Broadly neutralizing antibody–derived CAR T cells reduce viral reservoir in individuals infected with HIV-1

BACKGROUND.Chimeric antigen receptor (CAR) T cells have emerged as an approach to treat malignant tumors.This strategy has also been proposed for the treatment of HIV-1 infection.We have developed a broadly neutralizing antibody-derived (bNAb-derived) CAR T cell therapy that can exert specific cytotoxic activity against HIV-1-infected cells. METHODS.We conducted an open-label trial of the safety, side-effect profile, pharmacokinetic properties, and antiviral activity of bNAb-derived CAR T cell therapy in individuals infected with HIV-1 who were undergoing analytical interruption of antiretroviral therapy (ART). RESULTS.A total of 14 participants completed only a single administration of bNAb-derived CAR T cells.CAR T cell therapy administration was safe and well tolerated.Six participants discontinued ART, and viremia rebound occurred in all of them, with a 5.3-week median time.Notably, the cell-associated viral RNA and intact proviruses decreased significantly after CAR T cell treatment.Analyses of HIV-1 variants before or after CAR T cell administration suggested that CAR T cells exerted pressure on rebound viruses, resulting in a selection of viruses with less diversity and mutations against CAR T cell-mediated cytotoxicity. CONCLUSION.No safety concerns were identified with adoptive transfer of bNAb-derived CAR T cells.They reduced viral reservoir.All the rebounds were due to preexisting or emergence of viral escape mutations.