A Combination of Anti-PD-L1 Treatment and Therapeutic Vaccination Facilitates Improved Retroviral Clearance via Reactivation of Highly Exhausted T Cells

PD-1-targeted therapies have shown modest antiviral effects in preclinical models of chronic viral infection. Thus, novel therapy protocols are necessary to enhance T cell immunity and viral control to overcome T cell dysfunction and immunosuppression. Here, we demonstrate that nanoparticle-based therapeutic vaccination improved PD-1-targeted therapy during chronic infection with Friend retrovirus (FV). Prevention of inhibitory signals by blocking PD-L1 in combination with therapeutic vaccination with nanoparticles containing the microbial compound CpG and a CD8(+) T cell Gag epitope peptide synergistically enhanced functional virus-specific CD8(+) T cell responses and improved viral clearance. We characterized the CD8(+) T cell populations that were affected by this combination therapy, demonstrating that new effector cells were generated and that exhausted CD8(+) T cells were reactivated at the same time. While CD8(+) T cells with high PD-1 (PD-1(hi)) expression turned into a large population of granzyme B-expressing CD8(+) T cells after combination therapy, CXCR5-expressing follicular cytotoxic CD8(+) T cells also expanded to a high degree. Thus, our study describes a very efficient approach to enhance virus control and may help us to understand the mechanisms of combination immunotherapy reactivating CD8(+) T cell immunity. A better understanding of CD8(+) T cell immunity during combination therapy will be important for developing efficient checkpoint therapies against chronic viral infections and cancer.