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Significance Identifying cell-surface receptors required for viral infection is important for developing antiviral therapies and effective vaccines. Human cytomegalovirus (HCMV) infects epithelial cells during interhost transmission. The pentameric protein complex (PC) was identified as being required for infection of this clinically relevant cell type. The majority of neutralizing antibody responses are directed against the PC. Here we describe an HCMV receptor, OR14I1, which binds to the PC and defines epithelial tropism. Importantly, we identified a peptide representing the N terminus of OR14I1 that blocks HCMV infection of epithelial cells. Moreover, an adenylate cyclase signaling pathway functioning downstream of OR14I1 contributes to HCMV infection and endocytosis. These findings reveal information useful for the development of new anti-HCMV therapies and vaccines.

OR14I1 is a receptor for the human cytomegalovirus pentameric complex and defines viral epithelial cell tropism