KS is currently the most commonly reported tumor in regions of Africa. Kaposi's Sarcoma-associated herpesvirus (KSHV, formally known as human herpesvirus 8, HHV-8) is an essential etiologic agent for KS. In KS, KSHV is found in the spindle cell, a cell of endothelial origin that is the tumor cell of KS. KSHV is also associated with primary effusion lymphoma (PEL), a B-cell lymphoproliferative disorder. PEL cell lines have been created and are used for many studies of KSHV. However, KS is an endothelial cell based neoplasm and thus it is important to study KSHV in endothelial cells as well. Herpesviruses are all characterized by having latent infection, where the virus is maintained for the life of the host but does not produce infectious particles, and lytic infection, where the virus replicates and lyses the host cell. Interestingly, KS apparently requires both lytic and latent phase infection for formation and maintenance. Since the lytically infected cell is dying, there must be paracrine factors produced that act on latently infected cells. We propose to characterize the function of lytic gene expression in maintenance of KS by studying the role of lytic genes in latently infected endothelial cells. We have created a tractable system for studying KSHV in endothelial cells and we will study KSHV gene expression and function in our endothelial cell system. We will create and purify recombinant KSHV isolates deleted in prominent lytic genes involved in signal transduction. Subsequent analysis will characterize the role of these genes in both lytic and latent infection. We will analyze growth and signaling capabilities during lytic infection and we will analyze how these lytic genes alter host transcription in latently infected cells.