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. IMPORTANCEOncolytic 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.

Recent advances in vesicular stomatitis virus-based oncolytic virotherapy: a 5-year update

“…The parental VSV and VSV encoding Maraba G (instead of VSV-G) have nearly identical host range properties and replication kinetics. However, in contrast to the parental VSV, the VSV encoding Maraba G was resistant to non-immune human serum [112].…”

Characterisation of Antibody Interactions with the G Protein of Vesicular Stomatitis Virus Indiana Strain and Other Vesiculovirus G Proteins

“…However, VSVind.G is cytotoxic to cells; thus, it is difficult to express it constitutively (36, 37). Moreover, VSVind.G pseudotyped LVs can be inactivated by human serum complement which limits their potential in vivo use (38-42). Therefore, there is a clear need for alternative envelopes to pseudotype LVs.…”

Pseudotyping of lentiviral vector with novel vesiculovirus envelope glycoproteins derived from Chandipura and Piry viruses

“…CNV-G pseudotype showed some level of inactivation by human sera, but still had much higher titer than VSV-G pseudotype. A recent study determined that VSV-G neutralization or inactivation by human sera is mediated by concerted actions of natural IgM and complement and that a related vesiculovirus, Maraba virus, G protein is relatively resistant to this phenomenon [36]. The marked resistance shown here by PRV-G and CNV-G to human serum exposure might be similar to that of Maraba virus G protein and thus confers an advantage over VSV-G pseudotyped vectors for their future use in in vivo applications.…”