Modulation of adenoviral vector immune responses through the over-expression of immune adaptor and viral immuno-modulatory genes (48.17)

Abstract

Abstract For the past two decades, adenoviral vector platforms have been used as both gene therapy vehicles and vaccine platforms in various human clinical trials. However, the use of these, as well as other viral vector platforms, has been tempered by the innate immune and adaptive immune responses elicited. Despite the development of advanced generation adenoviral vectors, the innate responses precipitated by these vectors have remained largely unchanged due to the particular nature of the viral capsid and infectious process. To more effectively use these vectors for different purposes, we constructed adenoviral vectors encoding overexpression cassettes for various TLR adaptors (MyD88 and TRIF), RIG-I pathway adaptor (MAVS), as well as immuno-modulatory viral genes (pp65) whose expression might accentuate or inhibit the innate immune response enabled by adenoviral infection. Our studies show that while all of these immuno-modulatory vectors were able to effectively enhance (TLR and MAVS vectors) or inhibit (pp65 vectors) the NF-kB and IFN-beta responses in vitro, only certain vectors were able to affect the adaptive responses elicited in vivo. While our findings show that vector manipulation can influence vector-specific innate and adaptive immune responses, they also offer evidence for the highly regulatory nature of the innate response, as evidenced by the limited impact of certain adaptor overexpression.