Navigation Links
Designing more effective anti-HIV antibodies
Date:11/19/2010

Boston, Mass. Although people infected with HIV produce many antibodies against the protein encapsulating the virus, most of these antibodies are strangely ineffective at fighting the disease. A new study suggests why some of the most common of these antibodies don't work: they target the protein in a form it takes after the virus has already invaded the cell, when it's too late, report researchers at Children's Hospital Boston and their colleagues.

The findings, published online Nov. 14 in the journal Nature Structural & Molecular Biology, refocus attention on the rare group of neutralizing antibodies that do work, described by the team in an earlier study. These antibodies home in on the protein at an earlier moment when the virus latches onto a healthy cell. Many people believe an effective HIV vaccine will need to greatly expand this rare antibody immune response to block infection. Children's has filed for patents on two new proteins designed to expand this rare antibody response.

"The key finding of this paper is that we can distinguish the shape of the protein targeted by useful antibodies," said senior author Bing Chen, PhD, of the Department of Molecular Medicine at Children's. "That means we can think about designing immunogens trapped in this defined structure and ways to prevent the protein from forming into an irrelevant conformation."

The same HIV protein, known as gp41, takes two such dramatically different configurations that it reacts with two different kinds of antibodies, Chen's group shows. In HIV, the protein travels under wraps on the surface of virus particles. When the virus locks onto a healthy cell, the protein briefly unfolds and stretches out to its full length, extending out like a person reaching high overhead. This is the shape that generates rare but useful neutralizing antibodies in some people.

Then comes another shape change. After taking hold of the cell membrane, the protein folds over, like a person touching his toes, to fuse the cell to the virus membrane. That final calisthenic to fuse the membranes also creates an opening that allows the viral contents to invade the cell. At this stage, the protein functions as a decoy, serving only to bring on fruitless antibody responses and to distract the immune system, the authors wrote in the paper.

"We now believe that the neutralizing antibodies bind to the intermediate state, which prevents further structural rearrangements and blocks membrane fusion," said Chen, who is also affiliated with Harvard Medical School. "The key is that we can now separate which antibody recognizes which state, so that we can move forward to design an immunogen to induce an effective antibody response."

The findings suggest a new way of generating more useful anti-HIV antibodies. The intermediate stage of the protein normally lasts only about 15 minutes, too quickly to mount a successful immune response. For earlier work, the team leveraged the power of the first fusion-inhibiting antiviral drug, T20 (enfuviritide), approved for late-stage disease when other treatment options are failing. The drug traps the protein in the shape that spurs useful antibodies, the researchers reported in an earlier paper. In the latest study, the team further refined the protein for this study in a variation that does not require the drug. Additional biochemical experiments confirmed that two rare neutralizing antibodies from patients tackled the fleeting intermediate state of the experimental protein.

"This paper helps to resolve key questions plaguing the field: Why do certain forms of the protein interact with certain antibodies, and why aren't these antibodies in general more effective?" said virologist Dan Barouch, professor of medicine at Harvard Medical School and Beth Israel Deaconess Medical Center, who was not involved in the study. "This paper shows how particular antibodies react with different conformation states of gp41, but the implications are well beyond that. The results also offer a new way of thinking about envelope immunogen design." Barouch is collaborating with Chen to test the immunogenicity of the protein in animal models.

Chen's team discovered the immune-evasion power of the decoy protein shape in studies led by Gary Frey, PhD, and Jia Chen, PhD. Frey and Chen solved the atomic structure of a useless antibody bond to the final form of the protein. "The postfusion state is very stable," said Chen, allowing plenty of time for the body to churn out worthless antibodies.

A companion paper from a Duke University group published simultaneously online shows another non-neutralizing antibody binding to a slightly different region of the protein in the postfusion form, further confirming the findings reported by Chen's group.


'/>"/>

Contact: Keri Stedman
keri.stedman@childrens.harvard.edu
617-919-3110
Children's Hospital Boston
Source:Eurekalert

Related biology news :

1. Designing touch-sensitive virtual reality tools to train and test tomorrows surgeons
2. Designing probiotics that ambush gut pathogens
3. New needle-free HPV vaccine increases effectiveness, availability in developing world
4. Online Publishers Association Unveils Biometric and Eye Tracking Research to Assess the Effectiveness of New OPA Ad Units
5. UV light nearly doubles vacuums effectiveness in reducing carpet microbes
6. Succimer found ineffective for removing mercury
7. Cheaper, more effective treatment of type 1 Gaucher disease possible
8. Second-generation device more effective in capturing circulating tumor cells
9. RD114 envelope proteins provide an effective and versatile approach to pseudotype lentiviral vectors
10. Light workout: Stanford scientists use optogenetics to effectively stimulate muscle movement in mice
11. More effective weight control strategies are urgently needed
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:11/15/2016)... , Nov. 15, 2016  Synthetic Biologics, Inc. ... therapeutics focused on the gut microbiome, today announced ... 25,000,000 shares of its common stock and warrants ... at a price to the public of $1.00 ... Synthetic Biologics from the offering, excluding the proceeds, ...
(Date:6/22/2016)... June 22, 2016  The American College of Medical Genetics ... Executive Magazine as one of the fastest-growing trade shows ... at the Bellagio in Las Vegas . ... percentage of growth in each of the following categories: net ... and number of attendees. The 2015 ACMG Annual Meeting was ...
(Date:6/16/2016)... June 16, 2016 The ... expected to reach USD 1.83 billion by 2024, ... Research, Inc. Technological proliferation and increasing demand in ... expected to drive the market growth. ... The development of advanced multimodal techniques for ...
Breaking Biology News(10 mins):
(Date:12/6/2016)... 6, 2016 According to a new market ... (Polymer, Glass, Silicon), Application (Genomics, Proteomics, Capillary Electrophoresis, POC, Clinical, Environmental, ... global market is projected to reach USD 8.78 Billion by 2021 ... during the forecast period (2016 to 2021). ... ...
(Date:12/6/2016)... , Dec. 6, 2016  SRI International has ... million from the National Institutes of Health,s National ... Division of AIDS (NIAID-DAIDS) to support the manufacturing ... pre-exposure (PreP) agents. Under the seven-year contract, SRI ... development services for candidate HIV-prevention products that emerge ...
(Date:12/6/2016)... ... 2016 , ... RoviSys, a leading independent provider of comprehensive ... the opening of their new office building today. Located at 480 Green Oaks ... 200 employees focused on providing sales, engineering, and support services to customers in ...
(Date:12/5/2016)... Dec 5, 2016 Research and Markets ... - Technologies, Markets and Companies" to their offering. ... , , ... discovery using various -omics technologies such as proteomics and metabolomics. Molecular ... tests are also based on biomarker. Currently the most ...
Breaking Biology Technology: