Abstract
Herpes viruses persist in the infected host and are transmitted between hosts in the presence of a fully functional humoral immune response, suggesting that they can evade neutralization by antiviral antibodies. Human cytomegalovirus (HCMV) encodes a number of polymorphic highly glycosylated virion glycoproteins (g), including the essential envelope glycoprotein, gN. We have tested the hypothesis that glycosylation of gN contributes to resistance of the virus to neutralizing antibodies. Recombinant viruses carrying deletions in serine/threonine rich sequences within the glycosylated surface domain of gN were constructed in the genetic background of HCMV strain AD169. The deletions had no influence on the formation of the gM/gN complex and in vitro replication of the respective viruses compared to the parent virus. The gN-truncated viruses were significantly more susceptible to neutralization by a gN-specific monoclonal antibody and in addition by a number of gB- and gH-specific monoclonal antibodies. Sera from individuals previously infected with HCMV also more efficiently neutralized gN-truncated viruses. Immunization of mice with viruses that expressed the truncated forms of gN resulted in significantly higher serum neutralizing antibody titers against the homologous strain that was accompanied by increased antibody titers against known neutralizing epitopes on gB and gH. Importantly, neutralization activity of sera from animals immunized with gN-truncated virus did not exhibit enhanced neutralizing activity against the parental wild type virus carrying the fully glycosylated wild type gN. Our results indicate that the extensive glycosylation of gN could represent a potentially important mechanism by which HCMV neutralization by a number of different antibody reactivities can be inhibited.
Highlights
Cytomegaloviruses (CMV) have co-evolved with their respective hosts
Our results indicate that glycosylation of glycoprotein N (gN) of Human cytomegalovirus (HCMV) represents a potentially important mechanism for evasion of antibody-mediated neutralization by a number of different antibody specificities
We demonstrated that recombinant viruses with under-glycosylated gN were more susceptible to antibodies directed against a number of different virion envelope proteins of HCMV that have been shown to be major targets of the neutralizing antibody response. Together these findings suggest that one function of the extensive glycosylation of gN could be to limit the activity of virus neutralizing antibodies directed at different envelope glycoproteins, a function similar to that of carbohydrates that serve as a glycan shield to limit antibody neutralization of RNA viruses
Summary
Cytomegaloviruses (CMV) have co-evolved with their respective hosts. During this long and continuing co-evolution these viruses have adapted to the host defense systems and vice versa to allow the life-long persistence of these viruses. Persistence and transmission between hosts eventually requires the evasion of immune control. Multiple mechanisms that permit evasion of immune control by the innate and adaptive cellular immune responses have been extensively documented [1,2,3]. Very little is known about mechanisms by which CMV can evade humoral immune responses that presumably consist of antiviral antibodies that potentially neutralize free virus or destroy infected cells via antibody mediated cytotoxicity. Since viral transmission between hosts in a community setting is thought to occur via cell free virus in most cases that have been studied, evading virus neutralizing antibodies is essential for successful spread and persistence of CMVs in the population
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