Structural basis for potent antibody-mediated neutralization of human cytomegalovirus

Chandramouli, Sumana; Malito, E.; Nguyen, Tuong-Vi; Luisi, Kate; Donnarumma, Danilo; Xing, Yi; Norais, Nathalie; Yü, Dong; Carfı́, Andrea

doi:10.1126/sciimmunol.aan1457

Cited by 84 publications

(96 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Over the past decade, the HCMV vaccine field has largely shifted its focus away from the elicitation of gB-specific antibody responses and towards the targeting of the gH/gL/UL128/UL130/UL131A pentameric complex (PC) because this protein construct was newly identified as a primary target of potent HCMV neutralizing antibodies (24, 43). Yet, it is important to recognize that the gB/MF59 vaccine platform, which did not include the PC, achieved approximately 50% vaccine efficacy in preventing primary HCMV infection in two phase II trials (14, 15) and demonstrated a protective benefit for transplant recipients (20) without the elicitation of potent neutralizing antibody responses (20, 25, 26).…”

Section: Discussionmentioning

confidence: 99%

HCMV glycoprotein B subunit vaccine efficacy was mediated by non-neutralizing antibody effector functions

Nelson

Huffman

Rosa

et al. 2018

Preprint

View full text Add to dashboard Cite

word count: 242 (250 max) 24Significance word count: 120 (120 max) 25Manuscript character count: 48,559 (49,000 max) 26 peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/246884 doi: bioRxiv preprint first posted online 2 Abstract: 27Human cytomegalovirus (HCMV) is the most common congenital infection worldwide, frequently 28 causing hearing loss and brain damage in afflicted infants. A vaccine to prevent maternal 29 acquisition of HCMV during pregnancy is necessary to reduce the incidence of infant disease. 30The glycoprotein B (gB) + MF59 adjuvant subunit vaccine platform is the most successful 31HCMV vaccine tested to-date, demonstrating approximately 50% efficacy in preventing HCMV 32 acquisition in phase II trials. However, the mechanism of vaccine protection remains unknown. 33Plasma from 33 gB/MF59 vaccinees at peak immunogenicity was tested for gB epitope

show abstract

Section: Discussionmentioning

confidence: 99%

HCMV glycoprotein B subunit vaccine efficacy was mediated by non-neutralizing antibody effector functions

Nelson

Huffman

Rosa

et al. 2018

Preprint

View full text Add to dashboard Cite

show abstract

“…Like gD, gp42 is a receptor binding protein for EBV and is considered a functional (albeit not structural) homologue of gD. Second, complexes of gH/gL with other viral proteins have been visualized for human cytomegalovirus (28,29). Third, when gB, gD, and gH/gL were swapped between HSV-1 and the closely related saimiriine herpesvirus 1 (SaHV-1), cell-cell fusion was observed only when gD and gH/gL were both from the same virus, suggesting that the two proteins interact with each other in a speciesspecific manner (19,20).…”

mentioning

confidence: 99%

Surface Plasmon Resonance Reveals Direct Binding of Herpes Simplex Virus Glycoproteins gH/gL to gD and Locates a gH/gL Binding Site on gD

Cairns

Ditto

Atanasiu

et al. 2019

J Virol

View full text Add to dashboard Cite

Herpes simplex virus (HSV) requires fusion between the viral envelope and host membrane. Four glycoproteins, gD, gH/gL, and gB, are essential for this process. To initiate fusion, gD binds its receptor and undergoes a conformational change that hypothetically leads to activation of gH/gL, which in turn triggers the fusion protein gB to undergo rearrangements leading to membrane fusion. Our model predicts that gD must interact with both its receptor and gH/gL to promote fusion. In support of this, we have shown that gD is structurally divided into two "faces": one for the binding receptor and the other for its presumed interaction with gH/gL. However, until now, we have been unable to demonstrate a direct interaction between gD and gH/gL. Here, we used surface plasmon resonance to show that the ectodomain of gH/gL binds directly to the ectodomain of gD when (i) gD is captured by certain anti-gD monoclonal antibodies (MAbs) that are bound to a biosensor chip, (ii) gD is bound to either one of its receptors on a chip, and (iii) gD is covalently bound to the chip surface. To localize the gH/gL binding site on gD, we used multiple anti-gD MAbs from six antigenic communities and determined which ones interfered with this interaction. MAbs from three separate communities block gD-gH/gL binding, and their epitopes encircle a geographical area on gD that we propose comprises the gH/gL binding domain. Together, our results show that gH/gL interacts directly with gD, supporting a role for this step in HSV entry. IMPORTANCE HSV entry is a multistep process that requires the actions of four glycoproteins, gD, gH/gL, and gB. Our current model predicts that gD must interact with both its receptor and gH/gL to promote viral entry. Although we know a great deal about how gD binds its receptors, until now we have been unable to demonstrate a direct interaction between gD and gH/gL. Here, we used a highly sensitive surface plasmon resonance technique to clearly demonstrate that gD and gH/gL interact. Furthermore, using multiple MAbs with defined epitopes, we have delineated a domain on gD that is independent of that used for receptor binding and which likely represents the gH/gL interaction domain. Targeting this interaction to prevent fusion may enhance both therapeutic and vaccine strategies. KEYWORDS glycoproteins, herpes simplex virus, surface plasmon resonance, virus entry H erpes simplex virus (HSV) entry into a cell requires four glycoproteins, gD, gH/gL, and gB, to promote fusion between the viral envelope and host membrane (1-4). In our ongoing studies to determine the mechanistic role for these proteins in viral entry, we have developed a model that posits that fusion is driven by a cascade of Citation Cairns TM, Ditto NT, Atanasiu D, Lou H, Brooks BD, Saw WT, Eisenberg RJ, Cohen GH. 2019. Surface plasmon resonance reveals direct binding of herpes simplex virus glycoproteins gH/gL to gD and locates a gH/gL binding site on gD. J Downloaded fromprotein-protein interactions, initiated by the binding of gD to one of its recep...

show abstract

“…The study of these nonhuman herpesviruses in their natural hosts or HHVs in humanized animal models could help to clarify the relevance of herpesvirus chemokines in the context of a natural viral infection. NOTE ADDED IN PROOF: While this review was in press, the structure of the gH/gL/UL128-UL130-UL131A pentamer was published [258]. This new structure resolves the controversies about the biochemistry and protein-protein interactions of this complex discussed in this review.…”

Section: Discussionmentioning

confidence: 90%

Chemokines encoded by herpesviruses

Pontejo

Murphy

2017

Journal of Leukocyte Biology

View full text Add to dashboard Cite

Viruses use diverse strategies to elude the immune system, including copying and repurposing host cytokine and cytokine receptor genes. For herpesviruses, the chemokine system of chemotactic cytokines and receptors is a common source of copied genes. Here, we review the current state of knowledge about herpesvirus-encoded chemokines and discuss their possible roles in viral pathogenesis, as well as their clinical potential as novel anti-inflammatory agents or targets for new antiviral strategies.

show abstract

Structural basis for potent antibody-mediated neutralization of human cytomegalovirus

Cited by 84 publications

References 42 publications

HCMV glycoprotein B subunit vaccine efficacy was mediated by non-neutralizing antibody effector functions

HCMV glycoprotein B subunit vaccine efficacy was mediated by non-neutralizing antibody effector functions

Surface Plasmon Resonance Reveals Direct Binding of Herpes Simplex Virus Glycoproteins gH/gL to gD and Locates a gH/gL Binding Site on gD

Chemokines encoded by herpesviruses

Contact Info

Product

Resources

About