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Antibodies with a "Special Shape" have been discovered, which may lead to new vaccine strategies for HIV and COVID.

The Duke Human Vaccine Institute (DHVI) has discovered a new form of anti-glycan antibody (Ab) that binds to a patch of HIV's outer shell's chain-like sugars, effectively neutralizing the virus. The newly discovered antibodies, which the researchers discovered in both macaques and humans, could contribute to the development of a novel vaccine strategy for SARS-CoV-2 and fungal pathogens.

Barton Haynes, MD, director of the Duke Human Vaccine Institute, said, "This represents a new type of host protection" (DHVI). “These new antibodies have a unique shape and may be successful against a wide range of pathogens,” says the researcher. It's a lot of fun.”

The paper publish in cell under titled “Fab-dimerized glycan-reactive antibodies are a structural category of natural antibodies.”

Surface glycans are expressed by many pathogens, including HIV Envelope (Env), the SARS-CoV-2 spike protein, and yeast, according to the writers. Glycans make up more than half of the outer layer of HIV. Finding a way to unleash anti-glycan antibodies to break down these sugar structures and activate immune B-cell lymphocytes to create antibodies that would then neutralize HIV has long been an appealing strategy, according to Haynes. However, he added, "Of course, it's not that easy."

Since HIV is cloaked in sugars that resemble the host's glycans, the virus appears to be a part of the host rather than a deadly pathogen. “... glycans found on HIV-1 and other pathogens are also present on host molecules, indicating that immune tolerance mechanisms can regulate the induction of Abs targeting pathogen glycans,” they wrote. Haynes and colleagues, including first author Wilton Williams, PhD, director of the Viral Genetics Analysis Core at DHVI, and co-author Priyamvada Acharya, PhD, director of the Division of Structural Biology at DHVI, discovered the new form of anti-glycan antibody through a series of studies examining whether an immune response to the glycans that cover the outer surface of HIV could be elicited.

The newly discovered anti-glycan antibodies, known as Fab-dimerized glycan-reactive (FDG) antibodies by the Duke team, had previously gone unnoticed as a possible HIV treatment choice. There had only been one previous observation of a related anti-glycan HIV antibody with an unusual structure, 2G12, which was discovered 24 years ago. The team explained that 2G12 is a broadly neutralizing antibody (bnAb) that targets a conserved glycan patch on Env of geographically diverse HIV-1 strains. “To date, the Ab 2G12 has become the only HIV-1 bnAb that interacts exclusively with Env glycans.”

The Duke team has now isolated multiple FDG antibodies and discovered that they have a unique structure that resembles 2G12. This structure allows the antibody to bind tightly to a dense patch of sugars on HIV, but not to other cellular surfaces covered in glycans from the host. The fact that FDG Abs can bind multiple glycan clusters and use multiple BCRs [B cell receptors], as well as the fact that FDG precursors are well represented in the human B cell repertoire, makes this new group of glycan-reactive B cells an appealing target for induction by HIV-1 vaccines, according to the researchers.

“These antibodies' structural and functional properties can be used to design vaccines that target this glycan patch on HIV, eliciting a B-cell response that neutralizes the virus,” Williams said. “These antibodies are far more common in blood cells than other neutralizing antibodies that target particular regions of the outer layer of the HIV virus... This is an exciting discovery because it solves one of the most difficult problems for other forms of widely neutralizing antibodies.”

The FDG antibodies, according to Williams, bind to the pathogenic yeast Candida albicans as well as viruses such as SARS-CoV-2. The researchers discovered a new class of glycan-reactive Abs that target a variety of pathogens, including HIV-1, SARS-CoV-2, and yeast. Additional research will look at how to harness the antibody to use it against these pathogens.

Other researchers have confirmed that the FDG antibody 2G12 can also neutralize influenza strains after the team submitted their work for publication, “... further demonstrating the breadth of cross-binding activity of the 2G12 FDG Ab for glycosylated virus pathogens,” Williams et al. concluded.

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