Development of a potent and infection-resistant anti-HIV CAR-T cells therapy

Abstract

Abstract Acquired immune deficiency syndrome (AIDS) caused by HIV infection is a serious global public health issue. The current combined antiretroviral therapy (ART) effectively controls HIV replication but fails to eliminate HIV reservoir cells, which allows a persistent viral infection. HIV-specific chimeric antigen receptor (CAR) T-cells have been designed to eliminate HIV-infected cells. The broad anti-viral activity, resistance to HIV infection and immune suppressive microenvironment determine a successful CAR-T therapy for HIV infection. In this study, we developed a potent CD4-based CAR-T cell with herpes virus entry mediator (HVEM) costimulatory domain. We intruded a S60C mutation in CD4 extracellular domain, which mediates a higher binding affinity to HIV envelope glycoprotein gp120 while preventes gp41-induced fusion between viral envelope and cell membrane. We demonstrated that CD4-based CAR-T cells bearing this 2C mutation were resistant to HIV infection. In addition, the HVEM costimulatory domain (CSD) mediated a superior effector T cell function than CD28 or 4-1BB-derived CSD did in CAR-T cells, showed by either cytotoxicity effect or cytokines response in contact with the HIV Envelope-transduced K562 cells in vitro. Furthermore, HVEM-CAR-T showed a better therapeutic efficacy than CD28 or 4-1BB CAR-T in humanized mouse model in vivo. Overall, we designed and developed a potent infection-resistant anti-HIV CAR-T cell by incorporating a mutant CD4 extracellular domain and HVEM-derived CSD.