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.IMPORTANCE Despite significant efforts, vaccines are not yet available for every infectious pathogen, and the search for a protective approach to prevent the establishment of chronic infections, i.e., with HIV, continues. Immune checkpoint therapies targeting inhibitory receptors, such as PD-1, have shown impressive results against solid tumors. However, immune checkpoint therapies have not yet been licensed to treat chronic viral infections, since a blockade of inhibitory receptors alone provides only limited benefit, as demonstrated in preclinical models of chronic viral infection. Thus, there is a high interest in the development of potent combination immunotherapies. Here, we tested whether the combination of a PD-L1 blockade and therapeutic vaccination with functionalized nanoparticles is a potent therapy during chronic Friend retrovirus infection. We demonstrate that the combination therapy induced a synergistic reinvigoration of the exhausted virus-specific CD8⁺ T cell immunity. Taken together, our results provide further information on how to improve PD-1-targeted therapies during chronic viral infection and cancer.

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