Featured Research

from universities, journals, and other organizations

New point of attack on HIV for vaccine development

Date:
April 24, 2014
Source:
Scripps Research Institute
Summary:
A new vulnerable site on the HIV virus has been found, which may lead researchers closer to developing a vaccine for the illness. "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 one researcher.

A team at The Scripps Research Institute has discovered a new vulnerable site on the HIV virus. Shown here is an electron microscopic reconstruction of the HIV-1 envelope glycoprotein trimer (pale blue) with antibodies representing each site of vulnerability in different colors, including the newly discovered PGT151 shown in red.
Credit: Image by Christina Corbaci, courtesy of The Scripps Research Institute.

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. The newly identified site can be attacked by human antibodies in a way that neutralizes the infectivity of 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.

"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 journal Immunity.

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.


Story Source:

The above story is based on materials provided by Scripps Research Institute. Note: Materials may be edited for content and length.


Journal References:

  1. Emilia Falkowska, Khoa M. Le, Alejandra Ramos, Katie J. Doores, Jeong Hyun Lee, Claudia Blattner, Alejandro Ramirez, Ronald Derking, Marit J. van Gils, Chi-Hui Liang, Ryan Mcbride, Benjamin von Bredow, Sachin S. Shivatare, Chung-Yi Wu, Po-Ying Chan-Hui, Yan Liu, Ten Feizi, Michael B. Zwick, Wayne C. Koff, Michael S. Seaman, Kristine Swiderek, John P. Moore, David Evans, James C. Paulson, Chi-Huey Wong, Andrew B. Ward, Ian A. Wilson, Rogier W. Sanders, Pascal Poignard, Dennis R. Burton. Broadly Neutralizing HIV Antibodies Define a Glycan-Dependent Epitope on the Prefusion Conformation of gp41 on Cleaved Envelope Trimers. Immunity, 2014; DOI: 10.1016/j.immuni.2014.04.009
  2. Claudia Blattner, Jeong Hyun Lee, Kwinten Sliepen, Ronald Derking, Emilia Falkowska, Alba Torrents de la Peña, Albert Cupo, Jean-Philippe Julien, Marit van Gils, Peter S. Lee, Wenjie Peng, James C. Paulson, Pascal Poignard, Dennis R. Burton, John P. Moore, Rogier W. Sanders, Ian A. Wilson, Andrew B. Ward. Structural Delineation of a Quaternary, Cleavage-Dependent Epitope at the gp41-gp120 Interface on Intact HIV-1 Env Trimers. Immunity, 2014; DOI: 10.1016/j.immuni.2014.04.008

Cite This Page:

Scripps Research Institute. "New point of attack on HIV for vaccine development." ScienceDaily. ScienceDaily, 24 April 2014. <www.sciencedaily.com/releases/2014/04/140424124702.htm>.
Scripps Research Institute. (2014, April 24). New point of attack on HIV for vaccine development. ScienceDaily. Retrieved October 1, 2014 from www.sciencedaily.com/releases/2014/04/140424124702.htm
Scripps Research Institute. "New point of attack on HIV for vaccine development." ScienceDaily. www.sciencedaily.com/releases/2014/04/140424124702.htm (accessed October 1, 2014).

Share This



More Health & Medicine News

Wednesday, October 1, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Ebola Cases Keep Coming for Monrovia's Island Hospital

Ebola Cases Keep Coming for Monrovia's Island Hospital

AFP (Oct. 1, 2014) — A look inside Monrovia's Island Hospital, a key treatment centre in the fight against Ebola in Liberia's capital city. Duration: 00:34 Video provided by AFP
Powered by NewsLook.com
Ebola Puts Stress on Liberian Health Workers

Ebola Puts Stress on Liberian Health Workers

AP (Oct. 1, 2014) — The Ebola outbreak is putting stress on first responders in Liberia. Ambulance drivers say they are struggling with chronic shortages of safety equipment and patients who don't want to go to the hospital. (Oct. 1) Video provided by AP
Powered by NewsLook.com
Doctors Reassure Public Ebola Patient Won't Cause Outbreak

Doctors Reassure Public Ebola Patient Won't Cause Outbreak

Newsy (Sep. 30, 2014) — After the announcement that the first U.S. patient had been diagnosed with Ebola, doctors were quick to say a U.S. outbreak is highly unlikely. Video provided by Newsy
Powered by NewsLook.com
TX Hospital Confirms Patient Admitted With Ebola

TX Hospital Confirms Patient Admitted With Ebola

AP (Sep. 30, 2014) — Medical officials from Texas Health Presbyterian Hospital confirm they are treating a patient with the Ebola virus, the first case found in the US. (Sept. 30 Video provided by AP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:

Strange & Offbeat Stories

 

Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:  

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins