Chimeric antigen receptor T‑cell therapy in chronic viral infections: a review

Despite the success of vaccination and small-molecule antivirals in significantly reducing mortality from acute viral infections, chronic viral infections such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), cytomegalovirus (CMV), and Epstein–Barr virus (EBV) remain persistent global health burdens. Latent reservoirs, drug resistance mutations, and immune evasion mechanisms enable these viruses to persist, highlighting the need for novel therapeutic approaches. Chimeric antigen receptor T-cell (CAR-T) therapy is an emerging immunotherapeutic strategy, initially developed to treat cancer, that harnesses a patient’s own immune cells to induce targeted immune responses. Chronic viral infections share significant similarities with tumors, including immune cell exhaustion, expression of inhibitory ligands, and metabolic suppression. Consequently, CAR-T-cell therapy holds promise as a new approach to treating chronic viral infections and has attracted considerable attention in recent years. This review systematically evaluates the progress in using CAR-T-cell therapy to treat chronic infections caused by HIV, HBV, CMV, and EBV, focusing on target selection and CAR-T-cell design strategies and highlighting the potential of these approaches to achieve disease control. CAR-T-cell therapy has shown progress against chronic viral infections, including HIV, HBV, CMV, and EBV. Constructs targeting multiple viral antigens have demonstrated antiviral activity in vitro and in animal models, and some have progressed to clinical trials. Despite these advances, CAR-T-cell therapy for chronic viral infections still faces key challenges, including the eradication of reservoirs, viral escape through mutations, risks of multiorgan toxicity, and ethical or regulatory concerns. Future directions include optimizing the CAR design, creating multifunctional CAR-T cells, combining CAR-T cells with other immunotherapies, and deriving CAR-T cells from hematopoietic stem cells to increase persistence. In parallel, robust ethical oversight and regulatory frameworks will be essential to ensure safe and responsible clinical translation.