Prostaglandin E2-Induced Immune Exhaustion and Enhancement of Antiviral Effects by Anti-PD-L1 Antibody Combined with COX-2 Inhibitor in Bovine Leukemia Virus Infection

Bovine leukemia virus (BLV) infection is a chronic viral infection of cattle and endemic in many countries, including Japan. Our previous study demonstrated that PGE(2), a product of cyclooxygenase (COX)(2) suppresses Th1 responses in cattle and contributes to the progression of Johne disease, a chronic bacterial infection in cattle. However, little information is available on the association of PGE(2) with chronic viral infection. Thus, we analyzed the changes in plasma PGE(2) concentration during BLV infection and its effects on proviral load, viral gene transcription, Th1 responses, and disease progression. Both COX2 expression by PBMCs and plasma PGE(2) concentration were higher in the infected cattle compared with uninfected cattle, and plasma PGE(2) concentration was positively correlated with the proviral load. BLV Ag exposure also directly enhanced PGE(2) production by PBMCs. Transcription of BLV genes was activated via PGE(2) receptors EP2 and EP4, further suggesting that PGE(2) contributes to disease progression. In contrast, inhibition of PGE(2) production using a COX-2 inhibitor activated BLV-specific Th1 responses in vitro, as evidenced by enhanced T cell proliferation and Th1 cytokine production, and reduced BLV proviral load in vivo. Combined treatment with the COX-2 inhibitor meloxicam and anti-programmed death-ligand 1 Ab significantly reduced the BLV proviral load, suggesting a potential as a novel control method against BLV infection. Further studies using a larger number of animals are required to support the efficacy of this treatment for clinical application.