Featured Research

from universities, journals, and other organizations

Tricky protein may help HIV vaccine development

Date:
January 13, 2014
Source:
Duke University
Summary:
Scientists have taken aim at what may be the Achilles' heel of the HIV virus. Combining expertise in biochemistry, immunology and advanced computation, researchers have determined the structure of a key part of the HIV envelope protein, the gp41 membrane proximal external region, which previously eluded complete, functional description. The research will help focus HIV vaccine development efforts.

This illustration shows how the envelope proteins covering the surface of an HIV virion (1, 2) bind to a host cell (3, 4). The trimeric MPER region of gp41 is shown in red and can be disabled by antibodies, shown in light blue.
Credit: Marian Miller

Duke scientists have taken aim at what may be an Achilles' heel of the HIV virus.

Combining expertise in biochemistry, immunology and advanced computation, researchers at Duke University have determined the structure of a key part of the HIV envelope protein, the gp41 membrane proximal external region (MPER), which previously eluded detailed structural description.

The research 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 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 three-parted 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.


Story Source:

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


Journal Reference:

  1. P. N. Reardon, H. Sage, S. M. Dennison, J. W. Martin, B. R. Donald, S. M. Alam, B. F. Haynes, L. D. Spicer. Structure of an HIV-1-neutralizing antibody target, the lipid-bound gp41 envelope membrane proximal region trimer. Proceedings of the National Academy of Sciences, 2014; DOI: 10.1073/pnas.1309842111

Cite This Page:

Duke University. "Tricky protein may help HIV vaccine development." ScienceDaily. ScienceDaily, 13 January 2014. <www.sciencedaily.com/releases/2014/01/140113163805.htm>.
Duke University. (2014, January 13). Tricky protein may help HIV vaccine development. ScienceDaily. Retrieved September 21, 2014 from www.sciencedaily.com/releases/2014/01/140113163805.htm
Duke University. "Tricky protein may help HIV vaccine development." ScienceDaily. www.sciencedaily.com/releases/2014/01/140113163805.htm (accessed September 21, 2014).

Share This



More Health & Medicine News

Sunday, September 21, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Sierra Leone in Lockdown to Control Ebola

Sierra Leone in Lockdown to Control Ebola

AP (Sep. 21, 2014) — Sierra Leone residents remained in lockdown on Saturday as part of a massive effort to confine millions of people to their homes in a bid to stem the biggest Ebola outbreak in history. (Sept. 20) Video provided by AP
Powered by NewsLook.com
Sierra Leone's Nationwide Ebola Curfew Underway

Sierra Leone's Nationwide Ebola Curfew Underway

Newsy (Sep. 20, 2014) — Sierra Leone is locked down as aid workers and volunteers look for new cases of Ebola. Video provided by Newsy
Powered by NewsLook.com
Changes Found In Brain After One Dose Of Antidepressants

Changes Found In Brain After One Dose Of Antidepressants

Newsy (Sep. 19, 2014) — A study suggest antidepressants can kick in much sooner than previously thought. Video provided by Newsy
Powered by NewsLook.com
Could Grief Affect The Immune Systems Of Senior Citizens?

Could Grief Affect The Immune Systems Of Senior Citizens?

Newsy (Sep. 19, 2014) — The study found elderly people are much more likely to become susceptible to infection than younger adults going though a similar situation. 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