Corporate Banner
Satellite Banner
Scientific Community
Become a Member | Sign in
Home>News>This Article

Scripps Researchers Find New Point of Attack on HIV for Vaccine Development

Published: Friday, April 25, 2014
Last Updated: Friday, April 25, 2014
Bookmark and Share
The newly identified site can be attacked by human antibodies in a way that neutralizes the infectivity of a wide variety of HIV strains.

A team led by 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. 

“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.

“It’s very exciting that we’re still finding new vulnerable sites on this virus,” said Ian A. Wilson, Hansen Professor of Structural Biology, chair of the Department of Integrative Structural and Computational Biology and member of the Skaggs Institute for Chemical Biology at TSRI and member of the NAC and CHAVI-ID.

The findings were reported in two papers—one led by Burton and the second led by TSRI Assistant Professor Andrew B. Ward, also a member of NAC and CHAVI-ID, and Wilson—appearing in the May issue of the journalImmunity.

The discovery is part of a large, IAVI- and NIH-sponsored effort to develop an effective vaccine against HIV. Such a vaccine would work by eliciting a strong and long-lasting immune response against vulnerable conserved sites on the virus—sites that don’t vary much from strain to strain, and that, when grabbed by an antibody, leave the virus unable to infect cells.

Cloaked by Shields

HIV generally conceals these vulnerable conserved sites under a dense layer of difficult-to-grasp sugars and fast-mutating parts of the virus surface. Much of the antibody response to infection is directed against the fast-mutating parts and thus is only transiently effective.

Prior to the new findings, scientists had been able to identify only a few different sets of “broadly neutralizing” antibodies, capable of reaching four conserved 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 from IAVI Protocol G, 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.

Emilia Falkowska, a research associate in the Burton laboratory who was a key author of the first paper, and colleagues soon found a set of eight closely related antibodies that accounted for most of one of the sample’s HIV neutralizing activity. The scientists determined that the two 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, or epitopes, on Env—and indeed failed to bind tightly anywhere on purified copies of gp120 or gp41, the two protein subunits of Env. Most previously described broadly neutralizing HIV antibodies bind to one or the other Env subunit. 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. PGT151 and 152 (which are nearly identical) turned out to have a binding site that occurs only on this mature and properly assembled Env trimer structure.

“These are the first HIV neutralizing antibodies we’ve found that unequivocally distinguish mature Env trimer from all other forms of Env,” said Falkowska. “That’s important because this is the form of Env that the virus uses to infect cells.”

Structure Revealed

The second of the two new studies was an initial structural analysis of the new vulnerable epitope.

Using an integrative approach that combined electron microscopy on the Env trimer complex with PGT151 (led by the Ward lab) with the structure of the PGT151 Fab by x-ray crystallography (led by the Wilson lab), the scientists were able to visualize the location of the PGT151-series binding site on the Env trimer—which includes a spot on one gp41 protein with two associated sugars (glycans), a patch on the gp120 protein and even a piece of the adjacent gp41 within the trimer structure—“a very complex epitope,” said Claudia Blattner, a research associate in the Wilson laboratory at TSRI and member of the IAVI Neutralizing Antibody Center who, along with graduate student Jeong Hyun Lee, was a first author of the second paper.

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.”

Although the PGT151 site is valuable in itself as an attack point for an HIV vaccine, its discovery also hints at the existence of other similar complex and vulnerable epitopes on HIV.

Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,800+ scientific posters on ePosters
  • More than 4,000+ scientific videos on LabTube
  • 35 community eNewsletters

Sign In

Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Scripps Research Institute Scientists Capture Picture of 'MicroRNA' in Action
The Findings Will Help Guide Drug Design.
Thursday, October 30, 2014
Scripps Research Institute Study Finds New Moves in Protein's Evolution
Findings point to new approach to drug design.
Monday, October 07, 2013
Study Reveals How Serotonin Receptors Can Shape Drug Effects from LSD to Migraine Medication
A team of scientists has determined and analyzed the high-resolution atomic structures of two kinds of human serotonin receptor.
Tuesday, March 26, 2013
Scripps Research Institute Scientists Find the Structure of a Key ‘Gene Silencer’ Protein
The structure reveals potential therapeutic targets in area with ‘untapped potential’.
Monday, April 30, 2012
Scripps Research Scientists find E. Coli Enzyme must move to Function
Slight oscillations lasting just milliseconds have a huge impact on an enzyme's function, according to a new study by Scripps Research Institute scientists.
Monday, April 18, 2011
Scripps Research Scientists Solve Protein Structure Revealing Secrets of Cell Membranes
The Findings May Lead to Better Methods to Deliver Drugs
Thursday, May 06, 2010
Scripps Scientists Uncover Mimicry at the Molecular Level that Protects Genome Integrity
Study draws new parallels between the Rad60 DNA repair factor and SUMO; both essential for maintaining genome stability during replication.
Wednesday, April 15, 2009
Scientists Create First Crystal Structure of an Intermediate Particle in Virus Assembly
A research team at the Scripps Research Institute has been able to produce the first crystal structure of a virus particle caught in the midst of assembling its impenetrable outer protein coat.
Monday, March 23, 2009
Scientific News
A New Way to Look at MOFs
International study challenges prevailing view on how metal organic frameworks store gases.
Major Advance in Crystal Structure Prediction Methods
The Cambridge Crystallographic Data Centre (CCDC) announces that the results of its 6th blind test of crystal structure prediction methods demonstrate significant advancement in in comparison with previous tests.
Protein Structure Discovery Opens Window on Basic Life Process
Biochemists at Oregon State University have made a fundamental discovery about protein structure that sheds new light on how proteins fold, which is one of the most basic processes of life.
Clearest Ever Images of Enzyme that Plays Key Roles in Aging, Cancer
UCLA-led research on telomerase could lead to new strategies for treating disease
New Approach to Treating Heparin-induced Blood Disorder
A potential treatment for a serious clotting condition that can strike patients who receive heparin to treat or prevent blood clots may lie within reach by elucidating the structure of the protein complex at its root.
Escape Prevention
Studying flu virus structure brings us a step closer to a permanent vaccine.
Structure of Protein at Root of Muscular Disease Decoded
Researchers at Rice University and Baylor College of Medicine have unlocked the structural details of a protein seen as key to treating a neuromuscular disease.
A Natural Light Switch
MIT scientists identify and map the protein behind a light-sensing mechanism.
First Complete Structural Study Of A Pegylated Protein
Significant data obtained at NUI Galway reports first crystal structure of a protein modified with a single PEG chain.
Cellular Contamination Pathway for Heavy Elements Identified
Berkeley Lab scientists find that an iron-binding protein can transport actinides into cells.
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,800+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,000+ scientific videos