Building Better HIV Antibodies: Biologists Create Neutralizing Antibody That Shows Increased Potency

The increased potency of a new HIV antibody (green and blue) is explained by an insertion (pink) that contacts the inner domain of the HIV gp120 spike protein (yellow). 

Science Daily  — Using highly potent antibodies isolated from HIV-positive people, researchers have recently begun to identify ways to broadly neutralize the many possible subtypes of HIV. Now, a team led by biologists at the California Institute of Technology (Caltech) has built upon one of these naturally occurring antibodies to create a more potent version they believe is a better candidate for clinical applications.

"NIH45-46 was already one of the broadest and most potent of the known anti-HIV antibodies," says Pamela Bjorkman, Max Delbrück Professor of Biology at Caltech and senior author on the study. "Our new antibody is now arguably the best currently available, broadly neutralizing anti-HIV antibodies."

Current advances in isolating antibodies from HIV-infected individuals have allowed for the discovery of many new, broadly neutralizing anti-HIV antibodies directed against the host receptor (CD4) binding site -- a functional site on the virus's surface that allows for cell entry and infection. Using a technique known as structure-based rational design, the team modified one already-known and particularly potent antibody -- NIH45-46 -- to target the binding site differently and more powerfully. A study outlining their process was published in the Oct. 27 issue of Science Express.

By conducting structural studies, the researchers could identify how NIH45-46 interacted with gp120 -- a protein on the surface of the virus required for the triumphant entry of HIV into cells -- to neutralize the virus. Using this information, they created a new antibody (dubbed NIH45-46^G54W) that is better able to grab onto and interfere with gp120. This improves the antibody's breadth -- or the extent to which it effectively targets many subtypes of HIV -- and potency by order of magnitude, according to Ron Diskin, a postdoctoral scholar in Bjorkman's lab at Caltech and the paper's lead author.

"Not only did we design an improved version of NIH45-46, our structural data are calling into question previous assumptions about how to make a vaccine to elicit such antibodies," says Diskin. "We hope these observations will help guide and improve future immunogen design."

By improving the efficacy of antibodies that can neutralize HIV, the researchers point to the possibility of clinical testing for NIH45-46^G54W and other antibodies as therapeutic agents. Understanding effective neutralization by potent antibodies may be helpful in vaccine development.

"The results uncover the structural underpinnings of anti-HIV antibody breadth and potency, offer a new view of neutralization by CD4-binding site anti-HIV antibodies, and establish principles that may enable the creation of a new group of HIV therapeutics," says Bjorkman, who is also a Howard Hughes Medical Institute investigator.

Other Caltech authors on the study, "Increasing the Potency and Breadth of an HIV Antibody by Using Structure-Based Rational Design," include Paola M. Marcovecchio, Anthony P. West, Jr., Han Gao, and Priyanthi N.P. Gnanapragasm. Johannes Scheid, Florian Klein, Alexander Abadir, Michel Nussenweig from Rockefeller University, and Michael Seaman from Beth Israel Deaconess Medical Center in Boston also contributed to the paper. The Bill & Melinda Gates Foundation, the National Institutes of Health, the Gordon and Betty Moore Foundation, and the German Research Foundation funded the research.