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Antibodies are primarily recognized for their role in attaching to and neutralizing various pathogens, including bacteria and viruses. However, these immune proteins have a broader function: they also trigger other parts of the immune system to combat infections. A recent study conducted by Scripps Research delves into the elements that affect how well antibodies communicate with specific immune cells.
The findings, published on April 22, 2025, in Cell Reports, reveal that a greater ratio of antibodies to viral proteins—specifically a segment of HIV—leads to improved engagement with two distinct types of immune cells. While this insight provides valuable guidance for the development of experimental HIV vaccines, it also has potential implications for a wider range of therapeutics.
Senior author Lars Hangartner, who is an associate professor of immunology at Scripps Research, notes, “Many therapeutics and vaccines leverage the immune-stimulating properties of antibodies. By comprehending the mechanisms that regulate this function, we can create enhanced versions that excel by maximizing this secondary role.”
In conducting their research, Hangartner’s team incorporated an artificial intelligence (AI) system to design modified versions of the HIV protein, expediting their work and potentially offering a model for future projects.
Antibodies, with their Y-shaped structure, attach to specific sites on a pathogen with their arms while the Fc region (the “stem”) binds to various immune cells. This includes phagocytes, which consume infected cells, and natural killer cells, which destroy them.
Earlier studies in Hangartner’s lab, along with other investigations, suggested that enhancing the interaction between antibodies and immune cells often boosts protective responses to infections, but knowledge about the determinants of how effectively the Fc region activates these cells remains limited.
Hangartner hypothesized that multiple factors might influence this interaction, such as the location of binding. Antibodies directed at the same viral protein may attach to different areas on its surface, known as epitopes. Moreover, the strength of the bond between an antibody and its epitope can vary, as can the number of antibodies clustering together.
To investigate these possibilities in their current study, Hangartner’s team highlighted the HIV Env protein, which the virus utilizes to infect human cells. However, due to the complexity of Env’s epitopes, they shifted to a simpler epitope derived from the influenza virus, better suited for their experimental needs regarding positional relocation on the viral protein.
Even with this more straightforward flu epitope, traditional techniques for attaching it to various locations on Env would have necessitated extensive trial and error, compounded by the cooperating capability of the protein.
The AI tool AlphaFold2 enabled the team to bypass these obstacles. Utilizing AlphaFold2, they engineered Env proteins with the flu epitope positioned precisely as required, subsequently selecting and refining these designs before producing the modified proteins.
The researchers assessed how the repositioning of the epitope influenced the actions of two immune cell types: natural killer cells and phagocytes. Additionally, they examined the immune cells’ responses when subjected to varying bond strengths between antibodies and the epitope. Lastly, they evaluated the immune response when one, two, or three antibodies bound to a set of three Env proteins.
Out of these factors, one emerged as significant: the ratio of antibodies to Env proteins. The immune cells displayed heightened destructive capabilities when three antibodies bound to each set of Env proteins. Phagocytes exhibited minimal activity with just one antibody; however, natural killer cells showed almost no activity unless at least two antibodies were present.
This research implies that HIV vaccines may not only stimulate antibody production against the virus but also enhance the responsiveness of additional immune cells. Vaccines designed to yield antibodies that can bind in higher ratios are most likely to capitalize on this secondary advantage.
Hangartner suggests that the influence of antibody ratios may apply to other infectious diseases as well. “I believe this principle likely holds for many other pathogens,” he remarks, though he acknowledges that only further testing can determine whether these adjustments lead to improved disease protection. “It seems probable, but it is not assured.”
The relationship between binding ratios and immune interactions remains unclear in the context of therapeutic antibodies targeting conditions like cancer or inflammatory diseases. Nonetheless, Hangartner emphasizes that a deeper understanding of these interactions can accelerate the advancement of related treatment methods.
This research was supported by funding from the National Institutes of Health (UM1Al44462 and R01 Al136621-05) and the European Molecular Biology Organization (fellowship ALTF 339-2021).
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