Researchers gain new insights into the potential power of broadly neutralizing antibodies
There is currently no HIV vaccine capable of eliciting protective immunity. One promising area of vaccine research has focused on broadly neutralizing antibodies (bNAbs)—specialized antibodies capable of inactivating diverse types of HIV. Of interest to researchers are a small number of people living with HIV called “elite neutralizers” who naturally develop bNAbs, providing models for vaccine development.
bNAbs obtained from such elite neutralizers are being studied for their possible use in HIV prevention, treatment, and cure interventions. While they have shown much potential—inactivating about half of all variants of HIV—there remain obstacles such as how to extend the duration of protection and how these antibodies can more effectively inactivate the virus.
The Research Question
Last year, researchers were able to protect monkeys against SIV—an HIV-like virus that causes disease similar to AIDS—through the infusion of bNAbs sourced from elite neutralizers. The study found that genetically modified bNAbs could provide long-term protection against the virus, and the modification did not affect the way they bound to the virus.
Previous studies have demonstrated which region of the virus is vulnerable to bNAbs. In this study, amfAR-funded researchers asked: How do changes in the way binding at this region occurs aid recognition and neutralization of HIV?
Researchers studied the region of HIV recognized by a bNAb obtained from an elite neutralizer. They used highly sophisticated scanning procedures such as ultra-high resolution cryo-electron microscopy—which examines the topography of proteins—to capture the molecular interactions between the antibody and the participant’s own HIV. Scientists used these stop motion animation-like scanning procedures to locate points of contact between the antibody and the virus, and to piece together specific interactions that lead to the antibody’s potent ability to neutralize HIV.
Researchers focused on interactions at the fusion peptide—a viral protein that folds back on itself to pull the bulk of the virus inside the cell. The fusion peptide is surrounded by a shield of sugar molecules that makes it largely inaccessible. Yet some antibodies have been known to penetrate the shield and neutralize the fusion peptide. The scanning techniques used by the researchers here revealed that this elite neutralizer’s bNAb could interact with the fusion peptide in an entirely new way. They also found that the fusion peptide is much more flexible than previously thought, making it amenable to targeting by this and perhaps other antibodies.
Knowledge of how the HIV fusion peptide can twist into multiple conformations, or shapes, illuminates antibody recognition strategies that can be used for HIV vaccine design.
Both Drs. Ozorowski and van Gils are funded by amfAR through the Mathilde Krim Fellowship program.
Dr. Laurence is amfAR’s senior scientific consultant.