Aguilera-Flores_2026_Arch.Virol_171_

Dipeptidyl Peptidase 4 (DPP4) is a type II transmembrane serine protease with diverse physiological roles in metabolic regulation and immune modulation. Beyond its native functions, DPP4 has emerged as a critical host factor exploited by a range of viruses to drive infection and pathogenesis. This review synthesizes the multifaceted interactions between DPP4 and viral pathogens. We examine the structural basis for direct receptor binding by coronaviruses such as MERS and PHEV, as well as the dual-receptor entry mechanism used by human astroviruses. Additionally, the review explores how viruses such as HIV-1 and HCV exploit DPP4's enzymatic and non-enzymatic functions to modulate T cell activation and promote viral persistence. Finally, we evaluate pharmacological perspectives, including DPP4 inhibitors, monoclonal antibodies, and soluble decoy receptors as host-directed therapies. By mapping these diverse viral strategies, this article provides a comprehensive framework for understanding DPP4 as a moonlighting protein and a promising target for broad-spectrum antiviral interventions.