Coreceptor restriction within the HLA-DQ locus for Epstein–Barr virus infection

Haan, Keith M.; Longnecker, Richard

doi:10.1073/pnas.160171697

Cited by 53 publications

(63 citation statements)

References 32 publications

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“…EBV virions contain two gH complexes (12,13) with mutually exclusive functions (11). Fusion with the plasma membrane of B cells is mediated by gH/gL/gp42 (14)(15)(16), but epithelial cell entry is triggered by gH/gL (11,12,17). The cell type in which EBV is produced can alter its tropism.…”

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confidence: 99%

Human cytomegalovirus uses two distinct pathways to enter retinal pigmented epithelial cells

Wang

Schröer

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Human cytomegalovirus infects multiple cell types, including fibroblasts and epithelial cells. It penetrates fibroblasts by fusion at the cell surface but is endocytosed into epithelial cells. In this report, we demonstrate by electron microscopy that the virus uses two different routes to enter retinal pigmented epithelial cells, depending on the cell type in which the infecting virus was produced. Virus produced in epithelial cells preferentially fuses with the plasma membrane, whereas fibroblast-derived virus mostly enters by receptor-mediated endocytosis. Treatment of epithelial cells with agents that block endosome acidification inhibited infection by virus produced in fibroblasts but had only a modest effect on infection by virus from epithelial cells. Epithelial cell-generated virions had higher intrinsic ''fusion-from-without'' activity than fibroblast-generated particles, and the two virus preparations triggered different cellular signaling responses, as evidenced by markedly different transcriptional profiles. We propose that the cell type in which a human cytomegalovirus particle is produced likely influences its subsequent spread and its contribution to pathogenesis.host cell transcriptome ͉ pathogenesis ͉ virus spread

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confidence: 99%

Human cytomegalovirus uses two distinct pathways to enter retinal pigmented epithelial cells

Wang

Schröer

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…In vitro experiments reveal that the minimal requirement for viral fusion with B cells includes EBV envelope glycoproteins gH, gL, gB, and gp42 (7). For infection of B cells, gp42 is known to specifically bind the host cell major histocompatibility complex (MHC) class II proteins to trigger viral-cell membrane fusion (6,8,10,16,32). Only those MHC class II receptors having a glutamic acid at beta chain residue 46, which includes all HLA-DR and -DP alleles but only some HLA-DQ alleles, can bind gp42 and thereby activate membrane fusion (6,30).…”

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confidence: 99%

Soluble Epstein-Barr Virus Glycoproteins gH, gL, and gp42 Form a 1:1:1 Stable Complex That Acts Like Soluble gp42 in B-Cell Fusion but Not in Epithelial Cell Fusion

Kirschner

Omerović

Попов

et al. 2006

J Virol

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110

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Epstein-Barr virus (EBV) is a herpesvirus that infects cells by fusing its lipid envelope with the target cellmembrane. The fusion process requires the actions of viral glycoproteins gH, gL, and gB for entry into epithelial cells and additionally requires gp42 for entry into B cells. To further study the roles of these membrane-associated glycoproteins, purified soluble forms of gp42, gH, and gL were expressed that lack the membrane-spanning regions. The soluble gH/gL protein complex binds to soluble gp42 with high affinity, forming a stable heterotrimer with 1:1:1 stoichiometry, and this complex is not formed by an N-terminally truncated variant of gp42. The effects of adding soluble gp42, gH/gL, and gH/gL/gp42 were examined with a virus-free cell-cell fusion assay. The results demonstrate that, in contrast to gp42, membrane fusion does not proceed with secreted gH/gL. The addition of soluble gH/gL does not inhibit or enhance B-cell or epithelial cell fusion when membrane-bound gH/gL, gB, and gp42 are present. However, the soluble gH/gL/gp42 complex does activate membrane fusion with B cells, similarly to soluble gp42, but it does not inhibit fusion with epithelial cells, as observed for gp42 alone. A gp42 peptide, derived from an N-terminal segment involved in gH/gL interactions, binds to soluble gH/gL and inhibits EBV-mediated epithelial cell fusion, mimicking gp42. These observations reveal distinct functional requirements for gH/gL and gp42 complexes in EBV-mediated membrane fusion.

