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
Broadly neutralizing antibodies (bNAbs) are thought to be the future for treating and preventing HIV infections. A bNAb recently characterized by researchers can neutralize the virus in several different states – increasing the antibody’s promise as a therapeutic.
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, envelope spike, present on the surface of all HIV strains and inhibiting, or neutralizing, the effects of the virus. 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 process of HIV infection begins when the virus comes into contact with CD4 T cells. 3-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.
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 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. “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 3D structure of this antibody in complex with the entire spike, and showed in detail exactly how the antibody recognizes the virus.”
RESULTS: 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.
NB: The most common form of HIV infection is when a virus in the bloodstream attaches to a T cell and infects the cell >> spikes in closed conformation until they contact the host cell. Most bNAbs could neutralize this virus. However, HIV also can spread directly from one cell to cell. As the antibody already is attached to the host cell, the spike is in an open conformation. But 8ANC195 can recognize and attach to it.
Med App of this antibody are the combination therapies, where 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.”
They have 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.
http://www.caltech.edu/news/antibody-can-attack-hiv-new-ways-47845
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