Incorporation of Host Complement Regulatory Proteins into Newcastle Disease Virus Enhances Complement Evasion

Abstract

bNewcastle disease virus (NDV), an avian paramyxovirus, is inherently tumor selective and is currently being considered as a clinical oncolytic virus and vaccine vector. In this study, we analyzed the effect of complement on the neutralization of NDV purified from embryonated chicken eggs, a common source for virus production. Fresh normal human serum (NHS) neutralized NDV by multiple pathways of complement activation, independent of neutralizing antibodies. Neutralization was associated with C3 deposition and the activation of C2, C3, C4, and C5 components. Interestingly, NDV grown in mammalian cell lines was resistant to complement neutralization by NHS. To confirm whether the incorporation of regulators of complement activity (RCA) into the viral envelope afforded complement resistance, we grew NDV in CHO cells stably transfected with CD46 or HeLa cells, which strongly express CD46 and CD55. NDV grown in RCA-expressing cells was resistant to complement by incorporating CD46 and CD55 on virions. Mammalian CD46 and CD55 molecules on virions exhibited homologous restriction, since chicken sera devoid of neutralizing antibodies to NDV were able to effectively neutralize these virions. The incorporation of chicken RCA into NDV produced in embryonated eggs similarly provided species specificity toward chicken sera.

Prostate-Specific Antigen-Retargeted Recombinant Newcastle Disease Virus for Prostate Cancer Virotherapy

“…However, our recent studies indicate that embryo-passaged NDV, but not human cellgrown NDV, was severely restricted by human complement (50). Human cell-grown NDV was protected against complement-mediated neutralization by the incorporation of host complementregulatory proteins CD46 and CD55 on the viral envelope (50). Therefore, chicken embryos may not be suitable for clinical-grade virus production for human clinical trails.…”

“…The inability of the PSA-cleavable mutant NDV to replicate in chicken embryos could be construed as a setback for virus stock production. However, our recent studies indicate that embryo-passaged NDV, but not human cellgrown NDV, was severely restricted by human complement (50). Human cell-grown NDV was protected against complement-mediated neutralization by the incorporation of host complementregulatory proteins CD46 and CD55 on the viral envelope (50).…”

“…Cytotoxicity induced by rNDV was assessed by trypan blue staining of virus-infected CaP cells and spheres. The EC 50 ranged from an MOI of 0.01 for AR ϩ cells/spheres (treated with R1881) to an MOI of 0.1 for AR Ϫ cells/spheres (supplemented with exogenous PSA) at 120 h postinfection (Fig. 5A and B).…”

Hepatitis B virus inhibits the expression of complement C3 and C4, in�vitro and in�vivo

“…As part of the body's innate immune system, these components are involved in regulating the body's immunity against invasion from foreign pathogens (8). However, viruses have developed a number of strategies to evade attack by the complement components (9); for example, certain types of viruses can incorporate the regulatory proteins for host complement into their viral envelope and regulate the expression of these proteins in infected cells (10)(11)(12).…”

“…As part of the body's innate immune system, these components are involved in regulating the body's immunity against invasion from foreign pathogens (8). However, viruses have developed a number of strategies to evade attack by the complement components (9); for example, certain types of viruses can incorporate the regulatory proteins for host complement into their viral envelope and regulate the expression of these proteins in infected cells (10)(11)(12).In the present study, the serological levels of C3 and C4 were compared between healthy controls and patients with chronic hepatitis B (CHB), and the molecular mechanisms at the cellular level were explored, which is expected to lay the foundation for understanding the pathogenesis of HBV. …”