Researchers Examine Strategy for Inducing Effective Immune Response to HIV

It may be possible to "reverse engineer" molecules that activate precursors of effective, neutralizing antibodies against the HIV virus.

The authors of “Rational HIV Immunogen Design to Target Specific Germline B Cell Receptors,” an abstract presented at the American Crystallographic Association Meeting, wrote that potent VRC01-class broadly neutralizing antibodies (bNAbs) against the CD4 binding site of HIV gp120 “have been isolated from HIV-1-infected individuals; however, such bNAbs have not been induced by vaccination.”

This is in part because “wild-type gp120 proteins lack detectable affinity for predicted germline precursors of VRC01-class bNAbs, making them poor immunogens to prime a VRC01-class response.”

Because vaccine development to induce bNAbs) against HIV-1 is “global health priority,” the authors used “computation-guided, in vitro screening to engineer a germline-targeting HIV gp120 outer domain immunogen (eOD-GT6) that binds to multiple VRC01-class bNAbs and germline precursors.”

They reported that “key engineered features that conferred eOD-GT6 germline reactivity were revealed in two crystal structures, one involving the immunogen in complex with a predicted VRC01 germline precursor, and the other consisting of the unliganded immunogen.”

When multimerized on nanoparticles, eOD-GT6 “activates germline and mature VRC01-class B cells. Thus, eOD-GT6 nanoparticles have promise as a vaccine prime. In principle, germline-targeting strategies could be applied to other epitopes and pathogens.”

A news release announcing these results said the authors had “developed a strategy for inducing a key part of an effective immune response to HIV. By tracing the evolution of HIV-recognizing molecules called antibodies taken from the blood of rare individuals whose immune systems are naturally able to target and neutralize the virus, they may have found a way to replicate this for everybody.”

Lead author Jean-Philippe Julien, Senior Post-Doctoral Research Associate at The Scripps Research Institute, said the research team tried to learn “how those… antibodies developed over the course of natural infection” and attempted to “guide the immune response in the direction of what we know works in certain HIV-infected individuals.”

Referring to these results as “a step in the right direction,” the release noted that researchers are currently testing the candidate molecule in animals “to see if it is able to kick start the desired immune response.” Julien noted that “further studies will examine whether it can protect animals against infection, and human trials for safety and vaccine efficacy would be next — though it may be years before those results are known.”