AAV Vectors Avoid Inflammatory Signals Necessary to Render Transduced Hepatocyte Targets for Destructive T Cells

Abstract

Studies in mice indicate that gene transfer to liver with vectors based on adeno-associated viruses (AAVs) is characterized by immunological tolerance to antigenic transgene products. Mechanisms to explain host nonresponsiveness have focused on aberrant T-cell responses. We propose a distinct mechanism for conferring tolerance to AAV-transduced hepatocytes that relates to diminished sensitivity of the target organ to T cell-mediated effects. T cells to beta-galactosidase (beta-gal) were adoptively transferred into RAG(-/-) mice expressing beta-gal in hepatocytes due to prior administration of either Ad or AAV vectors. Adoptive transfer was associated with extinction of LacZ expression in Ad-LacZ-transduced RAG(-/-) mice and had no effect on liver LacZ expression in AAV-LacZ-transduced RAG(-/-) mice. Systemic administration of TLR ligands lipopolysaccharide (LPS) and CpG at the time of adoptive transfer did lead to extinction of LacZ expression. Systemic TLR ligands were associated with upregulation of major histocompatibility complex (MHC) class I and the cell adhesion molecules ICAM and VCAM as was seen with Ad-LacZ alone. These data indicate that AAV transduction lacks the inflammatory signals necessary to render hepatocyte targets for cytotoxic T lymphocytes (CTLs). Underlying liver pathology may confound vector performance and should be considered in the design of clinical trials.

Combination therapy utilizing shRNA knockdown and an optimized resistant transgene for rescue of diseases caused by misfolded proteins

“…One interpretation for the discrepancy between human and mouse is that transgene tolerance has been demonstrated by AAV vector targeting the liver in mice. Recent studies have shown that the liver tolerance can be reversed by up-regulation of inflammatory signals (15). Accumulation of Fig.…”

Adaptive Immune Responses Elicited by Baculovirus and Impacts on Subsequent Transgene Expression In Vivo

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Evaluation of Adeno-Associated Viral Vectors for Liver-Directed Gene Transfer in Dogs

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