title: Assessment of oncolytic HSV efficacy following increased entry-receptor expression in malignant peripheral nerve sheath tumor cell lines.
abstract: Limited expression and distribution of nectin-1, the major herpes simplex virus (HSV) type-1 entry-receptor, within tumors has been proposed as an impediment to oncolytic HSV (oHSV) therapy. To determine whether resistance to oHSVs in malignant peripheral nerve sheath tumors (MPNSTs) was explained by this hypothesis, nectin-1 expression and oHSV viral yields were assessed in a panel of MPNST cell lines using γ134.5-attenuated (Δγ134.5) oHSVs and a γ134.5 wild-type (wt) virus for comparison. Although there was a correlation between nectin-1 levels and viral yields with the wt virus (R=0.75, P =0.03), there was no correlation for Δγ134.5 viruses (G207, R7020 or C101) and a modest trend for the second-generation oHSV C134 (R=0.62, P=0.10). Nectin-1 overexpression in resistant MPNST cell lines did not improve Δγ134.5 oHSV output. While multistep replication assays showed that nectin-1 overexpression improved Δγ134.5 oHSV cell-to-cell spread, it did not confer a sensitive phenotype to resistant cells. Finally, oHSV yields were not improved with increased nectin-1 in vivo. We conclude that nectin-1 expression is not the primary obstacle of productive infection for Δγ134.5 oHSVs in MPNST cell lines. In contrast, viruses that are competent in their ability to counter the antiviral response may derive benefit with higher nectin-1 expression.
authors.affiliation: Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Jackson
authors.affiliation: Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: McMorris
authors.affiliation: Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Roth
authors.affiliation: Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Coleman
authors.affiliation: Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Whitley
authors.affiliation: 1] Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA [2] Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
authors.forename: G Y
authors.initials: GY
authors.lastname: Gillespie
authors.affiliation: 1] Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35233, USA [2] Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Carroll
authors.affiliation: 1] Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA [2] Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35233, USA [3] Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Markert
authors.affiliation: 1] Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35233, USA [2] Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Cassady
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D003412:Cricetulus; D006801:Humans; D051379:Mice; D000075983:Nectins; D018317:Nerve Sheath Neoplasms / Q000378:metabolism* / Q000821:virology; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000378:metabolism / Q000502:physiology*; D011991:Receptors, Virus / Q000378:metabolism*; D018139:Simplexvirus / Q000502:physiology*
chemical_list: D015815:Cell Adhesion Molecules; C000619010:NECTIN1 protein, human; C000619015:Nectin1 protein, mouse; D000075983:Nectins; D011991:Receptors, Virus; C049545:simplexvirus receptor