title: Prostaglandin E2 and programmed cell death 1 signaling coordinately impair CTL function and survival during chronic viral infection.
abstract: More than 10% of the world's population is chronically infected with HIV, hepatitis C virus (HCV) or hepatitis B virus (HBV), all of which can cause severe disease and death. These viruses persist in part because continuous antigenic stimulation causes the deterioration of virus-specific cytotoxic T lymphocyte (CTL) function and survival. Additionally, antiviral CTLs autonomously suppress their responses to limit immunopathology by upregulating inhibitory receptors such as programmed cell death 1 (PD-1). Identification and blockade of the pathways that induce CTL dysfunction may facilitate the clearance of chronic viral infections. We found that the prostaglandin E2 (PGE₂) receptors EP2 and EP4 were upregulated on virus-specific CTLs during chronic lymphocytic choriomeningitis virus (LCMV) infection and suppressed CTL survival and function. We show that the combined blockade of PGE₂ and PD-1 signaling was therapeutic in terms of improving viral control and augmenting the numbers of functional virus-specific CTLs. Thus, PGE₂ inhibition is both an independent candidate therapeutic target and a promising adjunct therapy to PD-1 blockade for the treatment of HIV and other chronic viral infections.
authors: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors: Jonathan H
authors: JH
authors: Chen
authors: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors: Curtis J
authors: CJ
authors: Perry
authors: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors: Yao-Chen
authors: YC
authors: Tsui
authors: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors: Matthew M
authors: MM
authors: Staron
authors: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors: Ian A
authors: IA
authors: Parish
authors: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors: Claudia X
authors: CX
authors: Dominguez
authors: Center for Molecular Medicine, The University of Connecticut Health Center, Farmington, Connecticut, USA.
authors: Daniel W
authors: DW
authors: Rosenberg
authors: 1] Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors: Susan M
authors: SM
authors: Kaech
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D000068579:Celecoxib; D002470:Cell Survival; D015232:Dinoprostone / Q000378:metabolism*; D005260:Female; D008216:Lymphocytic Choriomeningitis / Q000276:immunology* / Q000821:virology; D008217:Lymphocytic choriomeningitis virus; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000378:metabolism; D015398:Signal Transduction; D013449:Sulfonamides / Q000737:chemistry; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013449:Sulfonamides; D000068579:Celecoxib; D015232:Dinoprostone