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“…gp42 is most closely related to natural killer (NK) receptors such as Ly49A and shares the functional characteristic of binding to major histocompatibility complex (MHC) superfamily members (14). By taking advantage of the high degree of polymorphism in HLA class II molecules, it was established that a glutamic acid at residue 46 of the HLA class II ␤ chain is necessary for EBV entry (9). At that time, it was noted that the domain surrounding residue 46 is homologous to a site on MHC class I that interacts with the murine NK receptor Ly49A (26).…”

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confidence: 99%

Mutational Analysis of the HLA Class II Interaction with Epstein-Barr Virus Glycoprotein 42

McShane

Mullen

Haan

et al. 2003

J Virol

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Entry of Epstein-Barr virus (EBV) into B lymphocytes requires the binding of viral glycoprotein 42 (gp42), a C-type lectin family member, to HLA class II. Recently, the structure of the gp42:HLA-DR1 complex was determined. In order to confirm the interaction as determined in the structural study and to identify other potential interactive residues, a mutational analysis of HLA class II was performed. A secreted form of gp42 (sgp42) reacted with a conformation-specific monoclonal antibody and blocked EBV infection. The binding of sgp42 and EBV entry to two sets of HLA class II mutants were tested. The first set of mutants were based on the known interaction of the C-type lectin Ly49A with HLA class I, and the second set of mutants were based on the identified interface in the gp42:HLA-DR1 complex. As expected, none of the mutants that would be predicted to interfere with the interaction of Ly49A with class I affected the interaction of gp42 with HLA class II, whereas mutants in amino acids identified in the gp42:HLA-DR1 structure inhibited sg42 binding to class II. In general, sgp42 binding correlated with efficient entry of EBV, as demonstrated by the necessity of glutamic acid 46 or arginine 72 in class II molecules. Furthermore, other HLA class II residues buried within the interface of gp42 and HLA class II when mutated had either no effect or a decrease in both binding and entry and implicate a region of class II important in stabilizing the interaction with gp42. These studies provide insight into the entry and fusion processes of the critical interaction between gp42 and HLA class II.Epstein-Barr virus (EBV), a gammaherpesvirus, causes infectious mononucleosis and is associated with a variety of malignancies, such as Burkitt's lymphoma and nasopharyngeal carcinoma (18). The host range of EBV in vitro is largely restricted to B cells. Entry of the virus occurs through multiple interactions of viral glycoproteins with receptors found on B cells. The initial entry step is the interaction of the major viral glycoprotein 350/220 (gp350/220) with the complement receptor type 2 molecule CD21 (CR2/CD21) (15,25). This interaction is thought to bring the virus closer to the B-cell membrane, allowing for attachment of the viral glycoprotein gp42 with B-cell surface HLA class II molecules. Fusion of the viral envelope with the B-cell membrane requires gp42 along with the concerted action of the EBV-encoded glycoproteins gB, gH, and gL (8). Furthermore, the association of gp42 and HLA class II seems to be the key signal for triggering virus entry and fusion into B cells as well as tropism. A virus lacking gp42 is not able to infect B cells, and the amount of gp42 present on the virion determines the cell type that EBV infects (2, 28).The HLA class II molecule, HLA-DR, was first shown to interact with gp42 in an expression library screen for proteins that bound a soluble gp42-Fc construct (23). HLA class II molecules are comprised of two distinct gene products, ␣ and ␤, which noncovalently heterodimerize to form mature ...

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Coreceptor restriction within the HLA-DQ locus for Epstein–Barr virus infection

Cited by 53 publications

References 32 publications

Human cytomegalovirus uses two distinct pathways to enter retinal pigmented epithelial cells

Human cytomegalovirus uses two distinct pathways to enter retinal pigmented epithelial cells

Soluble Epstein-Barr Virus Glycoproteins gH, gL, and gp42 Form a 1:1:1 Stable Complex That Acts Like Soluble gp42 in B-Cell Fusion but Not in Epithelial Cell Fusion

Mutational Analysis of the HLA Class II Interaction with Epstein-Barr Virus Glycoprotein 42

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