Combining metabolic and checkpoint therapy: 1,25-dihydroxyvitamin D₃ enhances the antiviral efficacy of anti-PD-1 in BVDV infection.

Abstract

Bovine viral diarrhea virus (BVDV) infection induces severe immunosuppression and peripheral blood lymphopenia, driven by PD-1/PD-L1-mediated T cell exhaustion. Emerging evidence highlights 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃, VD), the active metabolite of vitamin D, as a critical modulator of antiviral immunity. However, its interplay with PD-1 signaling in BVDV pathogenesis remains unexplored. This study investigated the therapeutic potential of VD alone or combined with PD-1 blockade in a murine BVDV infection model. We found that BVDV infection significantly reduced serum and intracellular concentrations of VD. Supplementation with VD effectively improved these levels, downregulated PD-1/PD-L1 expression, reduced lymphopenia, and reduced CD8T cell apoptosis. While both monotherapies showed benefits, their combination yielded superior outcomes. The combined therapy significantly enhanced viral clearance, improved pathological changes in spleen and duodenum, and enhanced CD8⁺ T cell proliferation and IFN-γ production. Mechanistically, the combination uniquely upregulated key anti-apoptotic signaling molecules (p-Akt, p-mTOR, p-ERK) in CD8⁺ T cells. Notably, therapeutic efficacy differed between cytopathic (CP) and non-cytopathic (NCP) biotypes, with PD-1 blockade showing greater dependency in CP infection. These findings highlight the therapeutic potential of targeting both metabolic dysregulation (via VD) and immune checkpoint inhibition (via PD-1 blockade) to combat BVDV-induced immunosuppression. This dual strategy may offer a novel approach for treating viral infections characterized by metabolic-viral-immune interplay.