Portal de Periódicos da CAPES

Dual CD4-based CAR T cells with distinct costimulatory domains mitigate HIV pathogenesis in vivo

2020; Nature Portfolio; Volume: 26; Issue: 11 Linguagem: Inglês

10.1038/s41591-020-1039-5

1546-170X

Colby R. Maldini, Daniel T. Claiborne, Ken Okawa, Tao Chen, Derrick L. Dopkin, Xiaochuan Shan, Karen A. Power, Radiana Trifonova, Katharine L. Krupp, Meredith Phelps, Vladimir Vrbanac, Serah Tanno, Timothy Bateson, George J. Leslie, James A. Hoxie, Christian L. Boutwell, James L. Riley, Todd M. Allen,

T-cell and B-cell Immunology

An effective strategy to cure HIV will likely require a potent and sustained antiviral T cell response. Here we explored the utility of chimeric antigen receptor (CAR) T cells, expressing the CD4 ectodomain to confer specificity for the HIV envelope, to mitigate HIV-induced pathogenesis in bone marrow, liver, thymus (BLT) humanized mice. CAR T cells expressing the 4-1BB/CD3-ζ endodomain were insufficient to prevent viral rebound and CD4+ T cell loss after the discontinuation of antiretroviral therapy. Through iterative improvements to the CAR T cell product, we developed Dual-CAR T cells that simultaneously expressed both 4-1BB/CD3-ζ and CD28/CD3-ζ endodomains. Dual-CAR T cells exhibited expansion kinetics that exceeded 4-1BB-, CD28- and third-generation costimulated CAR T cells, elicited effector functions equivalent to CD28-costimulated CAR T cells and prevented HIV-induced CD4+ T cell loss despite persistent viremia. Moreover, when Dual-CAR T cells were protected from HIV infection through expression of the C34-CXCR4 fusion inhibitor, these cells significantly reduced acute-phase viremia, as well as accelerated HIV suppression in the presence of antiretroviral therapy and reduced tissue viral burden. Collectively, these studies demonstrate the enhanced therapeutic potency of a novel Dual-CAR T cell product with the potential to effectively treat HIV infection. Chimeric antigen receptor T cells targeting HIV-infected cells prevent T cell loss and reduce virus in blood and tissues of HIV-infected humanized mice, highlighting a path toward a cell-based therapy for HIV infection.