Mechanistic Insights into Adenovirus Resistance to UV: Dose-Dependent Repair and Delayed Suppression of Host DNA Damage Response

Adenoviruses are among the most UV-resistant waterborne pathogens, posing significant challenges to disinfection strategies in potable reuse and wastewater treatment. This study investigates the DNA repair mechanisms underlying adenoviral recovery following UV exposure. Adenovirus type 2 (Adv 2) was irradiated with low-pressure (254 nm) UV at doses ranging from 0 to 80 mJ/cm² and then introduced into A549 host cells. Viral infectivity, genome integrity, and gene expression (E1A, E4orf3, E4orf4, and Hexon) were tracked across a 48 h infection period. Results showed a threshold inactivation response: doses ≤ 15 mJ/cm² caused DNA lesions without loss of infectivity, whereas doses ≥ 20 mJ/cm² resulted in significant inactivation (>1 log). DNA repair was dose-dependent and temporally distinct. At low UV doses, lesion clearance was delayed, coinciding with viral transcription and consistent with transcription-coupled nucleotide excision repair (TC-NER). At higher doses, lesions were repaired rapidly, preceding early gene expression, suggesting activation of global-genome NER (GG-NER). Delayed expression of E4 genes at high UV doses may facilitate host-mediated repair before the viral shutdown of DNA damage responses. These findings provide mechanistic insight into adenoviral UV resistance and underscore the limitations of current UV treatment benchmarks, informing risk assessment and the design of more robust disinfection protocols.