Broadly Neutralizing Antibody Can Pin HIV with Either of Dual Holds

An antibody is a large, Y-shaped protein produced by plasma cells that the immune system uses to identify and neutralize pathogens such as bacteria and viruses.   Even broadly neutralizing antibodies (bNAbs) have difficulty grappling with HIV, but one such antibody has shown that it can prevent HIV from slipping away. This particular bNAb, 8ANC195, can take down HIV whether the virus’s main vulnerability, its envelope spike, is in the closed or open conformation. Most bNAbs can recognize only the closed conformation.

The envelope spike, a trimer protein that projects from the HIV particle, can change conformation at different stages of HIV infection. The closed conformation is typically found in free-roaming HIV. A partially open conformation occurs once HIV attaches to a host cell. Attacking the closed conformation allows most bNAbs to inhibit one mode of HIV infection, the mode in which the virus’ genetic material is passed from viral particle to host cell. Yet HIV infection also progresses in another way, in which HIV moves from one host cell to another.

The possibility of inhibiting either mode with a single bNAb was uncovered by researchers from Caltech. These researchers, led by Caltech’s Pamela Bjorkman, Ph.D., emphasize that this bNAb could prove especially useful in combination therapies, treatments in which a patient is given a cocktail of several antibodies that work in different ways to fight off HIV as it rapidly changes and evolves.

Bjorkman and colleagues described their work on September 10 in the journal Cell in an article entitled, “Broadly Neutralizing Antibody 8ANC195 Recognizes Closed and Open States of HIV-1 Env.” This work extends previous findings established by Dr. Bjorkman’s group and colleagues from Rockefeller University. In 2014, the collaborators identified 8ANC195 in the blood of HIV patients whose immune systems could naturally control their infections. They also discovered that this antibody could neutralize HIV by targeting a different epitope than any previously identified bNAb.

In work described in the recent Cell paper, Dr. Bjorkman’s lab investigated how 8ANC195 functions—and how its unique properties could benefit HIV therapies.

“To determine whether 8ANC195 recognizes the CD4-bound open Env conformation that leads to co-receptor binding and fusion, one of several known conformations of virion-associated Env, we solved EM structures of an Env/CD4/CD4-induced antibody/8ANC195 complex,” wrote the authors. “8ANC195 binding partially closed the CD4-bound trimer, confirming structural plasticity of Env by revealing a previously unseen confirmation.”

“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 Dr. Bjorkman’s laboratory and the first author of 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.”

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

Furthermore, the availability of complete information about how 8ANC195 binds to the viral spike will allow researchers 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,” Dr. Bjorkman concluded.