A team of scientists at The Scripps Research Institute (TSRI) working with the International AIDS Vaccine Initiative (IAVI) has discovered a new vulnerable site on the HIV virus. The newly identified site can be attacked by antibodies in a way that neutralizes a wide variety of HIV strains.
“HIV has very few known sites of vulnerability, but in this work we've described a new one, and we expect it will be useful in developing a vaccine,” said Dennis R. Burton, professor in TSRI's Department of Immunology and Microbial Science and scientific director of the IAVI Neutralizing Antibody Center (NAC) and of the National Institutes of Health's Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) on TSRI's La Jolla campus.
The findings were reported in two papers in the May issue of the journal Immunity—one led by Burton and the second led by TSRI Assistant Professor Andrew B. Ward, also a member of NAC and CHAVI-ID.
Prior to the new findings, scientists had been able to identify only a few different sets of “broadly neutralizing” antibodies, capable of reaching four vulnerable sites on the virus. All these sites are on HIV's only exposed surface antigen, the flower-like envelope (Env) protein (gp140) that sprouts from the viral membrane and is designed to grab and penetrate host cells.
The identification of the new vulnerable site on the virus began with tests of blood samples in which IAVI and its NAC partnered with clinical research centers in Africa, India, Thailand, Australia, the United Kingdom, and the United States to collect blood samples from more than 1,800 healthy, HIV-positive volunteers to look for rare, broadly neutralizing antibodies. The serum from a small set of the samples indeed turned out to block the infectivity, in test cells, of a wide range of HIV isolates, suggesting the presence of broadly neutralizing antibodies. In 2009, scientists from IAVI, TSRI, and Theraclone Sciences succeeded in isolating and characterizing the first new broadly neutralizing antibodies to HIV seen in a decade.
The scientists determined that two of the eight closely related, broadest neutralizers among these antibodies, PGT151 and PGT152, could block the infectivity of about two-thirds of a large panel of HIV strains found in patients worldwide.
Curiously, despite their broad neutralizing ability, these antibodies did not bind to any previously described vulnerable sites on Env. The researchers eventually determined, however, that PGT151 and PGT152 attach not just to gp120 or gp41 but to bits of both.
In fact, gp120 and gp41 assemble into an Env structure not as one gp120-gp41 combination but as three intertwined ones—a trimer, in biologists’ parlance.
A surprise finding was that the PGT151-series antibodies bind to the Env trimer in a way that stabilizes its otherwise fragile structure. “Typically when you try to purify the native Env trimer, it falls apart, which has made it very hard to study,” said Ward. “It was a key breakthrough to find an antibody that stabilizes it.”