Human cytomegalovirus-encoded US28 chemokine receptor (US28)

The Human cytomegalovirus-encoded US28 chemokine receptor (US28) is a viral G protein-coupled receptor (GPCR) that is essential for the viral life cycle and pathogenesis (Frontiers in Immunology, 2023). Unlike most human GPCRs, US28 exhibits high constitutive signaling activity, activating pathways such as phospholipase C (PLC), NF-κB, and MAPK independently of ligand binding (NIH, 2014). This activity is critical for maintaining viral latency by suppressing the major immediate early promoter (MIEP) and promoting oncogenic processes like cell proliferation, migration, and angiogenesis in HCMV-associated malignancies such as glioblastoma (PNAS, 2006). US28 also functions as a "chemokine sink," binding and internalizing a broad range of host CC and CX3C chemokines to evade immune detection (Journal of Virology, 2002). Because it is expressed during both lytic and latent phases, US28 is a prime therapeutic target for eliminating latent viral reservoirs through "shock and kill" strategies or targeted toxin delivery (Frontiers in Immunology, 2023). Pharmacological agents under development include small molecule inverse agonists, nanobodies, and fusion toxin proteins designed to disrupt its signaling or exploit its rapid internalization for cell-specific killing (NIH, 2023). These strategies aim to address the limitations of current standard-of-care antivirals, which only target the lytic phase of infection (Frontiers in Immunology, 2023). However, targeting US28 presents challenges, including potential off-target effects on human chemokine receptors and the risk of uncontrolled viral reactivation (NIH, 2023).

Other names

pUS28US28HCMV US28Viral G protein-coupled receptor US28Viral chemokine receptor US28

Inhibition of constitutive signaling via inverse agonism, antagonism of ligand binding, and exploitation of receptor internalization for targeted delivery of cytotoxic toxins or photosensitizers.