Vectored antibody delivery: impact on and synergy with the host’s immune defense in chronic viral infection

Gene therapy-based antibody delivery (vectored immunotherapy, VIT) represents an innovative approach to fight chronic viral diseases but its synergy with and impact on the host’s endogenous immune defense remain ill-defined. Here we developed an adeno-associated viral (AAV) vector to establish persistent high titers of a lymphocytic choriomeningitis virus- (LCMV-) neutralizing monoclonal antibody in chronically infected mice. Chronic viremia subsided in AAV-treated wildtype animals but not in mice lacking either CD8+ T cells or endogenous antiviral antibody responses. Persistence in the latter was due to the emergence of VIT-escape variants, which were effectively controlled by the endogenous antibody response of wildtype hosts. Vectored antibody delivery resulted in lowered expression of PD-1 and LAG3 on antiviral CD8+ T cells, increased endogenous antiviral antibody responses as well as elevated numbers of antiviral germinal center B cells and antibody-secreting cells in spleen. Our observations document that the therapeutic efficacy of vectored antibody therapy in chronic viral infection relies on its synergy with the host’s CD8+ T cell and antibody responses, both of which are functionally improved by vectored antibody delivery and contribute essentially to prevent viral mutational escape. VIT should be considered both an antiviral and an immunostimulatory approach to persistent viral infection