By Liz Highleyman

In the February 15, 2007 issue of Nature, a collaborative research team led by investigators from the U.S. National Institute of Allergy and Infectious Diseases (NIAID) further clarified how HIV binds to host cells -- a finding that may further the development of an effective HIV vaccine.

"The remarkable diversity, glycosylation, and conformational flexibility" of the HIV-1 envelope, including "substantial rearrangement of the gp120 glycoprotein upon binding the CD4 receptor," allow the virus to evade antibody-mediated neutralization, the authors wrote as background.

Despite this complexity, the HIV-1 envelope must retain certain conserved segments in order to bind with CD4 receptors and allow entry into cells.

To evaluate how these determinants might provide opportunities for antibody recognition, the researchers created gp120 variants stabilized in the CD4-bound state. They then assessed binding of CD4 and receptor-binding-site antibodies, and determined the structure of the broadly neutralizing antibody b12 in complex with gp120.

A resulting image of the complex (available at http://www3.niaid.nih.gov) revealed that b12 binds to gp120 at the same point where gp120 initially attaches to CD4. But in contrast to the gp120-CD4 interaction, b12 can attach to CD4 without requiring gp120 to change shape.

They found that the antibody b12 "binds to a conformationally invariant surface of the HIV-1 envelope that overlaps a distinct subset of the CD4-binding site. This surface is involved in the meta-stable attachment of CD4, before the gp120 rearrangement required for stable engagement."

"A site of vulnerability, related to a functional requirement for efficient association with CD4, can therefore be targeted by antibody to neutralize HIV-1," the authors concluded.

Implications for Vaccine Development

"This elegant work by Dr. Kwong and his colleagues provides us with a long-sought picture of the precise interaction between the HIV gp120 surface protein and this neutralizing antibody," said NIAID Director Anthony S. Fauci, MD. "This finding could help in the development of an HIV vaccine capable of eliciting a robust antibody response."

In 1998, Dr. Kwong and colleagues published the first X-ray snapshot of the core of HIV gp120 as it attaches to a cellular receptor known as CD4, according to a press release from NIAID announcing the findings. "That image gave researchers a glimpse of some sites on the virus that could be targets of drugs or vaccines, but it also revealed the extent of HIV's overlapping defenses."

While the earlier study provided a picture of the CD4-gp120 complex, the new findings clarify the stepwise sequence of interaction between gp120 and the CD4 receptor, beginning with initial contact as a specific point and then expanding to encompass a broader surface that stabilizes the interaction.

"The first contact is like a cautious handshake, which then becomes a hearty bear hug," said study co-author Gary Nabel, MD, PhD.

"One of our primary goals is to develop HIV vaccines that can stimulate broadly neutralizing antibodies," Nabel continued. "The structure of this gp120 epitope, and its susceptibility to attack by a broadly neutralizing antibody, shows us a critical area of vulnerability on the virus that we may be able to target with vaccines."

National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD; Scripps Research Institute, La Jolla, CA; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Center for Cancer Research, National Cancer Institute, Frederick, MD.

02/20/07

References

T Zhou, L Xu, B Dey, and others. Structural definition of a conserved neutralization epitope on HIV-1 gp120. Nature 445 (7129): 732-737. February 15, 2007.

NIAID. Scientists Unveil Piece of HIV Protein That May Be Key to AIDS Vaccine Development. Press release. February 18, 2007.