Structure of a Human Astrovirus Capsid-Antibody Complex and Mechanistic Insights into Virus Neutralization.
|Title||Structure of a Human Astrovirus Capsid-Antibody Complex and Mechanistic Insights into Virus Neutralization.|
|Publication Type||Journal Article|
|Year of Publication||2017|
|Authors||Bogdanoff, Walter A., Campos Jocelyn, Perez Edmundo I., Yin Lu, Alexander David L., and DuBois Rebecca M.|
|Date Published||2017 Jan 15|
|Keywords||Amino Acid Sequence, Antibodies, Neutralizing, Antibodies, Viral, Antibody Specificity, Capsid, Capsid Proteins, Conserved Sequence, Humans, Mamastrovirus, Models, Molecular, Mutation, Neutralization Tests, Protein Binding, Protein Conformation, Protein Multimerization, Single-Chain Antibodies, Virion|
Human astroviruses (HAstVs) are a leading cause of viral diarrhea in young children, the immunocompromised, and the elderly. There are no vaccines or antiviral therapies against HAstV disease. Several lines of evidence point to the presence of protective antibodies in healthy adults as a mechanism governing protection against reinfection by HAstV. However, development of anti-HAstV therapies is hampered by the gap in knowledge of protective antibody epitopes on the HAstV capsid surface. Here, we report the structure of the HAstV capsid spike domain bound to the neutralizing monoclonal antibody PL-2. The antibody uses all six complementarity-determining regions to bind to a quaternary epitope on each side of the dimeric capsid spike. We provide evidence that the HAstV capsid spike is a receptor-binding domain and that the antibody neutralizes HAstV by blocking virus attachment to cells. We identify patches of conserved amino acids that overlap the antibody epitope and may comprise a receptor-binding site. Our studies provide a foundation for the development of therapies to prevent and treat HAstV diarrheal disease.
IMPORTANCE: Human astroviruses (HAstVs) infect nearly every person in the world during childhood and cause diarrhea, vomiting, and fever. Despite the prevalence of this virus, little is known about how antibodies in healthy adults protect them against reinfection. Here, we determined the crystal structure of a complex of the HAstV capsid protein and a virus-neutralizing antibody. We show that the antibody binds to the outermost spike domain of the capsid, and we provide evidence that the antibody blocks virus attachment to human cells. Importantly, our findings suggest that a subunit-based vaccine focusing the immune system on the HAstV capsid spike domain could be effective in protecting children against HAstV disease.
|Alternate Journal||J. Virol.|
|PubMed Central ID||PMC5215351|
|Grant List||K22 AI095369 / AI / NIAID NIH HHS / United States |
R25 GM058903 / GM / NIGMS NIH HHS / United States
T32 GM008646 / GM / NIGMS NIH HHS / United States