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

Abstract

Bovine leukemia virus (BLV) infection is a chronic viral infection of cattle and endemic in many countries, including Japan. Our previous study demonstrated that PGE₂, 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 PGE₂ with chronic viral infection. Thus, we analyzed the changes in plasma PGE₂ 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 PGE₂ concentration were higher in the infected cattle compared with uninfected cattle, and plasma PGE₂ concentration was positively correlated with the proviral load. BLV Ag exposure also directly enhanced PGE₂ production by PBMCs. Transcription of BLV genes was activated via PGE₂ receptors EP2 and EP4, further suggesting that PGE₂ contributes to disease progression. In contrast, inhibition of PGE₂ 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.