Crystal Structure Reveals How Neutralizing Antibody Blocks Astrovirus Infection

By Gerald M. Slutzky, PhD
Posted on 08 Dec 2016

$Image: Neutralizing antibodies bind to a structure known as the astrovirus capsid spike domain, which projects from the surface of astrovirus particles. By binding to the spike domain, the antibodies block the virus\'s ability to attach to and infect human cells (Photo courtesy of Walter Bogdanoff, University of California, Santa Cruz).$

Image: Neutralizing antibodies bind to a structure known as the astrovirus capsid spike domain, which projects from the surface of astrovirus particles. By binding to the spike domain, the antibodies block the virus\'s ability to attach to and infect human cells (Photo courtesy of Walter Bogdanoff, University of California, Santa Cruz).

A team of molecular virologists used X-ray crystallography to establish how a neutralizing antibody bound to the surface of the gastroenteritis-causing astrovirus and blocked its entry into uninfected cells.

Human astroviruses (HAstVs) are a leading cause of viral diarrhea in young children, the immune compromised, 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 has been hampered by the gap in knowledge of protective antibody epitopes on the HAstV capsid surface.

To better understand how neutralizing antibodies bind to HAstV, investigators at the University of California, Santa Cruz (USA) used X-ray crystallography to examine the structure of the HAstV capsid spike domain bound to the neutralizing monoclonal antibody PL-2.

The investigators reported in the November 2, 2016, online edition of the Journal of Virology that the antibody used all six complement-determining regions to bind to a quaternary epitope on each side of the dimeric capsid spike. Furthermore, the investigators determined that the HAstV capsid spike was a receptor-binding domain and that the antibody neutralized HAstV by blocking virus attachment to cells.

These findings suggested that a subunit-based vaccine focusing the immune system on the HAstV capsid spike domain could be effective in protecting children against HAstV disease.

"We have identified a site of vulnerability on the surface of the virus that we can now target for development of a vaccine or antiviral therapy," said senior author Dr. Rebecca DuBois, assistant professor of biomolecular engineering at the University of California, Santa Cruz. "These are the first results showing how a neutralizing antibody blocks this virus. Antibody therapeutics is a rapidly growing field. Many immunotherapies are being developed to target cancer cells, and we expect to see a growing number of antibody therapies for infectious diseases over the next ten years."

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University of California, Santa Cruz