Therefore, B7/CD28 costimulation is a critical rate-limiting step that determines the success of PD-1 therapies, and we demonstrate that it is plausible to reinforce B7/CD28 costimulation during chronic viral infection by triggering TLR4 with LPS, rendering exhausted CD8 T cells more responsive to PD-1 therapy. Here, TLR4 is linked to viral infectious disease.