US28 chemokine receptor (human cytomegalovirus) (US28)

The US28 chemokine receptor is a viral G protein-coupled receptor encoded by the human cytomegalovirus (HCMV). It is expressed during both lytic replication and latent infection phases. Structurally similar to class A rhodopsin-like GPCRs but distinct from endogenous human receptors, it binds a broad range of CC-type chemokines—including CX3CL1—with high affinity. Uniquely among GPCRs, it exhibits robust constitutive activity independent of ligand binding, activating multiple intracellular signaling pathways via promiscuous coupling with various G proteins such as Gi, Gq/11, and G12/13. Functionally, US28 acts as a "chemokine sink," sequestering host chemokines from the environment around infected cells, thereby subverting host immunity. It also plays an essential role in establishing and maintaining HCMV latency by modulating host-cell gene expression—particularly repressing immediate early gene transcription—and altering cellular environments favorable for persistent infection. Its constitutive activity has been implicated in promoting cancer-associated cellular processes. Due to its unique properties—broad ligand recognition profile, rapid internalization from the cell surface into endocytic compartments, critical role in viral persistence/latency maintenance—US28 has become an attractive therapeutic target. Experimental strategies include small molecules that block its function or exploit its trafficking behavior for targeted delivery of cytotoxic agents into latently infected cells.

Other names

HCMV US28Cytomegalovirus US28Viral G protein-coupled receptor US28vGPCR US28

Drugs or biologics targeting this molecule act by: Blocking chemokine binding to prevent immune evasion and viral persistence; Inhibiting constitutive or ligand-induced G protein signaling to disrupt maintenance of latency or oncogenic pathways; Exploiting rapid internalization for delivery of toxins into infected cells, leading to selective cell death of HCMV-infected reservoirs.