Fusion of epithelial cells by Epstein-Barr virus proteins is triggered by binding of viral proteins gHgL to integrins avb6 or avb8

Louisiana State University in Shreveport, Shreveport, Louisiana, United States
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 11/2009; 106(48):20464-9. DOI: 10.1073/pnas.0907508106
Source: PubMed


Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus that is causally implicated in the development of lymphoid and epithelial tumors. Entry of virus requires fusion of virus envelopes and cell membranes. Fusion with B lymphocytes requires virus glycoprotein gB and a 3-part complex of glycoproteins, gHgLgp42. It is triggered by interactions between glycoprotein 42 (gp42) and HLA class II. However, fusion with epithelial cells is impeded by gp42 and instead is triggered by interactions between an unknown epithelial protein and a 2-part complex of gHgL. We report here that gHgL binds with high affinity to epithelial cells and that affinity of binding is increased by 3 orders of magnitude in the presence of Mn(2+). Binding and infection can be reduced by fibronectin and vitronectin, by down-regulation of integrin alphav, or by a peptide corresponding to 13 aa of gH which include a KGDE motif. Fusion of cells expressing gB and gHgL can be blocked by vitronectin or triggered by addition of soluble truncated integrins alphavbeta6 and alphavbeta8. We conclude that the direct interaction between EBV gHgL and integrins alphavbeta6 and alphavbeta8 can provide the trigger for fusion of EBV with an epithelial cell.

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Available from: Stephen Nishimura, Mar 10, 2015
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    • "As with MuHV-4 and KSHV, the EBV gH–gL contributes to both epithelial-cell binding and membrane fusion; as with HSV-1, it binds to integrins (Chesnokova et al., 2009). EBV-neutralizing mAbs to gH appear to disrupt gH–gL integrin binding or a post-binding conformation change (Chesnokova & Hutt-Fletcher, 2011). "
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    ABSTRACT: Herpesviruses consistently transmit from immunocompetent carriers, implying that their neutralization is hard to achieve. Murid herpesvirus-4 (MuHV-4) exploits host IgG Fc receptors to bypass blocks to cell binding, and pH-dependent protein conformation changes to unveil its fusion machinery only after endocytosis. Nevertheless, neutralization remains possible by targeting the virion glycoprotein H (gH)-gL heterodimer, and the neutralizing antibody responses of MuHV-4 carriers are improved by boosting with recombinant gH-gL. We analysed here how gH-gL-directed neutralization works. The MuHV-4 gH-gL binds to heparan sulfate. However, most gH-gL-specific neutralizing antibodies did not block this interaction; neither did they act directly on fusion. Instead, they blocked virion endocytosis and transport to the late endosomes, where membrane fusion normally occurs. The poor endocytosis of gH-gL-neutralized virions was recapitulated precisely by virions genetically lacking gL. Therefore, driving virion uptake appears to be an important function of gH-gL that provides a major target for antibody-mediated neutralization.
    Full-text · Article · Feb 2012 · Journal of General Virology
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    • "It is worth mentioning in this respect that an in vitro model of EBV infection in premalignant nasopharyngeal epithelial cells was described by Tsang and colleagues [123]. The direct infection of epithelial cells requires the interaction between EBV glycoproteins gHgL and cellular ανβ6 and ανβ8 integrins [124]. In addition, an alternative process named “transfer infection” was proposed to explain the interplay between EBV and epithelial cells: the infection of memory B cells determines CD21-mediated capping of virus and activation of adhesion molecules, which in turn facilitates conjugate formation between B cells and epithelial cells and then the subsequent entry of EBV into epithelial cells [125]. "
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    ABSTRACT: The recent demonstration that immunotherapeutic approaches may be clinically effective for cancer patients has renewed the interest for this strategy of intervention. In particular, clinical trials using adoptive T-cell therapies disclosed encouraging results, particularly in the context of Epstein-Barr-virus- (EBV-) related tumors. Nevertheless, the rate of complete clinical responses is still limited, thus stimulating the development of more effective therapeutic protocols. Considering the relevance of innate immunity in controlling both infections and cancers, innovative immunotherapeutic approaches should take into account also this compartment to improve clinical efficacy. Evidence accumulated so far indicates that innate immunity effectors, particularly NK cells, can be exploited with therapeutic purposes and new targets have been recently identified. We herein review the complex interactions between EBV and innate immunity and summarize the therapeutic strategies involving both adaptive and innate immune system, in the light of a fruitful integration between these immunotherapeutic modalities for a better control of EBV-driven tumors.
    Full-text · Article · Jan 2012 · Clinical and Developmental Immunology
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    • "Interestingly, recent studies have shown that CR2/CD21 is expressed on tonsilar epithelial cells indicating that, in some cases, EBV attachment to epithelial cells may be similar to B cells (Jiang et al., 2008). Finally, integrins have been found to serve as gH/gL receptors, allowing efficient EBV entry into epithelial cells independent of CR2/CD21 and HLA class II (Chesnokova et al., 2009). The use of different glycoprotein-receptor combinations to enter epithelial and B cells allows EBV to regulate cell tropism. "
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    ABSTRACT: The Epstein-Barr virus (EBV) glycoprotein 42 (gp42) is a type II membrane protein essential for entry into B cells but inhibits entry into epithelial cells. X-ray crystallography suggests that gp42 may form dimers when bound to human leukocyte antigen (HLA) class II receptor (Mullen et al., 2002) or multimerize when not bound to HLA class II (Kirschner et al., 2009). We investigated this self-association of gp42 using several different approaches. We generated soluble mutants of gp42 containing mutations within the self-association site and found that these mutants have a defect in fusion. The gp42 mutants bound to gH/gL and HLA class II, but were unable to bind wild-type gp42 or a cleavage mutant of gp42. Using purified gp42, gH/gL, and HLA, we found these proteins associate 1:1:1 by gel filtration suggesting that gp42 dimerization or multimerization does not occur or is a transient event undetectable by our methods.
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