CD163 at the crossroads: a viral-exploited immunomodulator

Porcine reproductive and respiratory syndrome virus (PRRSV) is a major pathogen in pigs and poses a significant economic threat to the pig industry. CD163 acts as a key cellular receptor for PRRSV infection, mediating viral entry into host cells. Beyond functioning as a viral entry factor, CD163 plays multifaceted roles in PRRSV infection by linking viral pathogenesis with host immune regulation. This review summarizes current understanding of CD163's structure, physiological functions, mechanisms in PRRSV entry, and immunomodulatory roles during infection. We explore how CD163 expression and ectodomain shedding influence macrophage polarization and cytokine dynamics, thereby shaping viral persistence and tissue injury. Key evidence indicates that PRRSV harnesses anti-inflammatory signaling to sustain CD163 expression and promote entry, whereas pro-inflammatory stimuli downregulate CD163 and restrict replication. Shed soluble CD163 (sCD163) exhibits dual functions: it can act as a decoy receptor to mitigate viral spread, yet may also exacerbate inflammatory pathology. We also review recent advances in CD163-targeted interventions, including gene-edited pigs resistant to PRRSV, neutralizing antibodies, and small-molecule inhibitors that disrupt CD163-virus interactions. Critical analysis supports that targeted deletion or modification of CD163 confers viral resistance without impairing its essential physiological functions. In summary, CD163 functions not only as a gateway for PRRSV entry but also as an immunomodulator influencing disease outcomes. Elucidating this duality provides new perspectives for developing control strategies that combine effective viral blockade with the maintenance of immune homeostasis.