Novel discoveries offer new ways to design HIV vaccine

Thursday, September 30, 2010

LONDON - Paving a new way for designing AIDS vaccines, researchers have made novel discoveries about the immune defenses of rare HIV patients who produce antibodies that prevent infection.

Researchers at Rockefeller University and colleagues have now made two fundamental discoveries about the so-called broadly neutralizing anti-HIV antibodies, which effectively keep the virus at bay.

By detailing the molecular workings of a proven immune response, the researchers hope their work will ultimately enable them to similarly arm those who are not equipped with this exceptional immunological firepower.

“Nobody yet can make a vaccine that elicits these broadly neutralizing antibodies, but here are patients who can do it, so let’s understand how,” Nature quoted Michel C. Nussenzweig, Sherman Fairchild Professor and head of the Laboratory of Molecular Immunology, as saying.

“That’s the theme in this work. The reason the research community is not making this vaccine is not that we’re not good engineers. We are. The reason is that we don’t understand how these patients produce these antibodies, and that’s what we’re figuring out. If we know how they’re doing it, we might learn how to reproduce it,” he added.

HIV strains mutate rapidly, making them notoriously evasive targets for the immune system.

In particular, the HIV envelope spike, called gp160, is the site of a host of mutations that obstruct the few elements that all of the virus strains share.

Prior research has shown that only four super antibodies block the activity of that protein in a broad range of HIV strains, neutralizing the virus. But all attempts to coax the human body into producing those four have failed.

Last year, the Nussenzweig lab showed that a diverse group of broadly neutralizing antibodies cloned from 433 B cells of six slow progressing HIV patients were as capable of knocking down a broad range of HIV strains as any one of the super antibodies.

In the new study, the researchers found that most antibodies are traditionally thought to bind to their target, or antigen, in a bivalent fashion, meaning they get a firm grip by taking hold of two specific handles.

But HIV virions do not allow for that possibility because the gp160 spikes are too far apart.

Therefore, antibodies to the virus are handicapped because they can only use one of their two high affinity arms to recognize the viral spike.

The researchers found that on average 75 percent of the anti-gp160-HIV antibodies in their large collection were selected by the immune system for polyreactivity, a property that allowed the second “free” arm of the antibody to enhance overall affinity by binding to the virion “non-specifically.”

Generally, the immune system weeds out polyreactive antibodies, even though they are naturally produced in significant quantities, because polyreactive antibodies could in theory attack the body itself.

But the experiments suggest that these “sticky” antibodies may be an opportunistic adaptation to difficult cases such as HIV, in which homotypic bivalent bonding may not be an option.

Researchers believe that vaccine designed to elicit antibodies that mimic these properties could be a promising strategy to beat the deadly virus.

The study has been published in the latest issue of the journal Nature. (ANI)

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