ORF74 potentially forms heterodimers with human chemokine receptors

Human chemokine receptors play an important role in the immune system by coordinating the migration of leukocytes to inflammatory sites. Kaposi’s sarcoma-associated herpesvirus (KSHV) has pirated and modified a chemokine receptor-encoding gene from the host for its own benefit. It is therefore believed this KSHV-encoded chemokine receptor named ORF74 is involved in evading antiviral immune responses to establish a lifelong infection with KSHV. Chemokine receptors, like many other G protein-coupled receptors (GPCRs), can form homoand heterodimers by physically interacting with each other. Importantly, heterodimers can exhibit altered functional characteristics compared to monomeric GPCR subtypes, including ligand binding, signaling and trafficking. We hypothesize that ORF74 physically interacts with host chemokine receptors to modify responsiveness of leukocytes in favor of the virus. We identified potential heterodimers between ORF74 and human chemokine receptors using bioluminescence resonance energy transfer (BRET), co-immunoprecipitation and proximity ligation assay (PLA).