September 14, 2009

Antibodies Reveal a New HIV-1 Vaccine Target

Illustration of an antibody binding to HIV Two antibodies (red) that neutralize HIV bind to a section of the HIV trimer (green and yellow ovals). The viral membrane is shown in blue.Christina Corbaci and Rob Pejchal.

Researchers have discovered 2 new human antibodies that neutralize the virus that causes AIDS. The finding points to a promising new target for vaccine development.

Most vaccines work by triggering the immune system to produce antibodies that help beat back infections. But this strategy hasn't been successful in defeating the human immunodeficiency virus (HIV), which causes AIDS. The proteins on the surface of HIV mutate rapidly and change shape continuously, preventing most antibodies from latching onto and neutralizing the virus. NIH scientists recently found antibodies that can neutralize many different isolates of HIV by binding to a specific region on an HIV surface protein known as gp120. Researchers continue to investigate strategies to target this area.

A team led by Laura Walker and Dr. Dennis R. Burton from the Scripps Research Institute and Dr. Sanjay Phogat at the International AIDS Vaccine Initiative (IAVI) set out to find other HIV-neutralizing antibodies and thus potential new viral targets. Their work was supported by IAVI, the Bill & Melinda Gates Foundation, the United States Agency for International Development and NIH's National Institute of Allergy and Infectious Diseases (NIAID).

The researchers systematically screened the blood of 1,800 HIV-1-infected people from Thailand, Australia, the United Kingdom, the United States and several sub-Saharan African countries for the ability to neutralize HIV. They previously reported finding several donors that produced broadly neutralizing antibodies. In the current study, they cultured about 30,000 memory B cells, which produce antibodies, from one donor. They looked for antibodies that could neutralize several different isolates of HIV.

As reported on September 3, 2009, in the advance online edition of Science, the researchers discovered 2 antibodies, called PG9 and PG16, that could neutralize multiple HIV strains. PG9 neutralized 127 out of 162 viruses tested; PG16 neutralized 119 out of 162.

Seeking clues to how PG9 and PG16 can neutralize so many different viruses, the researchers did further experiments to discover where the antibodies bound to HIV. Both recognize a specific region of the gp120 protein, but only when it's in its native form—in envelope spikes, or trimers. The HIV trimer is made of 3 gp41 proteins that form a stem on the viral surface supporting 3 gp120 molecules. The trimer has been difficult to study because it falls apart when it's isolated from the virus.

"These new antibodies, which are more potent than other antibodies described to date while maintaining great breadth, attach to a novel, and potentially more accessible site on HIV to facilitate vaccine design," says Burton. "So now we may have a better chance of designing a vaccine that will elicit such broadly neutralizing antibodies, which we think are key to successful vaccine development."

The researchers continue to investigate other blood samples with neutralizing antibodies. In the meantime, these results provide a promising new target for vaccine development to fight AIDS.

—by Harrison Wein, Ph.D.

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