Targeting Sindbis virus-based vectors to Fc receptor-positive cell types

• Published in: Virology (New York, N.Y.) N.Y.), 2005-07, Vol.338 (1), p.9-21
• Main Authors: Klimstra, William B., Williams, Jacqueline C., Ryman, Kate D., Heidner, Hans W.
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; ADE; Alphavirus; Amino Acid Sequence; ANIMAL CELLS; Animals; ANTIBODIES; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; BALB 3T3 Cells; Binding Sites - genetics; Cell Line; Cricetinae; Fc receptor; Genetic Vectors; GLYCOPROTEINS; Humans; IMMUNE SERUMS; Immunoglobulin kappa-Chains - metabolism; Immunoglobulin Variable Region - metabolism; IMMUNOGLOBULINS; In Vitro Techniques; Mice; Molecular Sequence Data; PHENOTYPE; Protein L; RECEPTORS; Receptors, Fc - metabolism; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Sindbis; Sindbis Virus - genetics; Sindbis Virus - pathogenicity; Targeting; Vaccines, Synthetic - genetics; Vector; Viral Envelope Proteins - genetics; Viral Envelope Proteins - metabolism; VIRUSES
• ISSN: 0042-6822; 1096-0341
• DOI: 10.1016/j.virol.2005.04.039

Some viruses display enhanced infection for Fc receptor (FcR)-positive cell types when complexed with virus-specific immunoglobulin (Ig). This process has been termed antibody-dependent enhancement of viral infection (ADE). We reasoned that the mechanism of ADE could be exploited and adapted to target alphavirus-based vectors to FcR-positive cell types. Towards this goal, recombinant Sindbis viruses were constructed that express 1 to 4 immunoglobulin-binding domains of protein L (PpL) as N-terminal extensions of the E2 glycoprotein. PpL is a bacterial protein that binds the variable region of antibody kappa light chains from a range of mammalian species. The recombinant viruses incorporated PpL/E2 fusion proteins into the virion structure and recapitulated the species-specific Ig-binding phenotypes of native PpL. Virions reacted with non-immune serum or purified IgG displayed enhanced binding and ADE for several species-matched FcR-positive murine and human cell lines. ADE required virus expression of a functional PpL Ig-binding domain, and appeared to be FcγR-mediated. Specifically, ADE did not occur with FcγR-negative cells, did not require active complement proteins, and did not occur on FcγR-positive murine cell lines when virions were bound by murine IgG-derived F(ab′) 2 fragments.