Glycoprotein C of Herpes Simplex Virus 1 Shields Glycoprotein B from Antibody Neutralization

Abstract

Viruses have evolved strategies to avoid neutralization by the host antibody response. Herpes simplex virus (HSV) glycoprotein C (gC) functions in viral entry and binds to complement component C3b, inhibiting complement-mediated immunity. We investigated whether gC protects HSV from antibody neutralization. HSV-1 that lacks gC was more sensitive to complement-independent neutralization by a panel of gB monoclonal antibodies than a wild-type gC rescuant virus. The presence of gC decreased neutralization by 2- to 16-fold. The gB in the native envelope of HSV-1 had reduced reactivity with antibodies in comparison to gB from the gC-null virus, suggesting that gC hampers the recognition of gB epitopes in the viral particle. The protein composition of the gC-null virus, including the surface glycoproteins essential for entry, was equivalent to that of the wild type, suggesting that gC is directly responsible for the reduced antibody recognition and neutralization. The neutralizing activity of antibodies to gD and gH antibodies was also increased in HSV lacking gC. Together, the data suggest that HSV-1 gC protects the viral envelope glycoproteins essential for entry, including gB, by shielding them from neutralization as a potential mechanism of immune evasion. IMPORTANCE HSV-1 causes lifelong infection in the human population and can be fatal in neonatal and immunocompromised individuals. There is no vaccine or cure, in part due to the ability of HSV to escape the host immune response by various mechanisms. The HSV particle contains at least 15 envelope proteins, four of which are required for entry and replication. This work suggests a novel role for gC in shielding the HSV entry glycoproteins. gC may function to help HSV escape neutralization by antibodies.

Herpes Simplex Virus Glycoprotein C Regulates Low-pH Entry

“…Envelope proteins gB, gD, gE, and gH were detected at equivalent levels in the two viruses by Western blotting (Fig. S1B) (38). As expected, gC was not detected in HSV-1 ΔgC virions.…”

“…We very recently demonstrated that HSV-1 gC protects gB from neutralizing antibodies (38). HSV-1 gC also binds to complement component C3b and inhibits complement-mediated immunity (52).…”

Antibodies Elicited in Response to a Single Cycle Glycoprotein D Deletion Viral Vaccine Candidate Bind C1q and Activate Complement Mediated Neutralization and Cytolysis

“…The deletion of gC from HSV-1 or HSV-2 results in an increased neutralization activity in the presence of human serum [ 28 ] and the neutralization titer of HSV gB mAbs was increased 2–16-fold when assayed against a gC null virus [ 28 ]. The importance of the antibodies that block the gE and gC immune evasion strategies is further supported by preclinical studies with a trivalent subunit protein or mRNA vaccine comprised of gD, gC and gE, which showed increased neutralizing titers and greater protection in small animal models compared to gD alone [ 29 , 30 ]. Presumably, ΔgD-2 overcomes these immune evasion strategies because it generates antibodies to gC and gE.…”

The requirement of glycoprotein C (gC) for interindividual spread is a conserved function of gC for avian herpesviruses

“…Some of the functions identified include primary attachment of cell-free virus to heparin sulfate (HS)- and chondroitin-like glycosaminoglycans (GAGs) on the surface of cells 2 , 3 , and involvement in late steps of virus egress from cultured cells 2 , 4 . Although gC is not essential for most herpesviruses studied thus far, it significantly increases the efficiency of infection by providing an additional binding mechanism 5 and helps shield the virus from antibody neutralization 6 . In addition to viral attachment and egress, gC homologues are thought to have immune evasion functions mediated by binding to and inhibiting the action of complement component C3 7 – 12 , as well as a role in chemokine-mediated leukocyte migration 13 .…”