Building Better HIV Antibodies
Caltech 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). [Credit: Ron Diskin/Caltech]](/images/2042-CT_Bjorkman_SPOTLIGHT_medium.jpg "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). [Credit: Ron Diskin/Caltech]") October 27, 2011 - PASADENA, Calif. - 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 the October 27 issue of 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 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 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.
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, and Michel Nussenweig from Rockefeller University, and Michael Seaman from Beth Israel Deaconess
Medical Center in Boston also contributed to the paper. The research was funded by the Bill & Melinda Gates Foundation, the
National Institutes of Health, the Gordon and Betty Moore Foundation, and the German Research Foundation.
Written by Katie Neith
Contact:
Deborah Williams-Hedges
debwms@caltech.edu
626-395-3227
California Institute of Technology
Source: Caltech
Caltech Media Relations prmedia@caltech.edu
1200 E. California Blvd, MC 0-71, Pasadena, CA 91125
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