Use of DAF-Displaying Adenovirus Vectors Reduces Induction of Transgene- and Vector-Specific Adaptive Immune Responses in Mice

Abstract

Adenovirus (Ad)-based vectors are attractive candidates for a variety of gene-transfer applications. In this study, we found that decay-accelerating factor (DAF)–displaying Ads induce significantly decreased cellular immune responses to transgenes expressed from the vectors in both Ad5-naive and Ad5-immune mice. Specifically, we found a diminished ability of splenocytes to secrete interferon-γ after recall exposure to multiple peptides derived from antigens expressed by DAF-displaying Ads. We also confirmed that DAF-displaying Ads induce decreased numbers of antigen-specific, CD8+ effector memory and central memory CD8+ T cells, thereby uncovering a unique role of complement in modulating the induction of robust memory T-cell responses. We also confirmed that DAF-displaying Ads generate significantly reduced titers of Ad capsid–specific neutralizing antibodies after gene transfer in vivo. In conclusion, DAF-displaying Ad5-based vectors exhibit decreased induction of complement-dependent, innate immune responses, resulting in both an improved safety profile and a decreased propensity to induce humoral and cellular adaptive immune responses to Ad capsid proteins and Ad vector-expressed transgene products. This attractive combination of features will be beneficial in a variety of clinically relevant gene-transfer applications. Seregin and colleagues report that adenovirus vectors displaying the human decay-accelerating factor (DAF) complement inhibitor elicited significantly decreased adaptive and neutralizing antibody responses to transgenes in both Ad5-naïve and Ad5-immune mice. This attractive combination of features in Ad vectors will be beneficial in a variety of clinically relevant genetransfer applications.