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Nat Med. 2015 Apr;21(4):327-34. doi: 10.1038/nm.3831. Epub 2015 Mar 23.

Prostaglandin E2 and programmed cell death 1 signaling coordinately impair CTL function and survival during chronic viral infection.

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Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
Center for Molecular Medicine, The University of Connecticut Health Center, Farmington, Connecticut, USA.
1] Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.


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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