Finding the Perfect Target
In the 30 years that have elapsed since the first reported AIDS cases, the disease has been transformed from a death sentence into a medically manageable condition. A newly diagnosed 20-year-old can expect to live another 50 years with the right combination of anti-HIV drugs.
Prevention, however, is always better than treatment; thus, in parallel with drug development, researchers have pursued vaccine strategies that might teach the immune system to destroy HIV before it wreaks havoc on the body. “The challenge is that HIV changes a lot,” said Tongqing Zhou, Ph.D. “Our human immune system is always one step behind.” Many antibodies are made during initial HIV infection, but most are not effective in neutralizing the virus.
Zhou is using structural biology to search for the perfect target on the HIV virus to form the basis of a vaccine: one that the virus requires in its exact form, is accessible to the immune system, and provokes a strong neutralizing antibody response. In 2007, Zhou and his colleagues published the discovery of such a site on HIV that fulfilled at least some of these criteria in the journal Nature.
For infection to occur, HIV requires the faithful binding of the gp120 protein to particular receptors found on human cells. The primary receptor is a molecule called CD4. “We found out the site on HIV gp120 that binds to the receptor CD4 is conserved for function and is vulnerable to antibodies,” explained Zhou. This result was promising, because the virus needs to preserve this binding site in order to proliferate. “But for a vaccine, we needed to know if patients could produce antibodies to this target.”
In rare cases, people infected with HIV are able to successfully mount an immune defense. Zhou and his colleagues used the structural information they had gleaned to devise a probe to look for B cells in human blood samples that produce the right anti-HIV antibodies. “From about 30 million cells, my colleagues identified 29 cells that were positive, out of which, three could generate potent and effective antibodies,” said Zhou. One antibody, in particular, was able to neutralize 90% of the currently circulating HIV viruses in the world. Solving the structure of this antibody-gp120 complex, Zhou found that this incredibly potent antibody had hit the bull’s eye of the vulnerability site on gp120 that the team had previously identified.
“My collaborators have recently identified more antibodies with similar properties from other patients. We again solved the structures in complex with HIV-1 gp120 and it turns out those antibodies from different patients exactly target the same site,” said Zhou. That these antibodies from different patients have very different genetic designs but hone in on the same target further strengthens the possibility of a successful vaccine. The next challenge will be to figure out how to use these insights to induce a strong human immune response to elicit such antibodies.
As part of the Vaccine Research Center (VRC), Zhou has several partners in the development of a vaccine roadmap. In addition to his fellow members of the Structural Biology Laboratory, led by Peter Kwong, Ph.D., Zhou works with the research teams led by Gary Nabel, M.D., Ph.D. and John Mascola, M.D., in an iterative process that shuttles between structural studies and living systems. These collaborations combine expertise in structural biology, virology, animal vaccination, virus neutralization and antibody isolation.
“The VRC is really unique. Gary, the original and current director, had the vision ten years ago to include structural biology in a vaccine research center for the first time,” said Zhou. ”It’s a great collaborative environment in which everyone shares one common goal: we want the vaccine.”
After arriving at the NIH on September 11, 2001, Zhou published his first papers in 2005. “That’s a long time without publications for a scientist,” remarked Zhou. Now, with a string of high-impact papers to his name, Zhou is grateful for the opportunity he had to build up his research into a bigger picture. “In 2007, after our Nature publication, even my hometown paper in China had an article about it,” said Zhou. After his high school featured him on their Web site, Zhou received a number of emails from students asking for career advice. What was his recommendation? “You have to be persistent in your goals.”
Tongqing Zhou, Ph.D., is a Staff Scientist in the Structural Biology Laboratory led by Peter Kwong, Ph.D., at the Vaccine Research Center (VRC) at the National Institute of Allergy and Infectious Diseases (NIAID).