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

Abstract

Bvirus (Macacine herpesvirus 1) is an enveloped, doublestranded DNA virus belonging to the genus Simplexvirus of the subfamily Alphaherpesvirinae. B virus generally produces either mild disease or asymptomatic infection in monkeys of the Macaca genus, which are natural reservoir hosts. Similar to human herpes simplex viruses (HSV), B virus in natural host animals initially infects mucosal or skin epidermal and dermal cells and then enters nerve terminals of the sensory neurons subserving these sites. Subsequently, B virus travels in a retrograde direction to the dorsal root ganglion, where it can establish a latent lifelong infection with periodic reactivation (1, 2). B virus infections of the central nervous system (CNS) are extremely rare in the natural host and are usually associated with immunosuppression or intercurrent diseases (3, 4). In most human cases, B virus spreads to the CNS, causing an acute ascending paralysis and encephalomyelitis with an ϳ80% mortality rate if not treated in a timely manner. 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

Infectious vaccine-derived rubella viruses emerge, persist, and evolve in cutaneous granulomas of children with primary immunodeficiencies

“…The structures of the rubella E1 protein (PDB entries 4ADG, 4ADI and 4ADJ) were used as templates for computer modeling. The mutations were modeled as described earlier using the software package ECMMS (Energy Calculations for Macro Molecular Systems) for molecular mechanics modeling [83, 84]. The illustrations of protein structures were prepared using DS Visualizer (http://accelrys.com/products/collaborative-science/biovia-discovery-studio/visualization.html; Accelrys Inc., CA).…”

Identification of unique B virus (Macacine Herpesvirus 1) epitopes of zoonotic and macaque isolates using monoclonal antibodies

“…It is likely that this particular mAb-detected epitope is not essential for virus entry. The B virus neutralizing ability of the anti-gD mAb, will be examined in B virus entry-resistant cells bearing a single gD receptor, human nectin-1 or -2 [ 28 , 29 ].…”

Questioning the Extreme Neurovirulence of Monkey B Virus(Macacine alphaherpesvirus 1)

“…Consistent with this, a number of glycoproteins have some degree of virus-specific antigenicity. The gB (UL27) and gD (US6) glycoproteins are major immunogens of BV, and while both are structurally conserved and have many cross-reactive epitopes, each also has some degree of antigenic BV-specificity [ 70 , 87 , 108 , 109 , 116 , 117 ]. Both the gG (US4) and gC (UL44) glycoproteins are much less conserved and are largely BV-specific antigens with respect to HSV, but still exhibit some antigenic cross-reactivity with the homologous glycoproteins of HVP2 and SA8 [ 25 , 109 , 110 , 116 , 118 – 120 ].…”

“…While BV encodes homologs of all the various HSV proteins mentioned above, little is known about these BV proteins regarding functional equivalency to their HSV counterparts. BV glycoproteins gC (UL44) and gD (US6) as well as VHS (UL41) have been shown to have similar structural and functional properties to their HSV homologs [ 75 , 117 , 120 – 122 ]. While AA homology suggests that BV proteins function much as their HSV homologs do, the functional equivalency of all other BV proteins has not been directly examined.…”

“…It has been shown that while the HSV gD glycoprotein binds host cell proteins HVEM, nectin 1 and nectin 2 to facilitate viral entry, the BV gD glycoprotein only binds nectin 1 and nectin 2 in both human and macaque cells [ 121 , 122 , 155 ]. While a single amino acid mutation was identified in the external domain of gD that affected the stability of binding to nectin 1, comparison of gD sequences from 19 clinical BV strains isolated from humans and macaques found that this mutation did not correlate with zoonosis [ 117 ], indicating that differing stability of gD binding to nectin 1 is not related to the ability of BV to infect human versus macaque cells. Consistent with this, the gD glycoprotein has been shown to be altogether dispensable for BV entry into both macaque and human cells [ 155 ].…”