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.
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Acknowledgements
The authors acknowledge C. Hao (Vanderbilt University, Nashville, Tennessee, USA) and E. Wherry (University of Pennsylvania, Philadelphia, Pennsylvania, USA) for generously providing EP2- and EP4-deficient mice and KbGP34 tetramers, respectively. This work was supported by RO1AI074699 (S.M.K.), the Yale Medical Scientist Training Program (T32GM07205 to J.H.C.) and the Howard Hughes Medical Institute (S.M.K.).
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J.H.C. designed and performed experiments, analyzed data, and wrote the paper; C.J.P., Y.-C.T., M.M.S. and C.X.D. designed and performed experiments; I.A.P. analyzed data and designed experiments; D.W.R. provided critical reagents; S.M.K. designed experiments, analyzed data and wrote the paper.
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J.H.C. and S.M.K. have applied for a patent based in part on the findings outlined in this paper.
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Chen, J., Perry, C., Tsui, YC. et al. Prostaglandin E2 and programmed cell death 1 signaling coordinately impair CTL function and survival during chronic viral infection. Nat Med 21, 327–334 (2015). https://doi.org/10.1038/nm.3831
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DOI: https://doi.org/10.1038/nm.3831
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