Newly Discovered Antibodies Could Neutralize HIV Infection

Broadly neutralizing antibodies may help defend the body against HIV.

Proteins called broadly neutralizing antibodies (bNAbs) hold much promise in defending the body against HIV infection.

These proteins have been found in patients whose immune systems can naturally control their infection. The 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.

Researchers at Caltech have discovered that one particular bNAb may be able to recognize envelope spikes, even as they reconfigure during infection, making it easier to detect and neutralize infection in a patient with HIV.

HIV infection commences when the virus comes into contact with T cells in the human immune system that carry a particular protein, CD4, on their surface. Trimer proteins (proteins with 3 parts) called envelop spikes on the surface bind to CD4 proteins. When the spike binds to the CD4, it will go from being in a closed conformation to an open one or vice versa if the protein is in a different conformation to start.

The open conformation triggers the fusion of the virus with the target cell, allowing HIV to deposit its genetic material inside the host cell which leads to the factory-like manufacturing of new viruses that can go on to infect other cells.

The bNAbs recognize the envelope spike on the surface of HIV and most of them 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 1 specific target, or epitope, on this protein.

Some bNAbs are more effective than others, due to the fact that some targets allow more effective neutralization of the virus. In 2014, Rockefeller University reported the initial characterization of a potent bNAb called 8ANC195, found in the blood streams of patients who could naturally control their infection.

This antibody is capable of neutralizing 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,” said Louise Scharf, a postdoctoral scholar in Pamela 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.”

Researchers found that although most bNAbs recognize the envelope spike in its closed conformation, this particular bNAb could recognize them in both the closed conformation and partially open conformation.

“We think it’s actually an advantage if the antibody can recognize these different forms,” said Scharf.

The most common form of HIV infection is when a virus in the bloodstream binds to a T cell and infects the cell. In this scenario, envelope spikes on the free-floating virus would mostly be in the closed position until they made contact with the host cell.

Most bNAbs could neutralize this virus. However, HIV can also be spread directly from one cell to another, in which case, because the antibody already is attached to the host cell, the spike is in an open conformation. But 8ANC195 can still recognize and attach to it.

Researchers think this could be applied in medical settings in combination therapies where patients are given a multitude of different antibodies to try and attack the virus from different angles.

“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 said. “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 using bNAbs therapeutically may not be far from clinical settings. Scharf said that the same collaborators at Rockefeller University are already testing bNAbs in ha human treatment in a clinical trial.

The trial will not include 8ANC195; however, the antibody may be included in a combination therapy trial in the near future, according to Scharf.

“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 said.