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

More than 10% of the world’s population is chronically infected with HIV, HCV or HBV, which cause severe disease and death. These viruses persist in part because continuous antigenic stimulation causes 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 clearance of chronic viral infections. We have identified that the prostaglandin E2 (PGE(2)) receptors EP2 and EP4 are upregulated on virus-specific CTLs during chronic LCMV infection and suppress CTL survival and function. We showed that the combined blockade of PGE(2) and PD-1 signaling was therapeutic in terms of improving viral control and augmenting the numbers of functional virus-specific CTLs. Thus, PGE(2) inhibition is both independent candidate therapeutic target and a promising adjunct therapy to PD-1 blockade for treatment of HIV and other chronic viral infections.