Human cytomegalovirus-encoded chemokine receptor US28 (US28)

The Human cytomegalovirus-encoded chemokine receptor US28 (US28) is a viral G protein-coupled receptor (GPCR) expressed by HCMV and is homologous to human chemokine receptors, but shows broader chemokine binding and unique intracellular signaling. US28 binds multiple chemokine families (CC and CX3C) and couples promiscuously to diverse G-proteins, including Gq, G12/13, and Gi, leading to constitutive and ligand-dependent signaling that promotes cell migration, inflammation, and survival of infected cells. It is a key modulator in HCMV pathogenesis, contributing to immune evasion, viral dissemination, and the establishment and maintenance of both lytic and latent viral infection. US28 also impacts vascular disease and has been implicated in oncogenesis, notably glioblastoma. Because it is expressed on both lytically and latently infected cells, US28 is an attractive therapeutic target, with small molecules, antibodies, and engineered fusion toxins in preclinical development to block signaling, force viral reactivation, or selectively kill infected cells. Safety concerns primarily involve cross-reactivity and potential impacts on host immune function.

Other names

HCMV US28Viral G protein-coupled receptor US28Cytomegalovirus US28

Small molecule antagonists/inverse agonists block US28 signaling; Fusion toxins internalized via US28, deliver cell-lytic agents selectively to infected cells; Antibody/nanobody-based inhibition (blocks ligand-dependent and constitutive activity).