Featured Research

from universities, journals, and other organizations

Scientists reveal surprising picture of how powerful antibody neutralizes HIV

Date:
October 19, 2011
Source:
Scripps Research Institute
Summary:
Researchers have uncovered the surprising details of how a powerful anti-HIV antibody grabs hold of the virus. The findings highlight a major vulnerability of HIV and suggest a new target for vaccine development.

This is the PGT 128 antibody in action.
Credit: Image courtesy of the Wilson lab, The Scripps Research Institute

Researchers at The Scripps Research Institute have uncovered the surprising details of how a powerful anti-HIV antibody grabs hold of the virus. The findings, published in Science Express on October 13, 2011, highlight a major vulnerability of HIV and suggest a new target for vaccine development.

"What's unexpected and unique about this antibody is that it not only attaches to the sugar coating of the virus but also reaches through to grab part of the virus's envelope protein," said the report's co-senior author Dennis Burton, a professor at The Scripps Research Institute and scientific director of the International AIDS Vaccine Initiative's (IAVI) Neutralizing Antibody Center, based on the Scripps Research La Jolla campus.

"We can now start to think about constructing mimics of these viral structures to use in candidate vaccines," said co-senior author Ian Wilson, who is Hansen Professor of Structural Biology and member of the Skaggs Institute for Chemical Biology at Scripps Research.

Other institutions in the United States, United Kingdom, Japan, and the Netherlands contributed to the research as part of an ongoing global HIV vaccine development effort.

Getting a Better Grip on HIV

Researchers from the current team recently isolated the new antibody and 16 others from the blood of HIV-infected volunteers, in work they reported online in the journal Nature on August 17, 2011. Since the 1990s, Burton, Wilson, and other researchers have been searching for such "broadly neutralizing" antibodies against HIV -- antibodies that work against many of the various strains of the fast-mutating virus -- and by now have found more than a dozen. PGT 128, the antibody described in the new report, can neutralize about 70 percent of globally circulating HIV strains by blocking their ability to infect cells. It also can do so much more potently -- in other words, in smaller concentrations of antibody molecules -- than any previously reported broadly neutralizing anti-HIV antibody.

The new report illuminates why PGT 128 is so effective at neutralizing HIV. Using the Wilson lab's expertise in X-ray crystallography, Robert Pejchal, a research associate in the Wilson lab, determined the structure of PGT 128 joined to its binding site on molecular mockups of the virus, designed in part by Robyn Stanfield and Pejchal in the Wilson group and Bill Schief, now an IAVI principal scientist and associate professor at Scripps Research, and his group. With these structural data, and by experimentally mutating and altering the viral target site, they could see that PGT 128 works in part by binding to glycans on the viral surface.

Thickets of these sugars normally surround HIV's envelope protein, gp120, largely shielding it from attack by the immune system. Nevertheless, PGT 128 manages to bind to two closely spaced glycans, and at the same time reaches through the rest of the "glycan shield" to take hold of a small part of structure on gp120 known as the V3 loop. This penetration of the glycan shield by PGT 128 was also visualized by electron microscopy with a trimeric form of the gp120/gp41 envelope protein of HIV-1 by Reza Kayat and Andrew Ward of Scripps Research; this revealed that the PGT 128 epitope appears to be readily accessible on the virus.

"Both of these glycans appear in most HIV strains, which helps explain why PGT 128 is so broadly neutralizing," said Katie J. Doores, a research associate in the Burton lab who was one of the report's lead authors. PGT 128 also engages V3 by its backbone structure, which doesn't vary as much as other parts of the virus because it is required for infection.

PGT 128's extreme potency is harder to explain. The antibody binds to gp120 in a way that presumably disrupts its ability to lock onto human cells and infect them. Yet it doesn't bind to gp120 many times more tightly than other anti-HIV antibodies. The team's analysis hints that PGT 128 may be extraordinarily potent because it also binds two separate gp120 molecules, thus tying up not one but two cell-infecting structures. Other mechanisms may also be at work.

Toward an AIDS Vaccine

Researchers hope to use the knowledge of these antibodies' binding sites on HIV to develop vaccines that stimulate a long-term -- perhaps lifetime -- protective antibody response against those same vulnerable sites.

"We'll probably need multiple targets on the virus for a successful vaccine, but certainly PGT 128 shows us a very good target," said Burton.

