Infection with viruses that have the capacity to modulate or evade the immune response can result in persistence, which can lead to a variety of chronic problems including neoplasia, immunosuppression, autoimmune-like syndromes, and selective organ failure. Recently, two promising new treatment approaches that target either the inhibitory receptor programmed cell death 1 (PD-1) or neutralize interleukin-10 (IL-10) during chronic viral infection have been described. We discuss how future combination therapies can be used to inhibit viral synthesis as well as strengthen the antiviral response without increasing immunopathology or the development of autoimmune disease.