Viral Immunomodulation as a Potential Driver of Trained Immunity: Emerging Mechanisms of Innate Immune Memory and Antiviral Protection

The discovery of trained immunity has challenged the longstanding view that immunological memory is restricted to the adaptive immune system. Trained immunity refers to the capacity of innate immune cells to undergo long-term functional reprogramming following exposure to microbial, endogenous, or environmental stimuli, resulting in enhanced responses to subsequent challenges. Trained immunity is mediated by epigenetic and metabolic remodeling, including changes in chromatin accessibility, histone modifications, and cellular metabolism. Recent studies further demonstrate that these memory-like properties can also be established in hematopoietic stem and progenitor cells (HSPCs), providing a basis for their long-term persistence. While Bacillus Calmette–Guérin (BCG) and β-glucan are the best-characterized inducers of trained immunity, increasing evidence indicates that viral infections and viral vaccines can also induce durable innate immune reprogramming. Epidemiological studies have demonstrated heterologous protective effects associated with vaccinia, measles, and oral polio vaccines, while cytomegalovirus infection and severe SARS-CoV-2 infection have been linked to long-lasting alterations in innate immune function. Notably, many of these viruses possess potent immune evasion mechanisms that suppress interferon signaling, modulate NF-κB activation, disrupt antigen presentation, and alter myeloid cell function. We propose that viral immune evasion and immunomodulatory strategies may promote trained immunity by triggering compensatory metabolic, epigenetic, and transcriptional reprogramming that persists after resolution of infection. This review summarizes the historical development and molecular basis of trained immunity and examines emerging evidence linking viral infections and viral vaccines to innate immune memory. We further discuss the potential roles of virus-induced autophagy and long non-coding RNAs as mechanistic bridges connecting viral infection, immune reprogramming, and trained immunity. Understanding how viral infections shape innate immune memory may provide new opportunities for antiviral therapies, vaccine design, and broad-spectrum immune protection.