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HIV Antigens Identified Can Jump-Start Broad Antibodies

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By Anette Breindl
Science Editor

Teams led by scientists from the Scripps Research Institute and the Seattle Biomedical Research Institute reported last week that they have engineered and identified, respectively, parts of HIV that can strongly stimulate naïve B cells to produce the sorts of antibodies that can ultimately become broadly effective against HIV – a step toward the development of an HIV vaccine that has long eluded researchers.

They published their findings in the March 28, 2013, advance online issue of Science and in the March 25, 2013, online issue of the Journal of Experimental Medicine, respectively.

HIV mutates at a rapid rate, and that is part of what has made it so hard to develop a vaccine against the virus. To be of any practical use at all, an antibody to HIV needs to be broadly neutralizing – that is, it needs to be able to bind to many different strains of HIV, as a single patient effectively ends up harboring dozens to hundreds of viral variant over the course of an infection.

Roughly 20 percent of all patients do ultimately produce such broadly neutralizing antibodies, and researchers have now identified a number of such broadly neutralizing antibodies. (See BioWorld Today, Sept. 9, 2009, and July 9, 2010.)

But getting the immune system to produce such antibodies in response to a vaccine has been a different matter altogether.

The reason is that HIV is not the only part of the system that evolves over time. Antibodies, too, change over time, in a process named affinity maturation.

Naïve or germline B cells that have not yet honed in on one particular antigen start out with receptors that are made up of several different chains. An impressive amount of variability already is programmed into those chains, in the form of different gene segments that can be rearranged to make many different binding sites.

Still, to bind strongly enough – and to avoid antigens that lead to autoimmune reactions – germline B cells need to undergo a process called affinity maturation, in which they evolve to ever-better binding of their targets.

In the case of HIV, such affinity maturation turns out to be a longer process than for many other viruses. Even patients who ultimately produce broadly neutralizing antibodies usually do not do so until they have been infected for several years.

And the antigens that ultimately elicit broadly stimulating antibodies are not particularly good at stimulating germline antibodies, meaning that in most cases, the process that could ultimately lead to a broadly neutralizing antibody never gets its start.

One question has been why most infected individuals never make antibodies at all – and in particular, whether there is something unusual about the antigens that stimulate them, or the immune systems of patients that make them.

The new work suggested that it is the antigens that are rare.

"It's the particular envelope that does the trick," Leonidas Stamatatos, of the Seattle Biomedical Research Institute, told BioWorld Today. Stamatatos is senior author of one of the papers published last week, and a co-author on the other.

In the first paper, which was published in the Journal of Experimental Medicine, Stamatatos and his colleagues took a naturally occurring form of HIV's envelope protein and altered it by removing sites where it is normally modified by the addition of a sugar group.

The altered version of the envelope protein was able to stimulate the germline precursors of broadly neutralizing antibodies.

In the second paper, which appeared in the March 28, 2013, advance online issue of Science, researchers used a bioinformatics approach to predict which antigens could stimulate germline precursors of broadly neutralizing antibodies and then engineered the predicted antigens. A nanoparticle covered in those antigens was able to activate both germline B cells and mature broadly neutralizing B cells in cell culture.

Collectively, Stamatatos said, the work reported in the papers creates antigens that could be used as a basis for vaccine design.

"We plan to test them experimentally," he said, first in animals, and then, if the results are encouraging, in humans. He estimated that such clinical trials are five years away at least. But the work has shown that in principle, it is possible to find, or make, antigens that start with a naïve B cell and end with a broadly neutralizing antibody.

Editor's note: See Thursday's issue of BioWorld Today for more news on recent advances in HIV vaccine research.