HIV Snapshot Offers Clues to Vaccine

BETHESDA, Md., Feb. 15 -- An atomic-level snapshot of a key HIV protein as it binds to a neutralizing antibody, a feat achieved here, may be a step toward an effective vaccine, the researchers said.

The x-ray crystallography finding identifies a "site of vulnerability" for the virus, a spot where the notoriously variable virus is unchanging, and is being heralded as a step forward in the search for an HIV vaccine, according to Peter Kwong, Ph.D., of the National Institute of Allergy and Infectious Diseases (NIAID).

The potentially vulnerable protein, known as gp120, is used to bind a viral particle to the CD4 receptor on target immune cells, Dr. Kwong and colleagues reported in the Feb. 15 issue of Nature.

And it appears to be vulnerable to an antibody known as b12, which has been isolated from the blood of HIV-infected patients whose immune systems appear to hold the virus at bay.

In macaques, the researchers noted, b12 has been shown to protect against simian-human immunodeficiency virus (SHIV).

The gp120 protein is one of the few targets on the surface of an HIV particle and has been the subject of several attempts to create a vaccine -- attempts that so far have been frustrated by HIV's ability to evade the immune system.

"Not only does HIV mutate rapidly and continuously -- defeating attempts by the immune system to identify and destroy it -- the virus is also swathed by sugary molecules," Dr. Kwong said in a statement. "This nearly impenetrable sugar cloak prevents antibodies from slipping in and blocking the proteins the virus uses to latch onto a cell and infect it."

The glycoprotein gp120 is the first point of contact between HIV and its target lymphocytes. In 1988, Dr. Kwong and colleagues were able to take an x-ray snapshot of the core of gp120 as it attached to a CD4 receptor.

They later learned that the initial contact causes the protein to change its shape, a process called conformational masking that helps to shield the virus from immune system attack.

In the current study, Dr. Kwong and colleagues used x-ray crystallography to show that the first contact between the two proteins occurs in a small, unchanging area.

But after the first touch, they found, the viral protein changes shape to allow a much broader contact with the cell surface.

"The first contact is like a cautious handshake, which then becomes a hearty bear hug," according to co-author Gary Nabel, M.D., Ph.D., director of NIAID's Vaccine Research Center.

The antibody b12 binds to that first small, invariant area but -- unlike the gp120-CD4 attachment -- without forcing gp120 to change shape, the researchers said.

For that reason, Dr. Nabel said in a statement, the invariant region -- called an epitope -- may be a target that could be exploited for a vaccine.

"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," he said. "This is certainly one of the best leads to come along in recent years."

Elias A. Zerhouni, M.D., director of the National Institutes of Health, said the researchers "have revealed a gap in HIV's armor" that may lead to a vaccine.