When the Epstein-Barr virus (EBV) infects cells, typically B cells, it relies on a protein called gp42. One part of the protein is involved in receptor binding, and another part is involved in membrane fusion. But now, both parts are revealed to be targetable by monoclonal antibodies (mAbs). This new development, which is due to research from the National Institute of Allergy and Infectious Diseases (NIAID), could lead to the development of therapeutics and vaccines.

Details of the research recently appeared in the journal Immunity, in an article titled, “Epstein-Barr virus gp42 antibodies reveal sites of vulnerability for receptor binding and fusion to B cells.”

“We isolated gp42-specific mAbs, A10 and 4C12, which use distinct mechanisms to neutralize virus infection,” the article’s authors reported. “mAb A10 was more potent than the only known neutralizing gp42 mAb, F-2-1, in neutralizing EBV infection and blocking binding to HLA class II. mAb 4C12 was similar to mAb A10 in inhibiting glycoprotein-mediated B cell fusion but did not block receptor binding, and it was less effective in neutralizing infection.”

These findings have broad importance because EBV, which causes infectious mononucleosis and is associated with B cell lymphomas, is so prevalent. Approximately 95% of the world’s population is infected with EBV, which remains in the body permanently, not just in B cells, but also in cells lining the throat and pharynx. Besides sometimes leading to B-cell cancers, including Burkitt, Hodgkin, and non-Hodgkin lymphomas, EBV has been implicated in gastric and nasopharyngeal cancers. Also, EBV infection was recently shown to significantly raise the risk of developing multiple sclerosis.

The high prevalence of EBV infections and the potential for dire outcomes are especially concerning because no vaccine or any specific treatment exists to counter EBV.

In the current study, NIAID scientists, led by senior investigator Jeffrey I. Cohen, MD, examined gp42 for vulnerabilities. Theoretically, a vaccine or antibody-based treatment capable of blocking gp42’s ability to bind to or fuse with B cells would prevent EBV infection and, thus, the virus’s ability to persist in those cells.

Besides generating two gp42-specific mAbs, the aforementioned A10 and 4C12, the scientist used X-ray crystallography to visualize how they interacted with gp42. The crystal structures revealed that the two mAbs interacted with distinct, non-overlapping sites on gp42. Monoclonal antibody A10 blocked the site on gp42 required for receptor binding, while 4C12 interfered with a different site that is involved in membrane fusion.

Next, the scientists tested A10, 4C12, and several other mAbs in mice for their ability to prevent EBV infection and EBV lymphomas. The mAb A10 provided nearly complete protection against EBV infection and none of the mice developed lymphoproliferative disease or lymphoma. In contrast, nearly all the mice treated with other mAbs became infected and some developed lymphoproliferative disease or lymphoma.

If future studies show mAb A10 to be safe and effective in humans, it could have clinical applications, particularly in people who have not been infected with EBV; those with immunodeficiency conditions, including severe combined immunodeficiency; or people receiving transplants. People with such conditions are at risk of developing severe or fatal cases of EBV disease during their initial encounter with the virus. The investigational monoclonal antibody could potentially be used prophylactically to prevent or better control EBV infections in such cases, the investigators noted.

Additionally, the study team suggested that identification of the vulnerable sites on gp42 also paves the way to designing future vaccines that could elicit antibodies against one or both of the newly described sites.

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