β-Arrestins modulate Adenovirus-vector-induced innate immune responses: Differential regulation by β-arrestin-1 and β-arrestin-2

Adenovirus (Ad)-based vectors have been utilized in human gene transfer clinical trials since 1993. Unfortunately, innate immune responses directed against the Ad capsid and/or its genetic cargo can significantly limit the usage of Ad vectors. Previous studies have demonstrated that several signaling pathways are triggered by Ads, inclusive of TLR-dependent pathways. The G-protein-coupled receptor adaptors β-arrestin-1 (β-Arr1) and β-arrestin-2 (β-Arr2) are known to have pivotal roles in regulating TLR4 triggered signaling and inflammatory responses. In this study, we examined the role of β-arrestins in Ad5-vector-induced inflammatory responses. Our studies reveal that both β-arrestins are capable of modulating Ad5-vector-induced inflammatory responses in vivo and in vitro. Importantly, our studies divulge another level of complexity to these responses, as our results demonstrate β-Arr1 to be a positive regulator, and β-Arr2 a negative regulator of Ad5 induced innate immune responses. These data may allow gene therapy biologists to more accurately study the mechanisms underlying Ad5-vector-induced immune responses, and may also direct future efforts to modulate these mechanisms to improve the safety and/or efficacy of this important gene transfer vector.