Viral Vectors

The complement system plays a dual role in viral infections and in therapeutic utilization of viral vectors. The complement as part of the innate immunity of the antiviral immune response limits infection by preventing attachment of viruses to viral receptors. Opsonization by C3b and or C4b proteolytic fragments may induce aggregation, lysis and clearance by phagocytic cells (Blue CE, Spiller OB 2004 Virology). This could inhibit therapeutic efficacy of viral vectors (Zaiss AK, Cotter MJ 2008 J Virol; Hotte SJ, Lorence RM 2007 Clin Cancer Res) and complement depletion may facilitate infection of tumor cells targeted by therapeutic viral vectors (Ikeda K, Wakimoto H 2000 J Virol). Virion N-glycans may serve as complement binding sites (Fraser IP, Koziel H 1998 Semin Immunol; Hubbard SC 1988 JBC; Ji X, Olinger GG 2005 J Gen Virol). Therefore, modulation of complement binding by modification of virion N-Glycan structures may be used to regulate elimination of virions by the complement system (Morizono K, Ku A 2010 J Virol). Also, incorporation of host complement regulatory proteins into virions may enhance complement evasion (Biswas M, Johnson JB 2012 J Virol).
In addition, virus induced complement activation may lead to inflammation, tissue injury (Zhang Z, Li Y 2010 Virol J) and / or acute respiratory distress (Hartman ZC, Appledorn DM 2008 Virol). Engineering viruses to reduce complement activation or application of complement inhibitors (Ricklin D, Lambris JD 2013 J Immunol) can therefore limit undesired side effects of viral therapy.

References

Biswas M, Johnson JB, Kumar SR, Parks GD, Elankumarana S Incorporation of host complement regulatory proteins into Newcastle disease virus enhances complement evasion. J Virol. 2012;86(23):12708-16

Blue CE, Spiller OB, Blackbourn DJ The relevance of complement to virus biology. Virology. 2004;319(2):176-84.

Fraser IP, Koziel H, Ezekowitz RA The serum mannose-binding protein and the macrophage mannose receptor are pattern recognition molecules that link innate and adaptive immunity. Semin Immunol. 1998;10(5):363-72

Hartman ZC, Appledorn DM, Serra D, Glass O, Mendelson TB, Clay TM, Amalfitano A Replication-attenuated Human Adenoviral Type 4 vectors elicit capsid dependent enhanced innate immune responses that are partially dependent upon interactions with the complement system. Virology. 2008;374(2):453-67

Hotte SJ, Lorence RM, Hirte HW, Polawski SR, Bamat MK, O’Neil JD, Roberts MS, Groene WS, Major PP An optimized clinical regimen for the oncolytic virus PV701. Clin Cancer Res. 2007;13(3):977-85.

Hubbard SC Regulation of glycosylation. The influence of protein structure on N-linked oligosaccharide processing. J Biol Chem. 1988;263(36):19303-17.

Ikeda K, Wakimoto H, Ichikawa T, Jhung S, Hochberg FH, Louis DN, Chiocca EA  Complement depletion facilitates the infection of multiple brain tumors by an intravascular, replication-conditional herpes simplex virus mutant. J Virol. 2000;74(10):4765-75.

Ji X, Olinger GG, Aris S, Chen Y, Gewurz H, Spear GT Mannose-binding lectin binds to Ebola and Marburg envelope glycoproteins, resulting in blocking of virus interaction with DC-SIGN and complement-mediated virus neutralization. J Gen Virol. 2005;86(Pt 9):2535-42.

Morizono K, Ku A, Xie Y, Harui A, Kung SK, Roth MD, Lee B, Chen IS Redirecting lentiviral vectors pseudotyped with Sindbis virus-derived envelope proteins to DC-SIGN by modification of N-linked glycans of envelope proteins. J Virol. 2010;84(14):6923-3

Ricklin D, Lambris JD Complement in immune and inflammatory disorders: pathophysiological mechanisms. J Immunol. 2013;190(8):3831-8.

Zaiss AK, Cotter MJ, White LR, Clark SA, Wong NC, Holers VM, Bartlett JS, Muruve DA Complement is an essential component of the immune response to adeno-associated virus vectors. J Virol. 2008;82(6):2727-40

Zhang Z, Li Y, Xu S, Chen F, Zhang L, Jiang B, Chen X Fusion to chicken C3d enhances the immunogenicity of the M2 protein of avian influenza virus. Virol J. 2010;7:89