title: Vesiculovirus neutralization by natural IgM and complement.
abstract: Because of its very low human seroprevalence, vesicular stomatitis virus (VSV) has promise as a systemic oncolytic agent for human cancer therapy. However, as demonstrated in this report, the VSV infectious titer drops by 4 log units during the first hour of exposure to nonimmune human serum. This neutralization occurs relatively slowly and is mediated by the concerted actions of natural IgM and complement. Maraba virus, whose G protein is about 80% homologous to that of VSV, is relatively resistant to the neutralizing activity of nonimmune human serum. We therefore constructed and rescued a recombinant VSV whose G gene was replaced by the corresponding gene from Maraba virus. Comparison of the parental VSV and VSV with Maraba G substituted revealed nearly identical host range properties and replication kinetics on a panel of tumor cell lines. Moreover, in contrast to the parental VSV, the VSV with Maraba G substituted was resistant to nonimmune human serum. Overall, our data suggest that VSV with Maraba G substituted should be further investigated as a candidate for human systemic oncolytic virotherapy applications.
  
  
  OBJECTIVE
  Oncolytic virotherapy is a promising approach for the treatment of disseminated cancers, but antibody neutralization of circulating oncolytic virus particles remains a formidable barrier. In this work, we developed a pseudotyped vesicular stomatitis virus (VSV) with a glycoprotein of Maraba virus, a closely related but serologically distinct member of the family Rhabdoviridae, which demonstrated greatly diminished susceptibility to both nonimmune and VSV-immune serum neutralization. VSV with Maraba G substituted or lentiviral vectors should therefore be further investigated as candidates for human systemic oncolytic virotherapy and gene therapy applications.
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Mulu Z
authors.initials: MZ
authors.lastname: Tesfay
authors.forename: Arun
authors.initials: A
authors.lastname: Ammayappan
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Federspiel
authors.forename: Glen N
authors.initials: GN
authors.lastname: Barber
authors.forename: David
authors.initials: D
authors.lastname: Stojdl
authors.forename: Kah-Whye
authors.initials: KW
authors.lastname: Peng
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Russell
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D003165:Complement System Proteins / Q000276:immunology*; D017931:DNA Primers / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology*; D009500:Neutralization Tests; D050130:Oncolytic Virotherapy / Q000379:methods; D014709:Vero Cells; D018116:Vesiculovirus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D014759:Viral Envelope Proteins / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D017931:DNA Primers; D007075:Immunoglobulin M; D014759:Viral Envelope Proteins; D049452:Green Fluorescent Proteins; D003165:Complement System Proteins