Molecular piracy of mammalian interleukin-8 receptor type B by herpesvirus saimiri

Viruses are known to acquire and modify the genes of their hosts to attain a survival advantage in the host environment. Herpesvirus saimiri (HVS) is a T-lymphotropic virus that causes fatal lymphoproliferative diseases in several non-human primates. The gene ECRF3 of HVS was most likely acquired from a primate host. ECRF3 encodes a putative seven-transmembrane-domain receptor that is remotely related (~30% amino acid identity) to the known mammalian α and β chemokine receptors, namely interleukin-8 receptor (IL8R) types A and B and the MIP-1α/RANTES receptor, respectively. Chemokines regulate the trafficking, activation, and, in some cases, proliferation of myeloid and lymphoid cell types. We now show that ECRF3 encodes a functional receptor for the α chemokines IL-8, GRO/melanoma growth stimulatory activity (MGSA), and NAP-2 but not for β chemokines, a specificity identical to that of IL8RB. Paradoxically, IL8RA shares 77% amino acid identity with IL8RB but is not a receptor for GRO/MGSA or NAP-2. This is the first functional characterization of a viral seven-transmembrane-domain receptor. It suggests a novel role for α chemokines in the pathogenesis of HVS infection by transmembrane signaling via the product of ECRF3.