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). Image: Ron Diskin/Caltech |
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 stronger version they believe is a
better candidate for clinical applications.
Current advances in isolating antibodies from
HIV-infected individuals have allowed for the discovery of a large number of
new, broadly neutralizing anti-HIV antibodies directed against the host
receptor (CD4) binding site—a functional site on the surface of the virus 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—so that it can target the binding site in a different and
more powerful way. A study outlining their process was published in Science Express.
“NIH45-46 was already one of the most broad and
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 of the currently available,
broadly neutralizing anti-HIV antibodies.”
By conducting structural studies, the researchers were
able to identify how NIH45-46 interacted with gp120—a protein on the surface of
the virus that’s required for the successful entry of HIV into cells—to neutralize
the virus. Using this information, they were able to create a new antibody
(dubbed NIH45-46G54W) that is better able to grab onto and interfere
with gp120. This improves the antibody’s breadth—or extent to which it
effectively targets many subtypes of HIV—and potency by an order of magnitude,
according to Ron Diskin, a postdoctoral scholar in Bjorkman’s laboratory 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 in order to elicit such antibodies,” says
Diskin. “We hope that these observations will help to 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 NIH45-46G54W and other antibodies as therapeutic agents. It’s
also plausible that understanding effective neutralization by powerful
antibodies may be useful 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.
Filed Under: Drug Discovery