2区 · 医学
ArticleOA
作者: Guan, Min ; Lim, Laura ; Holguin, Leo ; Han, Tianxu ; Vyas, Vibhuti ; Urak, Ryan ; Miller, Aaron ; Browning, Diana L. ; Echavarria, Liliana ; Li, Shasha ; Li, Shirley ; Chang, Wen-Chung ; Scott, Tristan ; Yazaki, Paul ; Morris, Kevin V. ; Cardoso, Angelo A. ; Blanchard, M. Suzette ; Le Verche, Virginia ; Forman, Stephen J. ; Zaia, John A. ; Burnett, John C. ; Wang, Xiuli
T cells engineered to express HIV-specific chimeric antigen receptors (CARs) represent a promising strategy to clear HIV-infected cells, but to date have not achieved clinical benefits. A likely hurdle is the limited T cell activation and persistence when HIV antigenemia is low, particularly during antiretroviral therapy (ART). To overcome this issue, we propose to use a cytomegalovirus (CMV) vaccine to stimulate CMV-specific T cells that express CARs directed against the HIV-1 envelope protein gp120. In this study, we use a GMP-compliant platform to engineer CMV-specific T cells to express a second-generation CAR derived from the N6 broadly neutralizing antibody, one of the broadest anti-gp120 neutralizing antibodies. These CMV-HIV CAR T cells exhibit dual effector functions upon in vitro stimulation through their endogenous CMV-specific T cell receptors or the introduced CARs. Using a humanized HIV mouse model, we show that CMV vaccination during ART accelerates CMV-HIV CAR T cell expansion in the peripheral blood and that higher numbers of CMV-HIV CAR T cells were associated with a better control of HIV viral load and fewer HIV antigen p24+ cells in the bone marrow upon ART interruption. Collectively, these data support the clinical development of CMV-HIV CAR T cells in combination with a CMV vaccine in HIV-infected individuals.