Headway on HIV

TSRI identifies Env ‘holes’ and bnAbs as potential new approaches in targeting HIV

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LA JOLLA, Calif.—Two recent sets of studies by The Scripps Research Institute (TSRI) have shown some progress in attacking HIV-AIDS by creating a blueprint of its structures, finding places where they are weak and designing attacks that exploit those weaknesses.
In the first study, TSRI researchers have discovered that certain antibodies may target holes that exist in the shield of glycan molecules that protect the virus. Those holes have been known to scientists since the 1990s, but it was unknown whether antibodies could recognize those holes as targets.
The scientists used a stabilized version of an HIV protein called the envelope glycoprotein (Env) trimer to prompt rabbit models to create antibodies and see where on the virus those antibodies attached themselves. To their surprise, they found that antibodies produced by three of the rabbits had attacked the same hole in Env.
The researchers analyzed the genetic sequences of thousands of strains of HIV and found that 89 percent of strains appear to have a targetable hole in the Env. Their hope is that future vaccines might create antibodies that similarly attack those holes.
“Targeting a hole could help the immune system get its foot in the door,” said Gabriel Ozorowski, a TSRI senior research associate.
The study’s authors note, however, that the virus quickly mutates to fill the gaps, and that it is possible that the holes may prove a distraction and should be filled in so the immune system can focus on targeting better sites for neutralizing the virus. Still, they believe that this new understanding of glycan holes could help researchers narrow down the field of molecules needed in potential HIV vaccines.
The study, published in August in the journal Cell Reports, was co-led by TSRI professor Dennis R. Burton, who is also scientific director of the International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center and of the National Institutes of Health’s Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) at TSRI; TSRI associate professor Andrew Ward, also of CHAVI-ID; and Rogier W. Sanders of the University of Amsterdam and Cornell University.
Breaking into its fortress is only one challenge when fighting HIV; another is trying to match and overwhelm its constantly mutating structure. In a series of other studies, TSRI researchers are exploring a new vaccination strategy in which the immune system can be prompted to mimic and accelerate the natural way in which antibodies slowly evolve to become better and better at targeting the constantly mutating HIV virus.
Scientists at TSRI and Cornell had recently published in PLOS Pathogens 3D maps of a structure on HIV known as the CD4 binding site, where they believe a successful attack by antibodies could cripple most strains of HIV. They also created high-resolution maps of rare antibodies, called “broadly neutralizing antibodies” (bnAbs), that could bind to the CD4 binding site.
The researchers took the next step by studying stripped-down versions of bnAbs required to create an effective vaccine, to see just which components were essential in targeting that CD4 binding site. The researchers now had a guide to which antibody mutations are most important for making them effective against the constantly mutating HIV, and a better idea of which antibody-eliciting molecules, called immunogens, could be given in booster shots to trigger the right mutations at the right time, deliberately and gradually building up a bnAb.
“We’re figuring how to boost antibodies to the next step—how to keep walking them along the path to increased breadth and potency after we get them started with a priming shot,” said Joseph Jardine, a TSRI research associate.
Researchers from TSRI and the IAVI led three studies, two published in September in Cell and one in Science, in which this method was tested on different mouse models. In the two Cell studies, they found that immunogens could make antibodies with the right mutations to target the CD4 binding site, even when the mouse models grew more complex to simulate the human immune system.
In the third study, published in Science, researchers attempted to “prime” antibodies in a mouse model with a human-like immune system developed by Kymab Ltd., a UK-based company. They found that the more complicated immune system of this mouse model made it more difficult for a vaccine protein to find and activate the “precursor” cells that have potential to produce bnAbs against the CD4 binding site.
But, although the scientists estimated that each Kymab mouse contained only one such precursor cell on average among approximately 75 million antibody-producing cells, their vaccine-priming protein activated the appropriate antibody precursors in one-third to one-half of mice tested. Since those targeted precursor cells are more plentiful in humans, they expect to see similar results in the clinical human trial planned for next year by IAVI and partners, which is intended to further develop and test whether the reductionist vaccine strategy will work in humans. If that trial is successful, the next step will be to test their booster immunogens.
The authors hope that their findings will have a broader application. “The reductionist vaccine approach we’re undertaking will hopefully not only lead to an HIV vaccine, but also could potentially be applied to other challenging vaccine targets,” said IAVI research scientist Devin Sok, who co-authored the Science study with Jardine and also with Bryan Briney, assistant professor of immunology at TSRI, and IAVI and TSRI staff scientist Daniel Kulp.

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