J Virol. 2019 May 15. pii: JVI.00289-19. doi: 10.1128/JVI.00289-19
Cairns TM, Ditto NT, Atanasiu D, Lou H, Brooks BD, Saw WT, Eisenberg RJ, Cohen GH
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, we have shown that gD is structurally divided into two “faces:” one for 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: 1) gD is captured by certain anti-gD monoclonal antibodies (MAbs) that are bound to a biosensor chip; 2) gD is bound to either one of its receptors on a chip; and 3) 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.
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