Virus-based vaccines with unique replication mechanisms differentially infect and activate dendritic cells leading to distinctive CD8+ T cell responses

Abstract

Abstract The precise mechanism by which many virus-based vectors activate immune responses remains unknown. Dendritic cells (DCs) play key roles in priming T cell responses and controlling virus replication, but their functions in generating protective immunity following vaccination with viral vectors are not well understood. We hypothesized that highly immunogenic viral vectors with unique replication mechanisms but identical cell entry pathways differentially infect and activate DCs and promote antigen presentation that leads to efficient induction of distinctive antigen-specific T cell responses. To evaluate differences in replication mechanisms, we utilized a rhabdovirus vector (VSV) and an alphavirus-rhabdovirus hybrid vector (VLV), which replicates like an alphavirus but enters the cell via the VSV glycoprotein. We found that while virus replication promotes CD8+ T cell activation by VLV, replication is absolutely required for VSV-induced responses. DC subtypes were differentially infected in vitro with VSV and VLV, and displayed differences in activation following infection that were dependent on vector replication. Although bone marrow-derived DCs produced type I IFN when infected with the vectors, the mechanism of DC infection and activation was independent of type I IFN receptor signaling. Additionally, the ability of the alphavirus-based vector to generate CD8+ T cells in the absence of replication relied on cDC1 cells that promote antigen cross-presentation. These results highlight the differential activation of DCs following infection with unique viral vectors, and indicate potentially distinct roles of DC subtypes in activating the immune response following immunization.