Human herpesvirus KSHV encodes a constitutively active G-protein-coupled receptor linked to cell proliferation

Kaposi's sarcoma-associated herpesvirus (KSHV, also known as human herpesvirus 8, or HHV 8) is a virus that is consistently present in Kaposi's sarcoma(1,2) and in primary-effusion (body-cavity-based) lymphomas(3), malignancies that occur frequently, but not exclusively in AIDS patients. KSHV is a gamma herpesvirus with homology to herpesvirus Saimiri and Epstein-Barr virus(1,4), both of which can transform lymphocytes(5). Cloning of a KSHV genome fragment revealed the presence of an open reading frame encoding a putative G-protein-coupled receptor(6) that is homologous to a G-protein-coupled receptor encoded by herpesvirus Saimiri(7,8) and to human interleukin-8 receptors(9,10). Here we show that the KSHV G-protein-coupled receptor is a bona fide signalling receptor which has constitutive (agonist-independent) activity in the phosphoinositide-inositoltrisphosphate-protein kinase C pathway. Furthermore, the KSHV G-protein-coupled receptor stimulates cellular proliferation, making it a candidate viral oncogene.