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

Area of Science:

• Gene Therapy
• Immunology
• Virology

Background:

• Recombinant adeno-associated virus (rAAV) is a leading viral vector for gene therapy.
• Host immune responses, particularly innate immunity, to rAAV vectors are not fully understood.
• Understanding innate immune interactions is crucial for improving rAAV gene transfer efficacy.

Purpose of the Study:

• To investigate the innate immune response of human monocyte-derived dendritic cells (moDCs) to rAAV8.
• To compare the transcriptomic changes induced by rAAV8 versus adenovirus infection in moDCs.
• To assess the immunogenicity of rAAV8 for potential gene therapy applications.

Main Methods:

• Quantitative transcriptomic analysis of moDCs from 12 healthy donors after infection with rAAV8.
• Comparison of gene expression profiles between rAAV8-infected and mock-infected moDCs.
• Comparative analysis with transcriptomic data from adenovirus-infected moDCs.

Main Results:

• rAAV8 particles were efficiently internalized by moDCs.
• No significant transcriptomic changes or inflammatory pathway activation were detected in rAAV8-infected moDCs.
• Adenovirus infection, in contrast, robustly upregulated anti-viral pathways in moDCs.

Conclusions:

• rAAV8 exhibits an immunologically favorable profile regarding innate immune activation in moDCs.
• Transcriptomic analysis of innate immune cells provides a powerful tool to assess viral vector immunogenicity.
• These findings support the development of rAAV vectors with reduced immunogenicity for gene therapy.