title: B Virus (Macacine Herpesvirus 1) Divergence: Variations in Glycoprotein D from Clinical and Laboratory Isolates Diversify Virus Entry Strategies.
abstract: B virus (Macacine herpesvirus 1) can cause deadly zoonotic disease in humans. Molecular mechanisms of B virus cell entry are poorly understood for both macaques and humans. Here we investigated the abilities of clinical B virus isolates to use entry receptors of herpes simplex viruses (HSV). We showed that resistant B78H1 cells became susceptible to B virus clinical strains upon expression of either human nectin-2 or nectin-1. Antibody against glycoprotein D (gD) protected these nectin-bearing cells from B virus infection, and a gD-negative recombinant B virus failed to enter these cells, indicating that the nectin-mediated B virus entry depends on gD. We observed that the infectivity of B virus isolates with a single amino acid substitution (D122N) in the IgV-core of the gD ectodomain was impaired on nectin-1-bearing cells. Computational homology-based modeling of the B virus gD-nectin-1 complex revealed conformational differences between the structures of the gD-122N and gD-122D variants that affected the gD-nectin-1 protein-protein interface and binding affinity. Unlike HSV, B virus clinical strains were unable to use herpesvirus entry mediator (HVEM) as a receptor, regardless of conservation of the gD amino acid residues essential for HSV-1 entry via HVEM. Based on the model of the B virus gD-HVEM interface, we predict that residues R7, R11, and G15 are largely responsible for the inability of B virus to utilize HVEM for entry. The ability of B virus to enter cells of a human host by using a combination of receptors distinct from those for HSV-1 or HSV-2 suggests a possible mechanism of enhanced neuropathogenicity associated with zoonotic infections.
  
  
  
  B virus causes brainstem destruction in infected humans in the absence of timely diagnosis and intervention. Nectins are cell adhesion molecules that are widely expressed in human tissues, including neurons and neuronal synapses. Here we report that human nectin-2 is a target receptor for B virus entry, in addition to the reported receptor human nectin-1. Similar to a B virus lab strain, B virus clinical strains can effectively use both nectin-1 and nectin-2 as cellular receptors for entry into human cells, but unlike HSV-1 and HSV-2, none of the clinical strains uses an HVEM-mediated entry pathway. Ultimately, these differences between B virus and HSV-1 and -2 may provide insight into the neuropathogenicity of B virus during zoonotic infections.
authors: Viral Immunology Center, Department of Biology, Georgia State University, Atlanta, Georgia, USA.
authors: Irina
authors: I
authors: Patrusheva
authors: Viral Immunology Center, Department of Biology, Georgia State University, Atlanta, Georgia, USA.
authors: Ludmila
authors: L
authors: Perelygina
authors: Viral Immunology Center, Department of Biology, Georgia State University, Atlanta, Georgia, USA Department of Computer Science, Moscow State University, Moscow, Russia.
authors: Ivan
authors: I
authors: Torshin
authors: Viral Immunology Center, Department of Biology, Georgia State University, Atlanta, Georgia, USA.
authors: Julia
authors: J
authors: LeCher
authors: Viral Immunology Center, Department of Biology, Georgia State University, Atlanta, Georgia, USA jhilliard@gsu.edu.
authors: Julia
authors: J
authors: Hilliard
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002522:Chlorocebus aethiops; D014644:Genetic Variation / Q000235:genetics*; D006566:Herpesviridae Infections / Q000378:metabolism / Q000821:virology*; D006568:Herpesvirus 1, Cercopithecine / Q000235:genetics* / Q000378:metabolism; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000378:metabolism; D018258:Herpesvirus 2, Human / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D000075983:Nectins; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000235:genetics / Q000378:metabolism; D011991:Receptors, Virus / Q000378:metabolism; D014709:Vero Cells; D014759:Viral Envelope Proteins / Q000235:genetics* / Q000378:metabolism; D053586:Virus Internalization
chemical_list: D015815:Cell Adhesion Molecules; C000619010:NECTIN1 protein, human; C000619015:Nectin1 protein, mouse; D000075983:Nectins; D053240:Receptors, Tumor Necrosis Factor, Member 14; D011991:Receptors, Virus; D014759:Viral Envelope Proteins; C039447:glycoprotein D, Human herpesvirus 1