Abstract
Human cytomegalovirus (HCMV) is a ubiquitous virus that is a major pathogen in newborns and immunocompromised or immunosuppressed patients. HCMV infects a wide variety of cell types using distinct entry pathways that involve different forms of the gH/gL glycoprotein: gH/gL/gO and gH/gL/UL128-131 as well as the viral fusion glycoprotein, gB. However, the minimal or core fusion machinery (sufficient for cell-cell fusion) is just gH/gL and gB. Here, we demonstrate that HCMV gB and gH/gL form a stable complex early after their synthesis and in the absence of other viral proteins. gH/gL can interact with gB mutants that are unable to mediate cell-cell fusion. gB-gH/gL complexes included as much as 16–50% of the total gH/gL in HCMV virus particles. In contrast, only small amounts of gH/gL/gO and gH/gL/UL128-131 complexes were found associated with gB. All herpesviruses express gB and gH/gL molecules and most models describing herpesvirus entry suggest that gH/gL interacts with gB to mediate membrane fusion, although there is no direct evidence for this. For herpes simplex virus (HSV-1) it has been suggested that after receptor binding gH/gL binds to gB either just before, or coincident with membrane fusion. Therefore, our results have major implications for these models, demonstrating that HCMV gB and gH/gL forms stable gB-gH/gL complexes that are incorporated virions without receptor binding or membrane fusion. Moreover, our data is the best support to date for the proposal that gH/gL interacts with gB.
Highlights
Entry of all herpesviruses into cells requires at least two membrane glycoproteins: gB and gH/ gL that form the primordial and core fusion machinery
human cytomegalovirus (HCMV) expresses two envelope proteins, gH/gL and gB that are essential for entry
Models for how herpesvirus gB and gH/gL molecules function describe binding of gH/gL to gB that leads to conformational changes and activation of membrane fusion and virus entry
Summary
Entry of all herpesviruses into cells requires at least two membrane glycoproteins: gB and gH/ gL that form the primordial and core fusion machinery. Unlike VSV G-protein, herpesvirus gB molecules require additional proteins for membrane fusion and entry. The most extensive data involves the α-herpesvirus HSV-1 that expresses glycoprotein gD that binds receptors, it is believed that gD interacts with glycoprotein gH/gL that interacts with gB to trigger membrane fusion [3]. We have proposed that the β-herpesvirus human cytomegalovirus (HCMV) utilizes different forms of gH/gL, a trimer of gH/gL/gO and a pentamer of gH/gL/ UL128-131 to bind distinct receptors and this promotes gB-mediated entry fusion [5]. A major tenet of all the models describing entry of α-, β-, and γ-herpesviruses suggests that gH/ gL is activated by receptor binding (or by gD for HSV-1) and binds to gB and in so doing, triggers gB for fusion
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