Targeting Sindbis virus-based vectors to Fc receptor-positive cell types.
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 FcgammaR-mediated. Specifically, ADE did not occur with FcgammaR-negative cells, did not require active complement proteins, and did not occur on FcgammaR-positive murine cell lines when virions were bound by murine IgG-derived F(ab')2 fragments.
Klimstra
William B
WB
Department of Microbiology and Immunology, Center for Molecular and Tumor Virology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA.
Williams
Jacqueline C
JC
Ryman
Kate D
KD
Heidner
Hans W
HW
D000595:Amino Acid Sequence; D000818:Animals; D041702:BALB 3T3 Cells; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D006224:Cricetinae; D005822:Genetic Vectors; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000378:metabolism; D007145:Immunoglobulin kappa-Chains / Q000378:metabolism; D066298:In Vitro Techniques; D051379:Mice; D008969:Molecular Sequence Data; D011961:Receptors, Fc / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012845:Sindbis Virus / Q000235:genetics* / Q000472:pathogenicity; D014614:Vaccines, Synthetic / Q000235:genetics; D014759:Viral Envelope Proteins / Q000235:genetics / Q000378:metabolism
D001426:Bacterial Proteins; D007135:Immunoglobulin Variable Region; D007145:Immunoglobulin kappa-Chains; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; D014614:Vaccines, Synthetic; D014759:Viral Envelope Proteins; C064950:glycoprotein E2, Sindbis virus