An animal model of HLA-independent, chimeric antigen receptor-mediated adoptive immunotherapy against cytomegaloviruses
Human cytomegalovirus (HCMV) is a member of the Herpesviridae that establishes lifelong latency following primary infection. While an infection in immunocompetent individuals is typically asymptomatic, HCMV poses a significant health threat to immunocompromised patients. This includes e.g. organ or hematopoietic stem cell transplant recipients and patients undergoing chemotherapy. The management of HCMV infection in these immunocompromised populations is complicated by antiviral resistances against conventional drugs and the virus’s ability to evade immune surveillance through immune modulation processes including downregulation of the major histocompatibility complex (MHC), thereby preventing cytotoxic T cell recognition. This work investigates a new strategy of immunotherapy using cytotoxic T cells expressing chimeric antigen receptors (CARs) on murine cytomegalovirus (MCMV) infections in vitro and in a mouse model. Originally used for cancer treatment, CAR T cells contain a chimeric receptor on its surface, which is composed of an extracelluar single-chain variable fragment (scFv) redirecting the cytotoxic T cell to a specific target structure. In addition to the CAR, the scFv region consists of a costimulatory domain, which is essential for T cell activation as it facilitates activation for intracellular signalling and costimulatory molecules. In previous projects, our research group described a variety of different CAR constructs. In this project a CAR construct directed against the viral glycoprotein gB is used. gB is expressed during the early phases of CMV replication and is required for virus maturation, making it an ideal target for CAR T cell therapy.