Intriguingly, the basic motif of PGT 128's target may mark a general vulnerability for HIV. "Other research is also starting to suggest that you can grab onto two glycans and a beta strand and get very potent and broad neutralizing antibodies against HIV," Wilson said.

In addition to Pejchal, Doores, and Khayat, Laura M. Walker of Scripps Research and Po-Ssu Huang of University of Washington at Seattle were co-first authors of the study, "A potent and broad neutralizing antibody recognizes and penetrates the HIV glycan shield." Along with Wilson, Burton, and Ward, additional contributors were Sheng-Kai Wang, Chi-Huey Wong, Robyn L. Stanfield, Jean-Philippe Julien, Alejandra Ramos, Ryan McBride, and James C. Paulson of Scripps Research, and Pascal Poignard, and William R. Schief of Scripps Research, IAVI and University of Washington at Seattle; Max Crispin and Christopher N. Scanlan of the University of Oxford; Rafael Depetris and John P. Moore of Weill Medical College of Cornell University; Umesh Katpally, Andre Marozsan, Albert Cupo, and William C. Olson of Progenics Pharmaceuticals; Sebastien Maloveste of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health; Yan Liu and Ten Feizi of Imperial College, London; Yukishige Ito of the RIKEN Advanced Science Institute in Japan; and Cassandra Ogohara of University of Washington at Seattle.

The research was supported by the International AIDS Vaccine Initiative, National Institutes of Health, the U.S. Department of Energy, the Canadian Institutes of Health Research, the UK Research Councils, the Ragon Institute, and other organizations.


Story Source:

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


Journal Reference:

  1. R. Pejchal, K. J. Doores, L. M. Walker, R. Khayat, P.-S. Huang, S.-K. Wang, R. L. Stanfield, J.-P. Julien, A. Ramos, M. Crispin, R. Depetris, U. Katpally, A. Marozsan, A. Cupo, S. Maloveste, Y. Liu, R. McBride, Y. Ito, R. W. Sanders, C. Ogohara, J. C. Paulson, T. Feizi, C. N. Scanlan, C.-H. Wong, J. P. Moore, W. C. Olson, A. B. Ward, P. Poignard, W. R. Schief, D. R. Burton, I. A. Wilson. A Potent and Broad Neutralizing Antibody Recognizes and Penetrates the HIV Glycan Shield. Science, 2011; DOI: 10.1126/science.1213256

Cite This Page:

Scripps Research Institute. "Scientists reveal surprising picture of how powerful antibody neutralizes HIV." ScienceDaily. ScienceDaily, 19 October 2011. <www.sciencedaily.com/releases/2011/10/111013141816.htm>.
Scripps Research Institute. (2011, October 19). Scientists reveal surprising picture of how powerful antibody neutralizes HIV. ScienceDaily. Retrieved April 20, 2014 from www.sciencedaily.com/releases/2011/10/111013141816.htm
Scripps Research Institute. "Scientists reveal surprising picture of how powerful antibody neutralizes HIV." ScienceDaily. www.sciencedaily.com/releases/2011/10/111013141816.htm (accessed April 20, 2014).

Share This



More Health & Medicine News

Sunday, April 20, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Nine-Month-Old Baby Can't Open His Mouth

Nine-Month-Old Baby Can't Open His Mouth

Newsy (Apr. 19, 2014) Nine-month-old Wyatt Scott was born with a rare disorder called congenital trismus, which prevents him from opening his mouth. Video provided by Newsy
Powered by NewsLook.com
'Holy Grail' Of Weight Loss? New Find Could Be It

'Holy Grail' Of Weight Loss? New Find Could Be It

Newsy (Apr. 18, 2014) In a potential breakthrough for future obesity treatments, scientists have used MRI scans to pinpoint brown fat in a living adult for the first time. Video provided by Newsy
Powered by NewsLook.com
Little Progress Made In Fighting Food Poisoning, CDC Says

Little Progress Made In Fighting Food Poisoning, CDC Says

Newsy (Apr. 18, 2014) A new report shows rates of two foodborne infections increased in the U.S. in recent years, while salmonella actually dropped 9 percent. Video provided by Newsy
Powered by NewsLook.com
Scientists Create Stem Cells From Adult Skin Cells

Scientists Create Stem Cells From Adult Skin Cells

Newsy (Apr. 17, 2014) The breakthrough could mean a cure for some serious diseases and even the possibility of human cloning, but it's all still a way off. Video provided by Newsy
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:
from the past week

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