Antibody-induced conformational changes in HSV gD reveal new targets for virus

32 As the receptor-binding protein of HSV, gD plays an essential role in virus entry. In its 33 native state, the last 56 amino acids of the ectodomain C-terminus (C-term) occlude 34 binding to its receptors, HVEM and nectin-1. Although it is clear that movement of the C35 term must occur to permit receptor binding, we believe that this conformational change is 36 also a key event for triggering later steps leading to fusion. Specifically, gD mutants 37 containing disulfide bonds that constrain the C-term are deficient in their ability to trigger 38 fusion following receptor binding. In this report, we show that two newly made MAbs, MC2 39 and MC5, have virus-neutralizing activity but do not block binding of gD to either receptor. 40 In contrast, all previously characterized neutralizing anti-gD MAbs block binding of gD to 41 receptor(s). Interestingly, instead of blocking receptor binding, MC2 significantly enhances 42 the affinity of gD for both receptors. Several non-neutralizing MAbs also enhanced gD43 receptor binding (MC4, MC10, MC14). While MC2 and MC5 recognized different epitopes 44 on the core of gD, these non-neutralizing MAbs recognized the gD C-term. Both the 45 neutralizing capacity and rate of neutralization of virus by MC2 is uniquely enhanced when 46 combined with MAbs MC4, MC10, or MC14. We suggest that MC2 and MC5 prevent gD from 47 performing a function that triggers later steps leading to fusion, and that the epitope for 48 MC2 is normally occluded by the C-term of the gD ectodomain. 49 50 on O cber 3, 2017 by gest http/jvi.asm .rg/ D ow nladed fom