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PD-1 and CTLA-4 Inhibitory Cosignaling Pathways in HIV Infection and the Potential for Therapeutic Intervention

Daniel E. Kaufmann^1,* and Bruce D. Walker^*,

^* Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard (formerly Partners AIDS Research Center), Massachusetts General Hospital, Charlestown, MA 02129; and Howard Hughes Medical Institute, Chevy Chase, MD 20185

The balance between proinflammatory mechanisms and the dampening of excessive immune activation is critical for successful clearance of a pathogen without harm to the host. In particular, molecules of the B7:CD28 family play a critical role in regulating T cell activation and peripheral tolerance. Chronic pathogens like HIV, which is characterized by ongoing viral replication despite detectable virus-specific T cell responses, and cancer cells have exploited these pathways to attenuate Ag-specific T cell immunity. This review summarizes evidence that molecules of the B7:CD28 family, PD-1, CTLA-4, and their ligands, play an active and reversible role in virus-specific T cell exhaustion associated with HIV infection in humans and in the SIV model in macaques. We discuss the potential for immunotherapeutic interventions based on manipulation of these inhibitory networks, the promising data obtained with blockade of the PD-1 pathway in animal models, and the challenges to such therapies.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Daniel Kaufmann, Massachusetts General Hospital East, Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Room 6618B, 149 13th Street, Charlestown, MA 02129. E-mail address: dkaufmann{at}partners.org

² Abbreviations used in this paper: PD-1, programmed death-1; DC, dendritic cell; LCMV, lymphocytic choriomeningitis virus; PD-L, programmed death ligand.

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