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Alternative In Vitro Methods for the Determination of Viral Capsid Structural Integrity
Published on: November 16, 2017
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Structural basis for norovirus neutralization by an HBGA blocking human IgA antibody
Sreejesh Shanker1, Rita Czakó2, Gopal Sapparapu3
1The Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030.
Summary
Human noroviruses (HuNoVs) are a major cause of gastroenteritis. Antibodies blocking histo-blood group antigen (HBGA) binding to the virus capsid offer protection, revealing insights into viral evolution and neutralization strategies.
Area of Science:
- Virology
- Immunology
- Structural Biology
Background:
- Human noroviruses (HuNoVs) cause widespread gastroenteritis, with susceptibility linked to histo-blood group antigen (HBGA) expression.
- HBGAs act as attachment factors, binding to the protruding (P) domain of the viral capsid protein, influencing strain diversity.
- Antibodies blocking HBGA binding correlate with protection, but mechanisms of blockade and genotypic influence remain unclear.
Purpose of the Study:
- To structurally characterize the interaction between a neutralizing antibody and the HuNoV P domain.
- To understand how antibodies block HBGA binding and how viral genotypic variations impact this interaction.
- To elucidate the role of antibody specificities in HuNoV evolution and neutralization.
Main Methods:
- X-ray crystallography was used to determine the structure of the GI.1 P domain in complex with a human IgA monoclonal antibody (IgA 5I2).
- Analysis of the antibody-antigen complex focused on the epitope recognized and the mechanism of HBGA binding site blockade.
- Comparative analysis of antibody recognition features, particularly the involvement of CDR light chain 1.
Main Results:
- The IgA 5I2 antibody recognizes a conformational epitope on the HuNoV P domain, engulfing the HBGA binding site without altering its structure.
- Antibody recognition predominantly involves the CDR light chain 1, an unusual feature compared to typical CDR heavy chain 3 involvement.
- The identified antigenic site provides a basis for understanding how genotypic variations enable viral immune escape.
Conclusions:
- Structural insights reveal how antibodies neutralize HuNoVs by blocking HBGA attachment.
- The unique antibody recognition mechanism highlights the diversity of antibody responses in viral neutralization.
- Understanding the interplay between HBGA specificity, antigenicity, and viral evolution is crucial for developing effective HuNoV countermeasures.
