Herpes B Virus Utilizes Human Nectin-1 but Not HVEM or PILRα for Cell-Cell Fusion and Virus Entry

Abstract

e To investigate the requirements of herpesvirus entry and fusion, the four homologous glycoproteins necessary for herpes simplex virus (HSV) fusion were cloned from herpes B virus (BV) (or macacine herpesvirus 1, previously known as cercopithecine herpesvirus 1) and cercopithecine herpesvirus 2 (CeHV-2), both related simian simplexviruses belonging to the alphaherpesvirus subfamily. Western blots and cell-based enzyme-linked immunosorbent assay (ELISA) showed that glycoproteins gB, gD, and gH/gL were expressed in whole-cell lysates and on the cell surface. Cell -

B Virus (Macacine herpesvirus 1) Glycoprotein D Is Functional but Dispensable for Virus Entry into Macaque and Human Skin Cells

“…Cell monolayers were infected with BV-⌬gDZ/ gD1ϩ, BV-⌬gDZ, or wt B virus (as a positive control), and then, after 2 days incubation under a semisolid overlay, either stained with X-Gal or, in the case of wt infection, immunostained with pooled rhesus B virus antibody-positive sera. Consistent with the previously published results (34), as well as our own unpublished observations, wt B virus was able to enter cells engineered to express human nectin-1 as the only entry mediator and to form large semisyncytial plaques (Fig. 4A).…”

“…At least one putative receptor for HSV-1 gB is paired Ig-like type 2 receptor alpha (PILR␣) (56,57). However, it is highly unlikely that PILR␣ serves as a receptor for B virus entry, because CHO cells expressing human PILR␣ failed to become infected with B virus (34). In addition, myelinassociated glycoprotein (MAG) and nonmuscle myosin IIA and IIB (NMHC-IIA and NMHC-IIB, respectively) isoforms have been reported to bind HSV-1 gB and to serve as entry receptors for HSV-1 (56-60).…”

“…Complete genome sequencing established that the envelope glycoproteins involved in alphaherpesvirus attachment and penetration, i.e., gC, gD, gB, gH, and gL, were present in the B virus genome and highly conserved, suggesting conservation of their functions in the viral replication cycle (22). Similar to HSV and animal alphaherpesviruses, B virus appears to utilize a gD-dependent entry strategy, as the alphaherpesvirus gD receptor nectin-1 can mediate B virus entry into target cells (34). Conversely, the inability of B virus gD-specific antibody to block B virus entry into host cells suggests that gD is nonessential for B virus cell entry (35).…”

B Virus (Macacine Herpesvirus 1) Divergence: Variations in Glycoprotein D from Clinical and Laboratory Isolates Diversify Virus Entry Strategies

“…Postmortem examinations reveal focal neuronal lesions occasionally seen in parietal neurons, but far more often in the brainstem and cervical spinal cord, which are primary sites of virus recovery (5-11). The molecular basis for the differences in neurovirulence between HSV and B virus in humans remains a mystery despite the fact that specific molecular differences between these two viruses have been identified (12)(13)(14)(15)(16)(17)(18)(19).B virus is genetically and immunologically closely related to HSV, and some aspects of cell entry and cell-to-cell transmission of B virus and HSV are conserved (14,(20)(21)(22)(23). The specific interactions of glycoprotein D (gD) with cognate cellular receptors, viz., herpesvirus entry mediator (HVEM), nectin-1, and nectin-2, as well as one of the several isoforms of 3-O-sulfated heparan …”

“…Postmortem examinations reveal focal neuronal lesions occasionally seen in parietal neurons, but far more often in the brainstem and cervical spinal cord, which are primary sites of virus recovery (5-11). The molecular basis for the differences in neurovirulence between HSV and B virus in humans remains a mystery despite the fact that specific molecular differences between these two viruses have been identified (12)(13)(14)(15)(16)(17)(18)(19).…”