Double trouble: how co- and superinfections shape viral dynamics and host responses

Concurrent infection of humans by multiple distinct viruses is a common biological phenomenon with important consequences for virus-host interactions. While coinfection refers to the simultaneous infection of an individual or cell with two or more viruses, superinfection denotes the establishment of a secondary infection following a primary one, in which the initial infection influences the susceptibility, replication, or outcome of the secondary infection. Virus-virus interactions can be antagonistic, facilitative, dependent/assisted, or neutral. Antagonistic interactions include superinfection exclusion, whereby a primary virus prevents or restricts secondary infection of the same cell, securing access to host resources and stabilizing replication while limiting genetic and viral diversity. In contrast, facilitative viral interactions arise when one virus disrupts tissue barriers, suppresses immune responses, or remodels cellular pathways, thereby increasing susceptibility to additional viral infections. These interactions intersect with fundamental viral strategies, including the generation of genetically diverse RNA virus quasispecies that promote rapid adaptation and the deployment of DNA virus immunoevasins that interfere with antigen presentation and host immune recognition. While each of these processes has been extensively studied individually, their combined impact during coinfection remains poorly defined. In this review, we synthesize current knowledge on virus-virus interactions, viral diversity, and immune evasion in the context of multi-viral infections. We focus on how interactions at cellular and tissue levels shape infection outcomes, influence viral evolution, and contribute to virus-host coevolution. Finally, we also highlight key gaps in our understanding of viral interference and cooperation and discuss emerging approaches needed to define the spatiotemporal dynamics of coinfection in vivo .