HIV Trick Helps Explain Failed Vaccine Attempts

Scientists have discovered a new way HIV evades the body's immune response, helping to explain why it has been so hard to develop a broadly effective AIDS vaccine. The finding adds the "final piece to the puzzle" of how HIV eludes the immune system's infection-fighting antibodies, which are produced in large numbers when the virus invades, said Dr. Peter Kwong, a vaccine researcher at the US National Institute of Allergy and Infectious Diseases and the study's lead author. The full report, "HIV-1 Evades Antibody-Mediated Neutralization Through Conformational Masking of Receptor-Binding Sites," is published in this week's issue of Nature (2002;420:623-624,678-681).

"All these antibodies are generated, but virtually none neutralizes the virus," said Kwong. And while scientists have learned a great deal in recent years about HIV's ability to evade the body's defenses, a big question has been precisely how a key protein on HIV's surface, gp120, escapes being neutralized by antibodies. Gp120 plays a vital role in getting HIV into the cells it targets for infection. But the protein also offers large exposed binding sites for neutralizing antibodies to latch onto, Kwong explained. So the question has been why these antibodies -- whether unleashed from the natural immune response or elicited by a vaccine -- largely fail to neutralize HIV.

Kwong and colleagues looked at the interaction between the gp120 molecule and a number of antibodies. They found that, in the face of nearly all of the antibodies, an "energetic barrier" was set up around the gp120 receptor sites. "The barrier's set up in a very specific way to prevent neutralization," Kwong said.

Kwong explained the antibodies only bind one at a time to the gp120 receptor sites on HIV. In contrast, the immune system cells that HIV infects have multiple sites that simultaneously bind to the gp120 receptors. So it appears that HIV is set up to have a barrier against interaction with antibodies, but not with its target cells.

Because of gp120's role in HIV infection, many experimental HIV vaccines have been based on the premise of generating neutralizing antibodies against the protein. The current study should spark efforts already under way to refine gp120-based HIV vaccines, according to Theodore Jardetsky of Northwestern University, whose commentary accompanies the findings. Kwong noted that researchers are also developing HIV vaccines that focus on immune system components other than the antibody arm.

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