Human herpesvirus 8 (HHV-8) is a lymphotropic herpesvirus linked to several disorders such as Kaposi's sarcoma, primary effusion lymphoma and multicentric Castleman's disease. Several HHV-8 proteins regulate host innate and adaptive immune response; in particular, orfK14 is expressed as an immediate early gene during the viral lytic cycle and encodes a surface glycoprotein (vOX2), significantly homologous to the cellular OX2, which delivers inhibitory signals to macrophages. Although it has been suggested that vOX2 may down-regulate basophil and neutrophil functions, its role in macrophages, a cell type lytically infected by HHV-8 in vivo, is still controversial. Therefore, we investigated the effect of vOX2 expression in human primary monocyte-derived macrophages (MDMs). In this report, we demonstrate that vOX2-expressing MDMs in basal conditions are induced to produce inflammatory cytokines and display higher phagocytic activity with respect to mock cells. By contrast, an opposite effect is exhibited by vOX2 in MDMs undergoing IFN-gamma-activation, with a down-modulation of the cytokine production and phagocytic activity. Moreover, we observed that, when MDMs are co-cultured with vOX2-expressing cells, the inflammatory cytokine release is increased, independently from the MDM activation state. Interestingly, we could correlate our results with the mRNA transcript level of the vOX2 cellular CD200R receptor. Finally, we demonstrate a down-regulation of the MHC class I and class II molecules on the cell surface of vOX2-transduced MDMs. Our results provide new insights into the immunomodulatory effects of HHV-8 vOX2 protein. J. Cell. Physiol. 219: 698-706, 2009. (c) 2009 Wiley-Liss, Inc.