Modulation of the Liver Immune Microenvironment by the Adeno-Associated Virus Serotype 8 Gene Therapy Vector

Abstract Adeno-associated viruses (AAVs) are emerging as one of the vehicles of choice for gene therapy. However, the potential immunogenicity of these vectors it is a major limitation of their use, leading to the necessity of a better understanding of how viral vectors engage the innate immune system. Here, we demonstrate the immune response mediated by an AAV vector in a mouse model. Mice were infected intravenously with 4x10ˆ12 cp/kg of AAV8 and the ensuing immune response was analyzed using intravital microscopy, over a period of weeks. Administration of AAV8 resulted in the infection of hepatocytes and this infection led to a moderate, but significant, activation of the immune system in the liver. This host immune response involved platelet aggregation, NET formation, and the recruitment of monocytes, B cells and T cells. The resident liver macrophage population, Kupffer cells, were necessary to initiate this immune response as their depletion abrogated platelet aggregation and NET formation and delayed the recruitment of immune cells. Moreover, the death of liver cells produced by this AAV is moderate and fails to result in a robust, sustained inflammatory response. Altogether, these data suggest that AAV8 is a suitable vector for gene therapy approaches.