Reprogramming CAR T Cells

The first step was to develop a CAR T cell that expressed the human CD4 protein. HIV uses CD4 to attack and infect cells, so adding it to the CAR T cells allowed them to recognize and target HIV-infected cells. Since HIV spreads quickly once it infects the body, the researchers powered up their CAR T cells by adding a stimulating signal that increases their ability to make new CAR T cells that live longer.

But this wasn’t enough against a virus as powerful as HIV.

“Even with a potent boost, the CAR T cells had no effect on the virus,” said Colby Maldini, a graduate student at the University of Pennsylvania and lead author of the study.

“Although we were disappointed, we weren’t surprised, given the tenacity of this virus,” said Danial Claiborne, PhD, a research fellow at the Ragon Institute and co-lead author of this study. The CAR T cells they designed were effective at targeting HIV, but they weren’t able to kill enough infected cells to have a significant impact.

To beat the virus, the CAR T cells needed another boost.

The researchers decided to add another stimulating signal to help the T cells more effectively kill their target cells. This created a new type of CAR T cell, called a Dual CAR T cell, that was double-engineered to fight HIV-infected cells.

The Dual CAR T cell was much better at killing infected cells, but the researchers still had to overcome one more problem: The CD4 allowed CAR T cells to recognize HIV, but it also made them more susceptible to infection. T cells are, after all, a favorite target for HIV infection.

To protect them, Riley’s group looked to a small peptide called C34, which prevents HIV from entering cells.

When the researchers used these new, HIV-resistant Dual CAR T cells in mice with humanized immune systems, they found that the Dual CAR T cells slowed HIV infection, protected the mice from loss of CD4+ T cells and left the mice with fewer HIV-infected cells.

When they used the Dual CAR T cells along with antiretroviral therapy (ART), a daily treatment that suppresses HIV in humans, the mice were able to suppress HIV infection faster than on ART alone and had fewer HIV-infected T cells. Additionally, the mice’s viral reservoirs—hidden copies of HIV RNA that lay in wait to infect new cells if ART is stopped—were much smaller.

What does this mean?

It shows that the Dual CAR T cells could be used to treat HIV infections and even attack the viral reservoirs—a long sought after goal for HIV. Researchers hope that one day they may even be able to use these cells to create a functional cure for HIV—a one- or two-dose treatment that could permanently suppress the virus and prevent it from causing disease.