December 7, 2009

Insights into How HIV Evades Immune System

Illustration of round virus with blunt spikes Artist’s illustration of HIV.

New details about how antibodies bind the human immunodeficiency virus (HIV) may help bring researchers closer to creating an effective HIV vaccine.

Vaccines typically work by triggering the immune system to produce antibodies that help to beat infections. But most antibodies can't latch onto and neutralize HIV. The proteins on the surface of the virus mutate rapidly and change shape continuously. They're also covered with immune-evading carbohydrates called glycans.

NIH scientists recently focused on one of these HIV surface proteins, called gp120. HIV uses what are called envelope spikes, or trimers, to bind and infect cells. These spikes support three gp120 molecules, which HIV uses to grip and to gain entry into the cells it infects.

Researchers had a major breakthrough in 2007 when they identified an unchanging region of gp120 as a potential site of viral weakness. Further studies, however, found that the vast majority of antibodies that bound to this site don't block HIV from infecting cells. Dr. Peter D. Kwong at the Vaccine Research Center of NIH's National Institute of Allergy and Infectious Diseases (NIAID) headed a research team investigating how the virus resists these antibodies.

The scientists revealed the virus's trick in the November 20, 2009, edition of Science. They determined the crystal structures of two poorly neutralizing human antibodies in complex with gp120. These antibodies bind to gp120, they found, with a key portion of the protein swung in or flared out. When swung in or flared out, gp120 doesn’t fit into the shape required to form the functional viral spike. In contrast, when a rare neutralizing antibody called b12 binds, gp120 is in the shape required to form the functional spike.

Most antibodies to gp120 don't bind its functional form, the researchers found. That's why they can't effectively neutralize HIV. “When an antibody binds to something that's quite flexible, it induces or selects shapes that are not necessarily appropriate for function,” Kwong explains. “In the functional viral spike, gp120 assumes a very specific shape. Most antibodies can't see that particular shape.”

This study highlights the challenge of generating HIV-neutralizing antibodies. Most gp120 appears as inactive single molecules or in viral debris. Future vaccines will have to generate antibodies to target the site of vulnerability on gp120 in the envelope spike. “We now know the factors guarding the site,” Kwong says. “The next step is learning how to overcome those barriers.”

Kwong points out that people with HIV can generate antibodies to this site—in fact, that's how it was discovered in the first place. “We just haven't yet learned how to do that by vaccination,” he says, “but we're working on it.”

—by Harrison Wein, Ph.D.

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