Epstein-Barr virus (EBV) and Kaposi’s Sarcoma Associated Herpesvirus (KSHV) are DNA tumor viruses that provide risk factors for Burkitt’s lymphoma, Hodgkin’s lymphoma, nasopharyngeal carcinoma, Kaposi’s Sarcoma and post-transplant lymphoproliferative disease. EBV infection has also been associated with multiple sclerosis. Healthy carriers consistently shed virus in saliva that infects naïve individuals despite being exposed to virus-specific antibody. This lack of neutralization contrasts completely with non-persistent mucosal infections such as that of poliovirus, and implies that gammaherpesviruses have evolved specific antibody evasion mechanisms.
Our understanding of EBV and KSHV is limited by their narrow species tropisms. Related animal viruses are therefore an important source of information. Two of the best established experimental models are provided by Murid herpesvirus 4 (MuHV-4) and Bovine herpesvirus 4 (BoHV-4). The homologs of gp350 are gp150 in MuHV-4 and gp180 in BoHV-4 are diverse in sequence but seem to be related in function, being involved in both binding to a cellular receptor and in blocking the infection of cells that do not express this receptor. So a non-essential glycoprotein hides some epitopes on cell-free virions from neutralization.
Antibody Evasion by a Gammaherpesvirus O-Glycan Shield. (2011) PLoS Pathog 7(11): e1002387. doi:10.1371/journal.ppat.1002387
All gammaherpesviruses encode a major glycoprotein homologous to the Epstein-Barr virus gp350. These glycoproteins are often involved in cell binding, and some provide neutralization targets. However, the capacity of gammaherpesviruses for long-term transmission from immune hosts implies that in vivo neutralization is incomplete. In this study, we used Bovine Herpesvirus 4 (BoHV-4) to determine how its gp350 homolog – gp180 – contributes to virus replication and neutralization. A lack of gp180 had no impact on the establishment and maintenance of BoHV-4 latency, but markedly sensitized virions to neutralization by immune sera. Antibody had greater access to gB, gH and gL on gp180-deficient virions, including neutralization epitopes. Gp180 appears to be highly O-glycosylated, and removing O-linked glycans from virions also sensitized them to neutralization. It therefore appeared that gp180 provides part of a glycan shield for otherwise vulnerable viral epitopes. Interestingly, this O-glycan shield could be exploited for neutralization by lectins and carbohydrate-specific antibody. The conservation of O-glycosylation sites in all gp350 homologs suggests that this is a general evasion mechanism that may also provide a therapeutic target.