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In this study, we show that blocking programmed death (PD)-1\/PD-L1 inhibitory signals on exhausted CD8+ T cells, in combination with therapeutic vaccination, synergistically enhances functional CD8+ T cell responses and improves viral control in mice chronically infected with lymphocytic choriomeningitis virus. This combinatorial therapeutic vaccination was effective even in the absence of CD4+ T cell help. Thus, our study defines a potent new approach to augment the efficacy of therapeutic vaccination by blocking negative signals. Such an approach may have broad applications in developing treatment strategies for chronic infections in general, and perhaps also for tumors.<\/jats:p>","DOI":"10.1084\/jem.20071949","type":"journal-article","created":{"date-parts":[[2008,3,11]],"date-time":"2008-03-11T16:58:35Z","timestamp":1205254715000},"page":"543-555","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":175,"title":["Enhancing therapeutic vaccination by blocking PD-1\u2013mediated inhibitory signals during chronic infection"],"prefix":"10.1084","volume":"205","author":[{"given":"Sang-Jun","family":"Ha","sequence":"first","affiliation":[{"name":"1Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott N.","family":"Mueller","sequence":"additional","affiliation":[{"name":"1Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. 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