Structural basis for Epstein–Barr virus host cell tropism mediated by gp42 and gHgL entry glycoproteins

Sathiyamoorthy, Karthik; Hu, Yao Xiong; Möhl, Britta S.; Chen, Jia; Longnecker, Richard; Jardetzky, Theodore S.

doi:10.1038/ncomms13557

Cited by 88 publications

(128 citation statements)

References 47 publications

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“…This tool has allowed for the ability to correlate surface phenotype with infection and has been shown to accurately and reproducibly reflect viral burden when compared to standard virological techniques. It is well established that human EBV infection is found primarily first in the epithelial cell compartment of the nasopharynx, followed by the B lymphocyte compartment where the virus takes up permanent residence 31,32. These findings were confirmed by qPCR for expression of the MHV-68 latent viral gene ORF50 as previously described (data not shown) 30.…”

supporting

confidence: 83%

Impact of selective CD28 blockade on virus-specific immunity to a murine Epstein-Barr virus homolog

Crepeau

Elengickal

Muraglia

et al. 2019

American Journal of Transplantation

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| INTRODUC TI ONLimiting immune-mediated damage of the allograft while maintaining protective immunity following transplantation requires precise regulation of the immune system. These processes are carefully controlled by the balance of costimulatory and coinhibitory signals T cells receive. The CD28/CTLA-4 pathway is the prototypic cosignaling pathway in T cells, with CTLA-4 coinhibition acting as the counter-signal to CD28 costimulation as they compete for the same ligands (CD80 and CD86). Because CD28 costimulation is necessary for optimal T cell activation, immunomodulation via blockade of this pathway has been a promising approach to prevent inappropriate T cell activation in the setting of transplantation.Belatacept, a recombinant CTLA-4Ig fusion protein, which binds to CD80/86 thus preventing CD28-mediated T cell activation was the first costimulation blocker to be approved by the US Food and CTLA-4Ig (belatacept) blocks the CD80/CD86 ligands for both CD28 and CTLA-4;thus, in addition to the intended effect of blocking CD28-mediated costimulation, belatacept also has the unintended effect of blocking CTLA-4-mediated coinhibition.Recently, anti-CD28 domain antibodies (dAb) that selectively target CD28 while leaving CTLA-4 intact were shown to more effectively inhibit alloimmune responses and prolong graft survival. However, the impact of selective CD28 blockade on protective immunity has not been extensively investigated. Here, we sought to compare the impact of CTLA-4Ig vs anti-CD28dAb on CD8 + T cell immunity to a transplant-relevant pathogen, a murine homolog of Epstein-Barr virus. Mice were infected with murine gammaherpesvirus-68 (MHV) and treated with vehicle, CTLA-4Ig, or anti-CD28dAb. Although anti-CD28dAb resulted in a decrease in virus-specific CD8 + T cell numbers as compared to CTLA-4Ig, cytolytic function and the expression of markers of high-quality effectors were not different from CTLA-4Ig treated animals.Importantly, MHV-68 viral load was not different between the treatment groups.These results suggest that preserved CTLA-4 coinhibition limits MHV-specific CD8 + T cell accumulation, but the population that remains retains cytolytic function and migratory capacity and is not inferior in its ability to control viral burden relative to T cell responses in CTLA-4Ig-treated animals. K E Y W O R D Sanimal models: murine, basic (laboratory) research/science, cellular biology, Epstein-Barr Virus, immunosuppressant-fusion proteins and monoclonal antibodies: belatacept, immunosuppressant-fusion proteins and monoclonal antibodies: costimulation molecule specific, lymphocyte biology: differentiation/maturation, T cell biology

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supporting

confidence: 83%

Impact of selective CD28 blockade on virus-specific immunity to a murine Epstein-Barr virus homolog

Crepeau

Elengickal

Muraglia

et al. 2019

American Journal of Transplantation

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“…The critical requirement for an interaction between gD and gH/gL in viral fusion is supported by several studies. First, in Epstein-Barr virus (EBV), cryoelectron microscopy and crystallography have revealed the structure of a gp42-gH/gL complex (26,27). Like gD, gp42 is a receptor binding protein for EBV and is considered a functional (albeit not structural) homologue of gD.…”

Section: Downloaded Frommentioning

confidence: 99%

“…However, despite numerous studies, both from our laboratory and others (19)(20)(21)(22)(23)(24)(25), that indirectly support the ability of gD to interact with gH/gL, before now we have been unable to show that gD and gH/gL bind to each other directly.The critical requirement for an interaction between gD and gH/gL in viral fusion is supported by several studies. First, in Epstein-Barr virus (EBV), cryoelectron microscopy and crystallography have revealed the structure of a gp42-gH/gL complex (26,27). Like gD, gp42 is a receptor binding protein for EBV and is considered a functional (albeit not structural) homologue of gD.…”

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

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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...

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“…LMP1 and BZLF1 promoter) which endow them with greatly enhanced epitheliotropism [5,8,9]. Distinct molecular processes appear to be involved in orchestrating the virus’ attachment, entry into, and replication in B lymphocytes and epithelial cells [4,6,10–12].…”

Section: Introductionmentioning

confidence: 99%

Characterization and establishment of a novel EBV strain simultaneously associated with nasopharyngeal carcinoma and B-cell lymphoma

Syn

et al. 2020

Preprint

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41Epstein-Barr virus (EBV) -the prototypical human tumor virus -is responsible for 1-2% of the 42 global cancer burden, but divergent strains seem to exist in different geographical regions with 43 distinct predilections for causing lymphoid or epithelial malignancies. Here we report the 44 establishment and characterization of Yu103, an Asia Pacific EBV strain with a highly remarkable 45 provenance of being derived from nasopharyngeal carcinoma biopsy but subsequently 46 propagated in human B-lymphoma cells and xenograft models. Unlike previously characterized 47 EBV strains which are either predominantly B-lymphotropic or epitheliotropic, Yu103 evinces an 48 uncanny capacity to infect and transform both B-lymphocytes and nasopharyngeal epithelial cells. 49 Genomic and phylogenetic analyses indicated that Yu103 EBV lies midway along the spectrum 50 of EBV strains known to drive lymphomagenesis or carcinogenesis, and harbors molecular 51 features which likely account for its unusual properties. To our knowledge, Yu103 EBV is currently 52 the only EBV isolate shown to drive human nasopharyngeal carcinoma and B-lymphoma, and 53 should therefore provide a powerful novel platform for research on EBV-driven hematological and 54 epithelial malignancies. PLoS Pathogens 55

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Structural basis for Epstein–Barr virus host cell tropism mediated by gp42 and gHgL entry glycoproteins

Cited by 88 publications

References 47 publications

Impact of selective CD28 blockade on virus-specific immunity to a murine Epstein-Barr virus homolog

Impact of selective CD28 blockade on virus-specific immunity to a murine Epstein-Barr virus homolog

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

Characterization and establishment of a novel EBV strain simultaneously associated with nasopharyngeal carcinoma and B-cell lymphoma

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