Navigation Links
Tricky protein may help HIV vaccine development
Date:1/13/2014

DURHAM, N.C. -- 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. 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.


'/>"/>
Contact: Erin Weeks
erin.weeks@duke.edu
919-681-8057
Duke University
Source:Eurekalert  

Related medicine news :

1. Migraine triggers tricky to pinpoint
2. Figuring Out Your Migraine Triggers Is Tricky
3. Shapeshifting computer program will open up drug discovery for tricky disease targets
4. Warwick scientists uncover how checkpoint proteins bind chromosomes
5. Specific protein triggers changes in neurons in brain reward center linked to cocaine addiction
6. Unusual protein helps regulate key cell communication pathway
7. Protein prevents DNA damage in the developing brain and might serve as a tumor suppressor
8. RANK protein promotes the initiation, progression and metastasis of human breast cancer
9. Protein may represent a switch to turn off B cell lymphoma
10. Protein RAL associated with aggressive characteristics in prostate, bladder and skin cancers
11. Breast cancer clinical trial tests combo of heat shock protein inhibitor and hormonal therapy
Post Your Comments:
*Name:
*Comment:
*Email:
Related Image:
Tricky protein may help HIV vaccine development
(Date:2/26/2017)... (PRWEB) , ... February 26, 2017 , ... ODH, Inc.™ ... Care Summit, February 27-28 at the Sheraton Pentagon City Hotel in Arlington, VA. ODH’s ... PerformCARE to use behavioral health analytics to improve Medicaid population health management. , ODH ...
(Date:2/24/2017)... , ... February 24, 2017 , ... ... newly designed TaskMate Go. Core benefits and advantages built into the home office ... stylish, functional look and feel. Ability to gain the benefits embedded in the ...
(Date:2/24/2017)... ... February 24, 2017 , ... An in-depth computational analysis ... University of Pittsburgh points to eight genes that may explain why susceptibility to one ... the results of a study published today in the journal npj Schizophrenia. , ...
(Date:2/24/2017)... ... 2017 , ... With millions of Americans and people worldwide ... all are aware of our options and are empowered with strength and information ... of its newest edition of "Vision and Hearing" in USA Today, that will ...
(Date:2/24/2017)... ... February 24, 2017 , ... The California State University Institute for Palliative ... in or interested in palliative care education and research. The Symposium, “Innovate. Investigate. ... County San Diego on Sept. 28 and 29, 2017, on the campus of California ...
Breaking Medicine News(10 mins):
(Date:2/24/2017)... YORK , Feb. 23, 2017  This report ... Thousand by the following Products: Intermediates, ... in the report include Pharmaceuticals, and Agrochemicals. The report ... Japan , Europe , and ... for the period 2015 through 2022. Also, a six-year ...
(Date:2/24/2017)... 24, 2017  Xynomic Pharmaceuticals, Inc., an oncology drug ... has acquired exclusive worldwide rights to develop, manufacture ... inhibitor targeting hematological and solid tumors. ... and 2 clinical trials of Abexinostat in US, ... already been completed, demonstrating that Abexinostat is clinically ...
(Date:2/23/2017)... -- Genesis Healthcare Services has merged with Hospice Cloud, a ... Bill Monast , President and CEO of Hospice Cloud ... , executives with Home Health Depot, Inc., the parent ... This acquisition helps Hospice Cloud maintain its position as ... equipment (DME) solutions for the hospice industry. Nathan ...
Breaking Medicine Technology: