The two new antibodies bind to the "top" of the HIV trimer. The model of the HIV-1 trimer (the viral protein that mediates binding and entry into target cells) is adapted from a recent electron-tomographic structure. The two newly identified broadly neutralizing antibodies, PG9 and PG16, are believed to bind to the variable loops on the trimer, which are represented in the model as green and yellow ovals. The approximate location of the viral membrane is shown in blue. The red structure located above the trimer is a human IgG molecule representative of PG9 and PG16.
[Illustration by Christina Corbaci and Rob Pejchal]
The discovery of two new broadly neutralizing antibodies against HIV is generating some exciting new targets for AIDS vaccine development, researchers say this week in Science.
The newly discovered antibodies act as a sort of key to a hidden viral lock, recognizing a motif on a conserved HIV protein that had not been described by researchers before. These antibodies neutralize a wide range of types of HIV, and appear to be more potent than other known broadly neutralizing antibodies.
Laura Walker from the Scripps Research Institute in La Jolla, CA, along with Sanjay Phogat at the International AIDS Vaccine Initiative (IAVI) and colleagues from various research labs across the United States, have used a high-throughput culture system to identify two previously unrecognized antibodies in an HIV-infected African donor. Their work reveals a possible Achilles Heel on the highly changeable virus that researchers might be able to exploit.
"The two newly discovered broadly neutralizing antibodies, called PG9 and PG16, are the first to have been identified in more than a decade and are the first to have been isolated from donors in developing countries, where the majority of new HIV infections occur," according to a collaborative press release by the IAVI, the Scripps Research Institute, and the biotechnology companies Theraclone Sciences and Monogram Biosciences.
The researchers involved with the project say that the identification of these antibodies and novel protein motif may open the door to intriguing new targets for vaccine development to fight AIDS in the future.
"These two antibodies offer the best combination of broad and potent neutralization we have identified so far," said Wayne Koff, senior vice-president of research and development at the IAVI, in a phone interview. "There are others, but these two seem to be the most potent antibodies against HIV, and they present us with a novel target for a possible vaccine."
In order to identify these broadly neutralizing antibodies, the researchers screened about 1,800 HIV-infected patients in Africa, Thailand, Australia, the United Kingdom, and the United States. Their results revealed broad neutralizing activity in about 10% of the volunteers screened. Additional screening of one of these "good" neutralizers led to the discovery of the two antibodies highlighted in the Science report, PG9 and PG16. Further analysis showed that the blood samples of just 1% of the volunteers, called "elite neutralizers," had an exceptional level of breadth and potency.
The broadly neutralizing antibodies are protein molecules that are able to neutralize and help destroy toxins and invading pathogens in order to fight infection, but there are still many questions about their mode of action and why they develop within certain HIV-infected individuals. Some researchers suggest that it is the unique shape of the proteins themselves that determine their effectiveness in neutralizing the virus. Others believe that the individual genetics of HIV-infected patients contribute to the development of potent antibodies. Regardless, there is ongoing research in this field aimed at learning more about the activity of these HIV antibodies.
"We have a program in Sub-Saharan Africa that tracks HIV positive individuals," Koff said. "There are some patients we've been tracking for a couple years now, and we will continue to check them for broadly neutralizing antibodies against the virus in the future. Eventually, we are hoping to learn where they come from."
In the meantime, researchers have two new promising leads to follow toward an eventual AIDS vaccine—and after more than a decade of dead ends, many of them are hoping that this discovery will inspire a Renaissance of sorts.
"Hopefully, the discovery of these two potent and broadly neutralizing antibodies will rekindle excitement in the field and accelerate research toward a vaccine," Koff said.
On September 24, 2009, the Scripps Research Institute and the IAVI will celebrate their grand opening of the IAVI Neutralizing Antibody Center in La Jolla, CA. The new research center will work in collaboration with a network of multi-disciplinary research institutions in Africa, Asia, Europe, and the United States in order to identify more neutralizing antibodies in the field and analyze them to design immunogens, the active ingredient in vaccines.
Since the discovery of PG9 and PG16, the same team of researchers has already identified more blood samples that seem to contain "good" antibodies—and they say it's only a matter of time before additional promising antibodies are found.