Two classes of protective antibodies against Pseudorabies virus variant glycoprotein B: Implications for vaccine design

Abstract

Pseudorabies virus (PRV) belongs to the Herpesviridae family, and is an important veterinary pathogen. Highly pathogenic PRV variants have caused severe epidemics in China since 2011, causing huge economic losses. To tackle the epidemics, we identified a panel of mouse monoclonal antibodies (mAbs) against PRV glycoprotein B (gB) that effectively block PRV infection. Among these 15 mAbs, fourteen of them block PRV entry in a complement-dependent manner. The remaining one, 1H1 mAb, however can directly neutralize the virus independent of complement and displays broad-spectrum neutralizing activities. We further determined the crystal structure of PRV gB and mapped the epitopes of these antibodies on the structure. Interestingly, all the complement-dependent neutralizing antibodies bind gB at the crown region (domain IV). In contrast, the epitope of 1H1 mAb is located at the bottom of domain I, which includes the fusion loops, indicating 1H1 mAb might neutralize the virus by interfering with the membrane fusion process. Our studies demonstrate that gB contains multiple B-cell epitopes in its crown and base regions and that antibodies targeting different epitopes block virus infection through different mechanisms. These findings would provide important clues for antiviral drug design and vaccine development.

Ginseng stem‐leaf saponins in combination with selenium enhance immune responses to an attenuated pseudorabies virus vaccine

“…The envelope of PrV consists of 11 different glycoproteins, of which gB is essential for viral entry into the host cells . Antibodies against gB can block PrV infection . In the present study, we observed that oral administration of GSLS followed by co‐injection of aPrV vaccine with Se induced a significantly stronger gB‐specific serum antibody responses than occurred in controls in a mouse model (Figures , a).…”

“…24 Antibodies against gB can block PrV infection. 25 In the present study, we observed that oral administration of GSLS followed by co-injection of aPrV vaccine with Se induced a significantly stronger gB-specific serum antibody responses than occurred in controls in a mouse model (Figures 1, 2a). Stronger gB-specific serum IgG responses indicate that the animal can more effectively block glycoprotein B, thus preventing PrV from entering the host cells.…”

A glycoprotein B-neutralizing antibody structure at 2.8 Å uncovers a critical domain for herpesvirus fusion initiation

“…Monoclonal antibodies (mAbs) to herpesvirus gB orthologues that neutralize viral infection are important for mapping functional domains because their activity depends on binding to gB before membrane fusion 4,[14][15][16][17][18][19] . Antibodies that bind to DI, DII, and DIV of gB orthologues have neutralizing activity against several herpesviruses 4,15,[20][21][22][23] . Although the molecular interactions for some of these antibodies with gB residues have been defined, it is currently not known whether these gB residues have roles in fusion function or virus infection.…”

Functional Role of N-Linked Glycosylation in Pseudorabies Virus Glycoprotein gH

“…gB then inserts its two fusion loops (FL) into the target membrane to subsequently merge the viral and cellular membranes by a large conformational change (5,8). gB is a type I transmembrane protein and is considered the bona fide fusion protein, since crystal structures of gB homologs from pseudorabies virus (PrV) (10,11), herpes simplex virus 1 (HSV-1) (12), human cytomegalovirus (HCMV) (13,14), and Epstein-Barr virus (EBV) (15) resemble those of typical class III postfusion trimers. However, despite its homology to, e.g., the vesicular stomatitis virus fusion protein G (16) or baculovirus gp64 (17), gB is not able to mediate membrane fusion on its own but requires the conserved gH/gL complex.…”