A NEW APPROACH PIONEERED AT UCLA TO TREAT HIV WITH chimeric antigen receptor (CAR) T gene therapy has yielded superior and longer-lasting results in mouse models than previous similar therapies, showing potential to not only destroy HIVinfected cells but also to create “memory cells” that could provide lifelong protection from infection with the virus that causes AIDS. CAR T gene therapy is a type of immunotherapy that involves genetically engineering the body’s own blood-forming stem cells to create HIV-fighting T cells.
CAR therapies have emerged as a powerful immunotherapy for various forms of cancer and show promise for treating HIV-1, the more prevalent of the two main forms of the virus. However, current applications of these therapies may not impart long-lasting immunity. Researchers have been seeking a T-cell–based therapy that can respond to malignant or infected cells that may reappear months or years after treatment. Once genet ical ly engineered stem cells that carry genes for CARs are transplanted into the body, they form specialized infection- fighting white blood cells, known as CAR T cells, that specifically seek out and kill cells infected with HIV.
CD4 is a glycoprotein on the surface of immune cells that sends signals to other types of immune cells. Because HIV binds to CD4 molecules in order to infect cells in the body, the researchers previously created a CAR molecule containing part of the CD4 molecule to hijack that interaction. When HIV would bind to the CD4 section of the CAR molecule on T cells, other regions of the CAR molecule would signal the cell to become activated and kill the virus. That molecule, however, contained two parts, or “domains,” that still had the potential to allow HIV infection.
For the new study, the researchers — who included Irvin S.Y. Chen, PhD, professor of microbiology, immunology & molecular genetics; Otto O. Yang, MD, professor of medicine; Jerome A. Zack, PhD, professor of microbiology, immunology & molecular genetics; and Scott Kitchen, PhD, professor of medicine — removed those domains while adding another one that makes the cells resistant to infection and allows for a more efficient and longer-lasting cell response against HIV than before.
The improved CAR therapy engineers the body’s immune response to HIV rather than waiting for the virus — or parts of the virus — to induce a response, in much the same way vaccines prime one’s immune system to respond against a virus. The new approach also leads to the production of a significant number of “memory” T cells that are capable of more potently and quickly responding to reactivated HIV. “Our study highlights the identification of a next-generation CAR molecule that protected cells from infection, targeted and reduced HIV burdens, and serves as an ideal developmental candidate for further clinical studies,” the researchers wrote. —Enrique Rivero
“Robust CAR-T Memory Formation and Function via Hematopoietic Stem Cell Delivery,” PLOS Pathogens, April 1, 2021