Intracellular iron positively modulates the replicative cycle of mimiviruses, increasing virus production.

Mimiviruses, members of the Nucleocytoviricota phylum, produce large, pseudo-icosahedral virions densely coated with fibrils, except at a specialized fivefold vertex known as the stargate. Stargate opening is essential for delivering the viral core into the cytoplasm of phagocytic amoebae. These professional phagocytes deploy antimicrobial mechanisms such as the modulation of transition metal concentrations within phagolysosomes to eliminate internalized pathogens. Yet, mimiviruses have evolved striking adaptations to resist such hostile environments and initiate replication within these compartments. Here, we investigated the role of metal ions-particularly iron-in the replication of three giant viruses: Acanthamoeba polyphaga mimivirus (APMV), Antarctica virus, and Tupanvirus (TPV). We show that infection by these viruses increases cellular iron uptake and that elevated intracellular iron enhances viral replication. These findings reveal a previously underappreciated facet of the mimivirus-host interaction, in which iron availability acts as a positive modulator of the viral replicative cycle.IMPORTANCEGiant viruses like Mimivirus infect amoebae, which normally destroy microbes using toxic conditions inside cellular compartments. This study shows that, instead of being harmed, these viruses benefit from one of those supposedly hostile factors: iron. Through this work, we discovered that infection by Mimivirus and related viruses increases the host cell's iron uptake-and that more iron boosts virus production by the host cell. This reveals a surprising twist in the virus-host relationship: what should be a defense mechanism is turned into an advantage by the virus. By highlighting iron as a key factor in viral success, this work opens new perspectives on how giant viruses adapt to-and even exploit-the internal environment of their hosts. It also adds an important piece to our understanding of the complex strategies viruses use to survive and thrive inside cells.