Resisting Infection From HIV

Antibodies tethered to immune cells more effectively block HIV than free-floating antibodies, a new study published in the Proceedings of the National Academy of Sciences found.

The investigators refer to the technique as the “neighbor effect,” which involves antibodies hanging on to a cell’s surface to block HIV from accessing a cell receptor and spreading infection. According to the investigators, an antibody stuck nearby is more effective than having many antibodies floating throughout the bloodstream.

“You don’t need to have so many molecules on one cell to be effective,” said first author Jia Xie.

Before the system was tested against HIV, the investigators first used rhinovirus as a model. The vector lentivirus was used to deliver a new gene to cultured human cells, and instruct them to synthesize antibodies that bind with the human cell receptor ICAM-1 that the rhinovirus needs.

When the antibodies monopolize the site, the virus is unable to enter the cell. “This is really a form of cellular vaccination,” said senior author Richard Lerner, MD.

Because the system cannot reach all the cells, the finished product ended up being a mix of both engineered and unengineered cells, according to the study. The investigators then added rhinovirus to the cell populations.

The results of the study showed that in approximately 2 days, a vast majority of cells died. In dishes containing only unengineered cells, the population never recovered. For the mixed engineered/unengineered populations, the investigators found that there was an initial die-off, but their numbers quickly came back.

After 125 hours, the cell population levels returned and were about the same as cells in the control group.

The success of the experiment led the investigators to test the same technique against HIV. They tested antibodies that could potentially protect the CD4 receptors that are normally killed by HIV.

“This research is possible because of the ability to select specialized antibodies from combinatorial antibody libraries,” Lerner said.

The technique was successful, and after introducing the cells to the virus, they were left with an HIV-resistant population. The antibodies could recognize the CD4 binding site and blocked HIV from reaching the receptor.

The findings were confirmed through additional experiments, concluding that tethered antibodies blocked HIV more effectively than free-floating, soluble antibodies.

The investigators plan to collaborate with scientists at City of Hope’s Center for Gene Therapy to evaluate the safety and efficacy of the new therapy.

“City of Hope currently has active clinical trials of gene therapy for AIDS using blood stem cell transplantation, and this experience will be applied to the task of brining this discovery to the clinic,” said John A. Zaia, MD, director of the Center for Gene Therapy in the Hematological Malignancy and Stem Cell Transplantation Institute at City of Hope. “The ultimate goal will be the control of HIV in patients with AIDS without the need for other medications.

In addition to the potential collaboration, Xie hopes to engineer antibodies to protect a different receptor on the cell surface.