Abstract
Herpes simplex virus (HSV) entry into the cells requires glycoproteins gD, gH/gL and gB, activated in a cascade fashion by conformational modifications induced by cognate receptors and intermolecular signaling. The receptors are nectin1 and HVEM (Herpes virus entry mediator) for gD, and αvβ6 or αvβ8 integrin for gH. In earlier work, insertion of a single chain antibody (scFv) to the cancer receptor HER2 (human epidermal growth factor receptor 2) in gD, or in gH, resulted in HSVs specifically retargeted to the HER2-positive cancer cells, hence in highly specific non-attenuated oncolytic agents. Here, the scFv to HER2 was inserted in gB (gBHER2). The insertion re-targeted the virus tropism to the HER2-positive cancer cells. This was unexpected since gB is known to be a fusogenic glycoprotein, not a tropism determinant. The gB-retargeted recombinant offered the possibility to investigate how HER2 mediated entry. In contrast to wt-gB, the activation of the chimeric gBHER2 did not require the activation of the gD and of gH/gL by their respective receptors. Furthermore, a soluble form of HER2 could replace the membrane-bound HER2 in mediating virus entry, hinting that HER2 acted by inducing conformational changes to the chimeric gB. This study shows that (i) gB can be modified and become the major determinant of HSV tropism; (ii) the chimeric gBHER2 bypasses the requirement for receptor-mediated activation of other essential entry glycoproteins.
Highlights
Herpes simplex virus encodes a multipartite entry apparatus made of four essential glycoproteins, named gD, the heterodimer gH/gL and gB, with distinct functions [1,2,3,4]. gD, whose structure includes an Ig-folded core with extensions, serves as a typical receptor-binding glycoprotein, and the major determinant of HSV tropism [5,6,7]
The heterodimer gH/gL is a multidomain protein, with no structural resemblance to any known protein [8,9,10]. gB is a trimer with structural features typical of viral fusion glycoproteins [11,12,13]. gH/gL and gB form the conserved fusion apparatus across the Herpesviridae family
The system of receptors for the quartet of glycoproteins appears to be more and more complex, and affects the process of glycoprotein activation at virus entry. gD interacts with three alternative receptors, nectin1, HVEM, and modified heparan sulphate [21,22,23,24]. gH/gL interact with the αvβ subfamily of integrins [25,26]. αvβ6 and αvβ8 are required for entry, in that their depletion, or block with antibodies, results in block to virus infection [26]
Summary
Herpes simplex virus encodes a multipartite entry apparatus made of four essential glycoproteins, named gD, the heterodimer gH/gL and gB, with distinct functions [1,2,3,4]. gD, whose structure includes an Ig-folded core with extensions, serves as a typical receptor-binding glycoprotein, and the major determinant of HSV tropism [5,6,7]. GD, whose structure includes an Ig-folded core with extensions, serves as a typical receptor-binding glycoprotein, and the major determinant of HSV tropism [5,6,7]. GB is a trimer with structural features typical of viral fusion glycoproteins [11,12,13]. The system of receptors for the quartet of glycoproteins appears to be more and more complex, and affects the process of glycoprotein activation at virus entry. PILRα was reported to be expressed, and possibly to play a role in HSV infection of monocytes, a cell type not usually targeted by HSV [27]. The lack of contribution of gB receptors to overall viral tropism is highlighted by the finding that abrogation of the gD interaction with one of its receptors abrogates virus entry in virtually any cell
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