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

Tricky Protein May Help HIV Vaccine Development

Published: Wednesday, January 15, 2014
Last Updated: Wednesday, January 15, 2014
Bookmark and Share
Researchers have determined the structure of a key part of the HIV envelope protein, the gp41 membrane proximal external region, which previously eluded detailed structural description.

The research from Duke University will help focus HIV vaccine development efforts, which have tried for decades to slow the spread of a virus that currently infects more than 33 million people and has killed 30 million more. The team reported the findings online in the Jan. 13 early edition of Proceedings of the National Academy of Sciences.

"One reason vaccine development is such a difficult problem is that HIV is exceptionally good at evading the immune system," said Bruce Donald, an author and professor in Duke's computer science and biochemistry departments. "The virus has all these devious strategies to hide from the immune system."

One of those strategies is a dramatic structural transformation that the virus undergoes when it fuses to a host cell. The envelope protein complex is a structure that protrudes from HIV's membrane and carries out the infection of healthy host cells. Scientists have long targeted this complex for vaccine development, specifically its three copies of a protein called gp41 and closely associated partner protein gp120.  

The authors said they think about a particular region of gp41, called membrane proximal external region (MPER), as an Achilles' heel of vulnerability. 

"The attractiveness of this region is that, number one, it is relatively conserved," said Leonard Spicer, senior author and a professor of biochemistry and radiology. In a virus as genetically variable as HIV, a successful vaccine must act on a region that will be conserved, or similar across subtypes of the virus.

"Second, this region has two particular sequences of amino acids that code for the binding of important broadly neutralizing antibodies," said Spicer. The HIV envelope region near the virus membrane is the spot where some of the most effective antibodies found in HIV patients bind and disable the virus.

When the virus fuses to a host cell, the HIV envelope protein transitions through at least three separate stages. Its pre- and post-fusion states are stable and have been well studied, but the intermediate step -- when the protein actually makes contact with the host cell -- is dynamic. The instability of this interaction has made it very difficult to visualize using traditional structure determination techniques, such as x-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy.

That's where Duke's interdisciplinary team stepped in, solving the structure using protein engineering, sophisticated NMR and software specifically designed to run on limited data. 

First author Patrick Reardon spent years engineering a protein that incorporated the HIV MPER, associated with a membrane and behaved just like gp41 in the tricky intermediate step, but was stable enough to study. Reardon, then a PhD student under Spicer, is now a Wiley postdoctoral fellow at the Environmental Molecular Sciences Laboratory, a scientific facility in the Department of Energy's Pacific Northwest National Laboratory. 

The result captured the shape of the symmetric, three-part MPER in its near-native state, but the protein needed to be more than structurally accurate -- it had to bind the broadly neutralizing antibodies.

"One of the most important aspects of the project was ensuring that this construct interacted with the desirable antibodies, and indeed, it did so strongly," Reardon said.

The team validated the initial structure using an independent method of data analysis developed by Donald's lab, which showed alternate structures were not consistent with the data.

"The software took advantage of sparse data in a clever way that gave us confidence about the computed structure," Donald said. It used advanced geometric algorithms to determine the structure of large, symmetric, or membrane-bound proteins -- varieties that are very difficult to reconstruct from NMR data.

Donald's lab has been perfecting the method for a nearly decade, and Donald said its application in this paper represents a culmination of that work, demonstrating how the two-pronged approach can illuminate the structure of complex protein systems.

The next steps of this research have already begun. In December, Duke received a grant of up to $2.9 million from the Bill & Melinda Gates Foundation to fund the development of an HIV vaccine that will build on these findings.

In addition to Donald, Reardon and Spicer, the paper's authors include Harvey Sage, S. Moses Dennison, Jeffrey W. Martin, S. Munir Alam and Barton F. Haynes, all from Duke.

Funding for this research came from a Collaboration for AIDS Vaccine Discovery grant from the Bill & Melinda Gates Foundation and National Institutes of Health grants GM-78031 and GM-65982.

Citation: "Structure of an HIV-1 Neutralizing Antibody Target. A Lipid Bound dp41 Envelope Membrane Proximal Region Trimer." Patrick F. Rearden, Harvey Sage, et al. Proceedings of the National Academy of Sciences, Jan. 13, 2014. doi:101073/pnas1309842111


Further Information

Join For Free

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 3,000+ scientific posters on ePosters
  • More than 4,400+ 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 TechnologyNetworks.com 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

Immunity Genes Could Protect Some From E. Coli
When a child comes home from preschool with a stomach bug that threatens to sideline the whole family for days, why do some members of the family get sick while others are unscathed?
Monday, January 25, 2016
Disrupting Cell’s Supply Chain Freezes Cancer Virus
When the cancer-causing Epstein-Barr virus moves into a B-cell of the human immune system, it tricks the cell into rapidly making more copies of itself, each of which will carry the virus.
Thursday, January 21, 2016
Molecular ‘Kiss Of Death’ Flags Pathogens For Destruction
Researchers have discovered that our bodies mark pathogen-containing vacuoles for destruction by using a molecule called ubiquitin, commonly known as the "kiss of death."
Wednesday, September 30, 2015
Drugs to Block Angiogenesis Could Provide New Treatment for TB
Blood supply gives invaders oxygen and a way out.
Monday, November 24, 2014
Gene Required for Recovery from Bacterial Infection Identified
Duke researchers have uncovered the genes that are normally activated during recovery from bacterial infection in the C. elegans worm. The finding could be key to new antibiotics and countering auto-immune disorders.
Monday, October 27, 2014
Ubiquitous Protein Controls Copying of Resistant DNA
Researchers have demonstrated how the protein could put antibiotic-resistant bugs in handcuffs.
Monday, June 09, 2014
Scientific News
Understanding Female HIV Transmission
Glowing virus maps points of entry through entire female reproductive tract for first time.
COPD Linked to Increased Bacterial Invasion
Persistent inflammation in COPD may result from a defect in the immune system that allows airway bacteria to invade deeper into the lung.
Finding Factors That Protect Against Flu
A clinical trial examining the body’s response to seasonal flu suggests new approaches for evaluating the effectiveness of seasonal flu vaccines.
Vaccinations Are More Effective When Administered In The Morning
Research from the University of Birmingham shows that influenza vaccinations have more protective responses when administered in the morning.
Secrets of a Deadly Virus Family Revealed
Scripps Research scientists uncover the glycoprotein structure of LCMV. The findings could guide development of treatments for Lassa fever.
Cytokine Triggers Immune Response at Expense of Blood Renewal
Research highlights promise of Anti-IL-1 drugs to treat chronic inflammatory disease.
Reduced Immune Response Causes Flu Deaths in Older Adults
Yale study suggests that immune response to flu causes death in older people, not the virus.
Exposure To Routine Viruses Makes Mice Better Test Subjects
Study shows that infections make mouse immune system act more like that in humans.
Immune Booster Tested in Advanced Merkel Cell Cancer
The immunotherapy drug produced durable responses in many patients.
Factors Influencing Influenza Vaccine Effectiveness Uncovered
The long-held approach to predicting seasonal influenza vaccine effectiveness may need to be revisited, new research suggests.
SELECTBIO

SELECTBIO Market Reports
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
3,000+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,400+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FOR FREE!