Transcriptomic Analysis Reveals the Inability of Recombinant AAV8 to Activate Human Monocyte-Derived Dendritic Cells

Recombinant Adeno-Associated Virus (rAAV) is considered as one of the most successful and widely used viral vector for in vivo gene therapy. However, host immune responses to the vector and/or the transgene product remain a major hurdle to successful AAV gene transfer. In contrast to anti-vector adaptive immunity, the initiation of the innate immunity towards rAAV is still poorly understood but is directly dependent on the interaction between the viral vector and innate immune cells. Here, we used a quantitative transcriptomic-based approach to determine the activation of inflammatory and anti-viral pathways after rAAV8-based infection of monocyte-derived Dendritic Cells (moDC) obtained from 12 healthy human donors. We have shown that rAAV8 particles are efficiently internalized, but that this uptake does not induce any detectable transcriptomic change in moDC cells in contrast to an adenoviral infection which upregulates anti-viral pathways. These findings suggest an immunological favorable profile for rAAV8 serotype with regards to in vitro activation of moDC cell model. Transcriptomic analysis of rAAV-infected innate immune cells is a powerful method to determine the ability of the viral vector to be seen by these sensor cells, which remains of great importance to better understand the immunogenicity of rAAV vectors and to design immune-stealth products. Overall design: Transcriptomic analysis of human monocyte-derived dendritic cells at 48h under non-activated, LPS-R848 treatment and 2 distinct activation states: rAAV8 infection or Adenovirus infection