Tripartite warfare: decoding the cell-virus-virophage arms race

Giant viruses constitute a remarkable group of large double-stranded DNA (dsDNA) viruses distinguished by their exceptional structural complexity and genomic features. Their genomes can reach 2.8 Mb, encoding hundreds of proteins, and virion diameters up to 1.5 μm. They infect diverse eukaryotic hosts and establish viral factories within host cells. Virophages are small dsDNA viruses (17-34 kb; 50-75 nm) that parasitize giant viruses. These satellite viruses hijack giant virus replication machinery while suppressing giant virus progeny, benefiting the host cell and creating a parasitic-symbiotic dynamic. This review examines the tripartite relationship between host cells, giant viruses, and virophages (CVv systems), focusing on: (1) virus-host interactions in amebae, marine flagellates, and unicellular algae; (2) molecular mechanisms of these interactions; and (3) ecological and evolutionary implications. We also identify current research challenges and propose future directions, particularly the molecular basis of viral interactions in CVv systems.