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.”
HIV-1 and HIV-2 Subtypes
- To date, two major groups of HIV-1 exist, “M” and “O” (for outlier). The virus that causes the great majority of HIV-1 infections diagnosed and studied in the world are in the M group. The O group includes a small number of isolates discovered in Africa (with one case found recently in the U.S.). These are genetically quite distant from the M group, and consequently may not show up on some standard laboratory tests for HIV-1.
- HIV-2 is divided in the subtypes A and B, but further subtypes C through E have recently been characterized by DNA sequencing.
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.
- In the predominant M group of HIV-1, 8 subtypes A through H have been identified to date. Most all are found in one area or another of Africa, while in other regions of the world, certain subtypes predominate.
- In Europe, subtype B is predominant in men who have sex with men, while a variety of subtypes are found in the relatively small numbers of people infected through heterosexual contact in Europe and the countries of the former Soviet Union. Subtype B has also been noted in Indonesia, the Philippines and Taiwan.
- In India, subtype C predominates, with a small number of A and B infections. In Thailand, E predominates, while a minority of B infections occur in drug users, and this B strain has also been found in drug users in Myanmar (Burma), Malaysia and southeast China.
- In the Americas (North, South and Central), as well as in Australia, New Zealand and Japan, subtype B is most common. Subtype F occurs in Romania, and along with subtype C also is found in a small proportion of strains in Brazil.
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.