Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

An antibody that can attack HIV in new ways

14.09.2015

Proteins called broadly neutralizing antibodies (bNAbs) are a promising key to the prevention of infection by HIV, the virus that causes AIDS. bNAbs have been found in blood samples from some HIV patients whose immune systems can naturally control the infection.

These antibodies may protect a patient's healthy cells by recognizing a protein called the envelope spike, present on the surface of all HIV strains and inhibiting, or neutralizing, the effects of the virus.


Broadly neutralizing antibodies to HIV-1 envelope glycoprotein are being evaluated as therapeutics to prevent or treat HIV-1 infection. Structural analysis of one such antibody, 8ANC195, revealed a new conformation of the envelope protein. The image shows the X-ray crystal structure of 8ANC195 in complex with the gp120 subunit of the envelope protein. The background shows schematic representations of HIV-1 virus particles studded with envelope proteins being recognized by 8ANC195 antibodies.

Credit: Louise Scharf/Caltech

Now Caltech researchers have discovered that one particular bNAb may be able to recognize this signature protein, even as it takes on different conformations during infection--making it easier to detect and neutralize the viruses in an infected patient.

The work, from the laboratory of Pamela Bjorkman, Centennial Professor of Biology, was published in the September 10 issue of the journal Cell.

The process of HIV infection begins when the virus comes into contact with human immune cells called T cells that carry a particular protein, CD4, on their surface. Three-part (or "trimer") proteins called envelope spikes on the surface of the virus recognize and bind to the CD4 proteins.

The spikes can be in either a closed or an open conformation, going from closed to open when the spike binds to CD4. The open conformation then triggers fusion of the virus with the target cell, allowing the HIV virus to deposit its genetic material inside the host cell, forcing it to become a factory for making new viruses that can go on to infect other cells.

The bNAbs recognize the envelope spike on the surface of HIV, and most known bNAbs only recognize the spike in the closed conformation. Although the only target of neutralizing antibodies is the envelope spike, each bNAb actually functions by recognizing just one specific target, or epitope, on this protein.

Some targets allow more effective neutralization of the virus, and, therefore, some bNAbs are more effective against HIV than others. In 2014, Bjorkman and her collaborators at Rockefeller University reported initial characterization of a potent bNAb called 8ANC195 in the blood of HIV patients whose immune systems could naturally control their infections. They also discovered that this antibody could neutralize the HIV virus by targeting a different epitope than any other previously identified bNAb.

In the work described in the recent Cell paper, they investigated how 8ANC195 functions--and how its unique properties could be beneficial for HIV therapies.

"In Pamela's lab we use X-ray crystallography and electron microscopy to study protein-protein interactions on a molecular level," says Louise Scharf, a postdoctoral scholar in Bjorkman's laboratory and the first author on the paper. "We previously were able to define the binding site of this antibody on a subunit of the HIV envelope spike, so in this study we solved the three-dimensional structure of this antibody in complex with the entire spike, and showed in detail exactly how the antibody recognizes the virus."

What they found was that although most bNAbs recognize the envelope spike in its closed conformation, 8ANC195 could recognize the viral protein in both the closed conformation and a partially open conformation. "We think it's actually an advantage if the antibody can recognize these different forms," Scharf says.

The most common form of HIV infection is when a virus in the bloodstream attaches to a T cell and infects the cell. In this instance, the spikes on the free-floating virus would be predominantly in the closed conformation until they made contact with the host cell. Most bNAbs could neutralize this virus. However, HIV also can spread directly from one cell to another. In this case, because the antibody already is attached to the host cell, the spike is in an open conformation. But 8ANC195 could still recognize and attach to it.

A potential medical application of this antibody is in so-called combination therapies, in which a patient is given a cocktail of several antibodies that work in different ways to fight off the virus as it rapidly changes and evolves. "Our collaborators at Rockefeller have studied this extensively in animal models, showing that if you administer a combination of these antibodies, you greatly reduce how much of the virus can escape and infect the host," Scharf says. "So 8ANC195 is one more antibody that we can use therapeutically; it targets a different epitope than other potent antibodies, and it has the advantage of being able to recognize these multiple conformations."

The idea of bNAb therapeutics might not be far from a clinical reality. Scharf says that the same collaborators at Rockefeller University are already testing bNAbs in a human treatment in a clinical trial. Although the initial trial will not include 8ANC195, the antibody may be included in a combination therapy trial in the near future, Scharf says.

Furthermore, the availability of complete information about how 8ANC195 binds to the viral spike will allow Scharf, Bjorkman, and their colleagues to begin engineering the antibody to be more potent and able to recognize more strains of HIV.

"In addition to supporting the use of 8ANC195 for therapeutic applications, our structural studies of 8ANC195 have revealed an unanticipated new conformation of the HIV envelope spike that is relevant to understanding the mechanism by which HIV enters host cells and bNAbs inhibit this process," Bjorkman says.

###

These results were published in a journal article titled "Broadly Neutralizing Antibody 8ANC195 Recognizes Closed and Open States of HIV-1 Env." In addition to Scharf and Bjorkman, other Caltech coauthors include graduate student Haoqing Wang, research technician Han Gao, research scientist Songye Chen, and Beckman Institute resource director Alasdair W. McDowall. Funding for the work was provided by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health; the Bill and Melinda Gates Foundation; and the American Cancer Society. Crystallography and electron microscopy were done at the Molecular Observatory at Caltech, supported by the Gordon and Betty Moore Foundation.

Media Contact

Deborah Williams-Hedges
debwms@caltech.edu
626-395-3227

 @caltech

http://www.caltech.edu 

Deborah Williams-Hedges | EurekAlert!

Further reports about: CD4 Cell HIV HIV infection HIV virus Technology attack electron microscopy infect neutralize proteins

More articles from Life Sciences:

nachricht A novel socio-ecological approach helps identifying suitable wolf habitats
17.02.2017 | Universität Zürich

nachricht New, ultra-flexible probes form reliable, scar-free integration with the brain
16.02.2017 | University of Texas at Austin

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Biocompatible 3-D tracking system has potential to improve robot-assisted surgery

17.02.2017 | Medical Engineering

Real-time MRI analysis powered by supercomputers

17.02.2017 | Medical Engineering

Antibiotic effective against drug-resistant bacteria in pediatric skin infections

17.02.2017 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>