Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) is etiologically linked to the endothelial tumor Kaposi's sarcoma and with two lymphoproliferatve disorders, primary effusion lymphoma and multicentric Castleman's disease. HHV-8 infects a variety of target cells both in vivo and in vitro, binds to the in vitro target cells via cell surface heparan sulfate, and uses the alpha(3)beta(1) integrin as one of the entry receptors. Within minutes of infection, HHV-8 induced the integrin-mediated signaling pathways and morphological changes in the target cells (S. M. Akula et al., Cell, 108: 407-419, 2002; P. P. Naranatt et al., J. Virol., 77: 1524-1539, 2003). As an initial step toward understanding the role of host genes in HHV-8 infection and pathogenesis, modulation of host cell gene expression immediately after infection was examined. To reflect HHV-8's broad cellular tropism, mRNAs collected at 2 and 4 h after infection of primary human endothelial [human adult dermal microvascular endothelial cells (HMVECd)] and foreskin fibroblast [human foreskin fibroblast (HFF)] cells and human B cell line (BJAB) were analyzed by oligonucleotide array with approximately 22,000 human transcripts. With a criteria of >2-fold gene induction as significant, approximately 1.72% of the genes were differentially expressed, of which, 154 genes were shared by at least two cells and 33 genes shared by all three cells. HHV-8-induced transcriptional profiles in the endothelial and fibroblast cells were closely similar, with substantial differences in the B cells. In contrast to the antiapoptotic regulators induced in HMVECd and HFF cells, proapoptotic regulators were induced in the B cells. A robust increase in the expression of IFN-induced genes suggestive of innate immune response induction was observed in HMVECd and HFF cells, whereas there was a total lack of immunity related protein inductions in B cells. These striking cell type-specific behaviors suggest that HHV-8-induced host cell gene modulation events in B cells may be different compared with the adherent endothelial and fibroblast target cells. Functional clustering of modulated genes identified several host molecules hitherto unknown to HHV-8 infection. These results indicate that early during infection, HHV-8 reprograms the host transcriptional machinery regulating a variety of cellular processes including apoptosis, transcription, cell cycle regulation, signaling, inflammatory response, and angiogenesis, all of which may play important roles in the biology and pathogenesis of HHV-8.