Human cytomegalovirus chemokine receptor US28 (US28)

Human cytomegalovirus chemokine receptor US28 is a viral G protein-coupled receptor (vGPCR) encoded by Human Cytomegalovirus (HCMV) that plays a pivotal role in viral pathogenesis and oncomodulation. Unlike typical human receptors, US28 exhibits high constitutive, ligand-independent signaling through various G-protein pathways (Gq/11, Gi/o, and G12/13), which promotes cell proliferation, migration, and survival (UniProt P09705; PMID: 24751564). It also acts as a 'chemokine sink' by binding and internalizing a wide range of human CC and CX3C chemokines, such as CCL2 and CX3CL1, thereby helping the virus evade the host immune response (PMID: 15159330). In clinical contexts, US28 expression is strongly linked to the progression of glioblastoma multiforme and other cancers, where it facilitates tumor growth and angiogenesis (PMID: 21743454). Pharmacological targeting of US28 is a significant area of research, focusing on small molecule inverse agonists like VUF2274 and specialized nanobodies that can inhibit its signaling or selectively eliminate US28-positive cells via targeted toxin delivery (PMID: 29505036). Its dual contribution to both viral persistence and oncogenic transformation makes it a high-value target for combined antiviral and antineoplastic therapeutic strategies.

Other names

HCMV US28pUS28Viral GPCR US28CMV US28Betaherpesvirus 5 protein US28

Targeting US28 involves the use of inverse agonists to suppress its high constitutive signaling activity, competitive antagonists to block chemokine binding, or nanobodies and immunotoxins to selectively neutralize the receptor or deliver cytotoxic payloads to HCMV-infected or tumor cells.