Infection of bronchial epithelial cells by the human adenoviruses A12, B3 and C2 differently regulates the innate antiviral effector APOBEC3B

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Abstract

Human adenoviruses (HAdVs) are a large family of DNA viruses counting more than 100 genotypes divided into seven species (A-G) and inducing respiratory tract infections, gastroenteritis and conjunctivitis. Genetically modified adenoviruses are also used as vaccines, gene therapies and anti-cancer treatments. The APOBEC3s are a family of cytidine deaminases that restrict viruses by introducing mutations in their genomes. Viruses developed different strategies to cope with the APOBEC3 selection pressure but nothing is known on the interplay between the APOBEC3s and the HAdVs. In this study, we focused on three HAdV strains: the B3 and C2 strains as they are very frequent and the A12 strain, less common but oncogenic in animal models. We demonstrated that the three HAdV strains induce a similar APOBEC3B upregulation at the transcriptional level. At the protein level however, the APOBEC3B is abundantly expressed during the HAdV-A12 and -C2 infection and shows a nuclear distribution. On the contrary, APOBEC3B is barely detectable in HAdV-B3-infected cells. APOBEC3B deaminase activity is detected in total protein extracts upon HAdV-A12 and -C2 infection. Bioinformatic analysis demonstrate that the HAdV-A12 genome bears a stronger APOBEC3 evolutionary footprint than the HAdV-C2 and HAdV-B3 genomes. Our results show that HAdV infection triggers the transcriptional upregulation of the antiviral innate effector APOBEC3B. The discrepancies between the APOBEC3B mRNA and protein levels might reflect the ability of some HAdV strains to antagonize the APOBEC3B protein. These findings point toward an involvement of APOBEC3B in HAdVs restriction and evolution.IMPORTANCEThe APOBEC3 family of cytosine deaminases has important roles in antiviral innate immunity and cancer. Notably, APOBEC3A and/or APOBEC3B are actively upregulated by several DNA tumor viruses and contribute to transformation by introducing mutations in the cellular genome. Human adenoviruses (HAdVs) are a large family of DNA viruses causing generally asymptomatic infections in immunocompetent adults. HAdVs encode several oncogenes and some HAdV strains like HAdV-A12 induce tumors in hamsters and mice. Here, we show that HAdV infection specifically promotes the expression of the APOBEC3B gene. We report that infection with the A12 strain induces a strong expression of an enzymatically active APOBEC3B protein in bronchial epithelial cells. We provide bioinformatic evidences that HAdVs' genomes and notably the A12 genome are under APOBEC3 selection pressure. Thus, APOBEC3B might contribute to adenoviral restriction, diversification and oncogenic potential of particular strains.

Original languageEnglish
JournalJournal of Virology
DOIs
Publication statusE-pub ahead of print - 14 Apr 2021

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