Efficient neutralization and disruption of rhinovirus by chimeric ICAM-1/immunoglobulin molecules.
The intercellular adhesion molecule 1 (ICAM-1) is used as a cellular receptor by 90% of human rhinoviruses (HRVs). Chimeric immunoadhesin molecules containing extracellular domains of ICAM-1 and constant regions of immunoglobulins (Igs) were designed in order to determine the effect of increased valency, Ig isotype, and number of ICAM-1 domains on neutralization and disruption of rhinovirus structure. These immunoadhesins include ICAM-1 amino-terminal domains 1 and 2 fused to the hinge and constant domains of the heavy chains of IgA1, IgM, and IgG1 (IC1-2D/IgA, -/IgM, and -/IgG). In addition, all five extracellular domains were fused to IgA1 (IC1-5D/IgA). Immunoadhesins were compared with soluble forms of ICAM-1 containing five and two domains (sICAM-1 and ICI-2D, respectively) in assays of HRV binding, infectivity, and conformation. In prevention of HRV plaque formation, IC1-5D/IgA was 200 times and IC1-2D/IgM and IC1-2D/IgA were 25 and 10 times more effective, respectively, than ICAM-1. The same chimeras were highly effective in inhibiting binding of rhinovirus to cells and disrupting the conformation of the virus capsid, as demonstrated by generation of approximately 65S particles. The results show that the number of ICAM-1 domains and a flexible Ig hinge are important factors contributing to the efficacy of neutralization. The higher efficiency of chimeras that bound bivalently in disrupting HRV was attributed to higher binding avidity. The IC1-5D/IgA immunoadhesin was effective at nanomolar concentrations, making it feasible therapy for rhinovirus infection.
Martin
S
S
Center for Blood Research, Boston, Massachusetts.
Casasnovas
J M
JM
Staunton
D E
DE
Springer
T A
TA
D001402:B-Lymphocytes / Q000502:physiology; D001483:Base Sequence; D001667:Binding, Competitive; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D007127:Immunoglobulin Constant Regions / Q000235:genetics / Q000502:physiology; D007074:Immunoglobulin G / Q000235:genetics / Q000502:physiology*; D018799:Intercellular Adhesion Molecule-1; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D011991:Receptors, Virus / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012229:Rhinovirus / Q000502:physiology*; D010948:Viral Plaque Assay; D014779:Virus Replication
D015815:Cell Adhesion Molecules; D007127:Immunoglobulin Constant Regions; D007074:Immunoglobulin G; D016169:Lymphocyte Function-Associated Antigen-1; D011991:Receptors, Virus; D011993:Recombinant Fusion Proteins; D018799:Intercellular Adhesion Molecule-1