Persistence of Integrase-Deficient Lentiviral Vectors Correlates with the Induction of STING-Independent CD8+ T Cell Responses

Summary: Lentiviruses are among the most promising viral vectors for in vivo gene delivery. To overcome the risk of insertional mutagenesis, integrase-deficient lentiviral vectors (IDLVs) have been developed. We show here that strong and persistent specific cytotoxic T cell (CTL) responses are induced by IDLVs, which persist several months after a single injection. These responses were associated with the induction of mild and transient maturation of dendritic cells (DCs) and with the production of low levels of inflammatory cytokines and chemokines. They were independent of the IFN-I, TLR/MyD88, interferon regulatory factor (IRF), retinoic acid induced gene I (RIG-I), and stimulator of interferon genes (STING) pathways but require NF-κB signaling in CD11c+ DCs. Despite the lack of integration of IDLVs, the transgene persists for 3 months in the spleen and liver of IDLV-injected mice. These results demonstrate that the capacity of IDLVs to trigger persistent adaptive responses is mediated by a weak and transient innate response, along with the persistence of the vector in tissues. : Lentiviruses (LVs) are among the most promising vaccine vectors. To develop safer LV-derived vaccines, integrase-deficient LVs (IDLVs) have been recently generated. Cousin et al. show here that IDLVs induce strong and persistent cytotoxic T cell responses and decipher the mechanisms by which IDLVs induce efficient adaptive immune responses. Keywords: integrase-deficient lentiviral vectors, cytotoxic T cell responses, memory, antigen persistence, innate pathways, pattern recognition receptors, vaccine