One virus—many strategies: type-specific interactions between human adenoviruses and innate immunity

Human adenoviruses (HAdVs) are double-stranded DNA viruses that can cause a wide range of infections, including respiratory, gastrointestinal, and ocular diseases, as well as less common conditions such as hepatitis, hemorrhagic cystitis, and encephalitis. While most infections in immunocompetent individuals remain clinically asymptomatic, immunocompromised patients are at a high risk of developing severe HAdV infections. Due to their exceptional transduction efficiency, HAdVs are also widely used as vaccine vectors, such as in vector-based COVID-19 vaccines. Although HAdVs are present as pathogens and vectors, the interaction between HAdVs and the human immune system remains insufficiently studied. Most adenoviral basic research in this context has focused on HAdV-C5. However, differences in capsid structure and genome organization exist not only between adenovirus species but also among types within the same species. These variations may influence the ability of the virus to evade or counteract the host immune system, ultimately influencing viral infectivity and replication efficiency. Further studies are needed to elucidate these differences. In this review, we summarize the differences in immune responses, with a particular emphasis on triggered IFN responses, across various HAdV species and their influence on infection outcomes, as well as their implications for the use of adenoviral vectors. Future research addressing these differences will be essential to better understand adenovirus pathogenesis and the rational design of adenovirus-based vectors.