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

Xiaofei, E; Meraner, Paul; Lü, Ping; Perreira, Jill M.; Aker, Aaron M.; McDougall, William M.; Chan, Gary; Gerstein, Rachel M.; Caposio, Patrizia; Yurochko, Andrew D.; Brass, Abraham L.; Kowalik, Timothy F.

doi:10.1073/pnas.1814850116

Cited by 108 publications

(53 citation statements)

References 72 publications

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“…Two glycoprotein complexes on the HCMV surface drive broad host cell tropism [22]. A pentameric complex of glycoprotein H (gH; UL75), gL (UL115), UL128, UL130 and UL131A mediates entry into epithelial and endothelial cells [23][24][25][26][27][28], possibly through engagement of neuropilin-2 [29] or the olfactory receptor OR14I1 [30] on the host cell. A trimeric complex of gH, gL and gO (UL74) is sufficient for entry into fibroblasts and is also necessary for entry into pentamer-requiring cell types by promoting membrane fusion [31][32][33].…”

Section: Introductionmentioning

confidence: 99%

Engineered receptors for human cytomegalovirus that are orthogonal to normal human biology

et al. 2020

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A trimeric glycoprotein complex on the surface of human cytomegalovirus (HCMV) binds to platelet-derived growth factor (PDGF) receptor α (PDGFRα) to mediate host cell recognition and fusion of the viral and cellular membranes. Soluble PDGFRα potently neutralizes HCMV in tissue culture, and its potential use as an antiviral therapeutic has the benefit that any escape mutants will likely be attenuated. However, PDGFRα binds multiple PDGF ligands in the human body as part of developmental programs in embryogenesis and continuing through adulthood. Any therapies with soluble receptor therefore come with serious efficacy and safety concerns, especially for the treatment of congenital HCMV. Soluble virus receptors that are orthogonal to human biology might resolve these concerns. This engineering problem is solved by deep mutational scanning on the D2-D3 domains of PDGFRα to identify variants that maintain interactions with the HCMV glycoprotein trimer in the presence of competing PDGF ligands. Competition by PDGFs is conformation-dependent, whereas HCMV trimer binding is independent of proper D2-D3 conformation, and many mutations at the receptor-PDGF interface are suitable for functionally separating trimer from PDGF interactions. Purified soluble PDGFRα carrying a targeted mutation succeeded in displaying wild type affinity for HCMV trimer with a simultaneous loss of PDGF binding, and neutralizes trimer-only and trimer/pentamer-expressing HCMV strains infecting fibroblasts or epithelial cells. Overall, this work makes important progress in the realization of soluble HCMV receptors for clinical application.

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Section: Introductionmentioning

confidence: 99%

Engineered receptors for human cytomegalovirus that are orthogonal to normal human biology

et al. 2020

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“…HCMV entry into host cells is extremely dynamic due to the usage of a variety of cellular entry receptors during virus-cell interactions [21][22][23][24]. It has been shown that depending on the cell type, HCMV can utilize multiple target cell receptors, including cell surface heparan sulfate (HS), different cellular integrins, platelet-derived growth factor receptor alpha (PDGF-Rα), neuropilin-2 and epidermal growth factor receptor (EGF-R), for cellular entry [25][26][27][28][29][30][31]. On the flip side, HCMV's multiple viral glycoproteins, including gB, gO, and gH-gL, engage these structurally and functionally unrelated receptors to penetrate cellular defenses.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Human Cytomegalovirus Entry into Host Cells through A Pleiotropic Small Molecule

Elste

Kaltenbach

Patel

et al. 2020

IJMS

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Human cytomegalovirus (HCMV) infections are wide-spread among the general population with manifestations ranging from asymptomatic to severe developmental disabilities in newborns and life-threatening illnesses in individuals with a compromised immune system. Nearly all current drugs suffer from one or more limitations, which emphasizes the critical need to develop new approaches and new molecules. We reasoned that a 'poly-pharmacy' approach relying on simultaneous binding to multiple receptors involved in HCMV entry into host cells could pave the way to a more effective therapeutic outcome. This work presents the study of a synthetic, small molecule displaying pleiotropicity of interactions as a competitive antagonist of viral or cell surface receptors including heparan sulfate proteoglycans and heparan sulfate-binding proteins, which play important roles in HCMV entry and spread. Sulfated pentagalloylglucoside (SPGG), a functional mimetic of heparan sulfate, inhibits HCMV entry into human foreskin fibroblasts and neuroepithelioma cells with high potency. At the same time, SPGG exhibits no toxicity at levels as high as 50-fold more than its inhibition potency. Interestingly, cell-ELISA assays showed downregulation in HCMV immediate-early gene 1 and 2 (IE 1&2) expression in presence of SPGG further supporting inhibition of viral entry. Finally, HCMV foci were observed to decrease significantly in the presence of SPGG suggesting impact on viral spread too. Overall, this work offers the first evidence that pleiotropicity, such as demonstrated by SPGG, may offer a new poly-therapeutic approach toward effective inhibition of HCMV.

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“…It is now accepted that the two main host cell receptors for HCMV involve the platelet-derived growth factor receptor α (PDGFRα) [66][67][68] and Neuropilin 2 (Nrp2) [55]. In addition, other cellular host factors were described as facilitators of viral entry such as the olfactory receptor family member OR14I1 [69], the adipocyte plasma membrane-associated protein (APMAP) [70], CD46 [71], and CD147 [72]. However, the biological relevance of this multitude of receptors remains to be understood.…”

Section: Hcmv Antigens As Vaccine Candidatesmentioning

confidence: 99%

Virus-Like Particles and Nanoparticles for Vaccine Development against HCMV

Perotti

Perez

2019

Viruses

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Human cytomegalovirus (HCMV) infects more than 70% of the human population worldwide. HCMV is responsible for high morbidity and mortality in immunocompromised patients and remains the leading viral cause of congenital birth defects. Despite considerable efforts in vaccine and therapeutic development, HCMV infection still represents an unmet clinical need and a life-threatening disease in immunocompromised individuals and newborns. Immune repertoire interrogation of HCMV seropositive patients allowed the identification of several potential antigens for vaccine design. However, recent HCMV vaccine clinical trials did not lead to a satisfactory outcome in term of efficacy. Therefore, combining antigens with orthogonal technologies to further increase the induction of neutralizing antibodies could improve the likelihood of a vaccine to reach protective efficacy in humans. Indeed, presentation of multiple copies of an antigen in a repetitive array is known to drive a more robust humoral immune response than its soluble counterpart. Virus-like particles (VLPs) and nanoparticles (NPs) are powerful platforms for multivalent antigen presentation. Several self-assembling proteins have been successfully used as scaffolds to present complex glycoprotein antigens on their surface. In this review, we describe some key aspects of the immune response to HCMV and discuss the scaffolds that were successfully used to increase vaccine efficacy against viruses with unmet medical need.

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

Cited by 108 publications

References 72 publications

Engineered receptors for human cytomegalovirus that are orthogonal to normal human biology

Engineered receptors for human cytomegalovirus that are orthogonal to normal human biology

Inhibition of Human Cytomegalovirus Entry into Host Cells through A Pleiotropic Small Molecule

Virus-Like Particles and Nanoparticles for Vaccine Development against HCMV

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