Kaposi sarcoma is considered a neoplasm of lymphatic endothelium infected with Kaposi sarcoma-associated herpesvirus. It is characterized by the expression of lymphatic lineage-specific genes by Kaposi sarcoma tumor cells. Here we show that infection of differentiated blood vascular endothelial cells with Kaposi sarcoma-associated herpesvirus leads to their lymphatic reprogramming; induction of ∼70% of the main lymphatic lineage-specific genes, including PROX1, a master regulator of lymphatic development; and downregulation of blood vascular genes.Kaposi sarcoma is the most frequently occurring malignant tumor in individuals infected with the human immunodeficiency (HIV) virus and also occurs in HIV-negative immunosuppressed individuals. Kaposi sarcoma mainly affects the skin and forms lesions of various types, including early inflammatory and patch stage lesions, and tumors with a predominant population of spindle cells. Infection with Kaposi sarcoma-associated herpesvirus (KSHV, also known as human herpesvirus-8) is essential for the formation of Kaposi sarcoma tumors 1,2 . Both latent viral genes, such as latency-associated nuclear antigen (LANA), and lytic viral genes, such as viral G-protein-coupled receptor, have been implicated in KSHV-mediated tumorigenesis 3 . In Kaposi sarcoma lesions, cells infected with KSHV characteristically appear spindle-shaped and are associated with slit-like spaces that sometimes contain red blood cells. Kaposi sarcoma is considered to be a neoplasm of KSHV-infected lymphatic endothelium, due to the morphological characteristics of the tumor cells and the expression of several lymphatic lineage-specific proteins, including VEGFR-3 and podoplanin [4][5][6][7] .The homeobox gene PROX1 is a master gene that controls lymphatic vessel development and differentiation 8 , and ectopic expression of PROX1 in differentiated blood vascular endothelial cells leads to lymphatic endothelial reprogramming of these cells 9,10 . Because KSHV can infect blood vascular endothelium, such as human umbilical vein endothelial cells, in vitro, we wondered whether KSHV infection might result in lymphatic reprogramming of blood vascular endothelium, potentially involving upregulation of PROX1.We first characterized the lineage-specific gene expression of cultured human lymphatic endothelial cells (LECs) versus blood vascular endothelial cells (BECs) 11 by Affymetrix HU133A gene arrays. We found that LECs, but not BECs, expressed PROX1, XLKD1 (encoding the hyaluronan receptor LYVE-1) and a number of other lymphatic lineage-specific genes ( Table 1). We then infected human dermal microvascular endothelial cells (HDMECs) with KSHV and carried out two independent transcriptional profiling studies 7 d later. Efficient KSHV infection was confirmed by high levels of expression of LANA mRNA in infected HDMECs. We found that 3-7% of infected HDMECs were ORF59-positive and 1.5-3% were K8.1 positive, in agreement with previous results [12][13][14] . This indicates that <10% of the cells were undergoing lytic reac...