Inflammation Promotes the Loss of Adeno-Associated Virus–Mediated Transgene Expression in Mouse Liver

Abstract

Background & Aims Transgenes delivered to livers of mice via adeno-associated virus (AAV) are expressed stably, via induction of immune tolerance. However, transgene expression is lost in higher-order primates. We investigated whether inflammatory processes, which likely differ between species, affect the stability of transgene expression. Methods We developed a mouse model of vector-unrelated, systemic inflammation following AAV-mediated transfer of genes to liver. Results Inflammation eliminated previously stable expression of trangenes delivered by AAV; the limited tissue destruction and persistence of AAV genomes implicated immune responses that were not mediated by cytotoxic T cells. Tumor necrosis factor (TNF)-α downregulated transgene expression from AAV, indicating a role for inflammatory cytokines in loss of transgene expression. Conclusions Inflammation and inflammatory cytokines such as TNF-α can reduce AAV-mediated expression of transgenes in livers of mice. Inflammation might therefore affect expression of transgenes from viral vectors in humans.

Engineered AAV vector minimizes in vivo targeting of transduced hepatocytes by capsid-specific CD8+ T cells

“…However, their ability to target AAV-transduced human hepatocytes in vivo has been indirectly inferred from correlations between their emergence in peripheral blood and onset of transaminitis, 11,18 whereas animal models failed to show this effect. Data presented here in a highly defined setting clearly demonstrate that capsid-specific CD8 1 T cells can target AAV-transduced liver 45 reported that inflammation could silence AAV-derived gene expression in the liver via a tumor necrosis factor a-dependent mechanism. Several reasons may explain why capsid-specific CTLs were effective in our mouse model while previous experimental approaches were not.…”

The Threefold Protrusions of Adeno-Associated Virus Type 8 Are Involved in Cell Surface Targeting as Well as Postattachment Processing

“…They combine several advantageous features, including a good safety profile, stable long-term gene expression in several tissues, the ability to transduce dividing and nondividing cells, and physicochemical stability (11,66). AAV vectors show generally a low innate immunity, as well as low efficiency to transduce professional antigen-presenting cells (87), although recent studies warrant a more differentiated view of the immune response to AAV-mediated gene transfer (8,22,23,26,29,32,33,37,50,65,84,88). Humoral immune responses are generated and memory CD8 ϩ T-cell responses have been observed in clinical trials (36,40,58).…”

In the rat liver, Adenoviral gene transfer efficiency is comparable to AAV

“…In this respect, the recent study of the group of Wilson showing that inflammation can prevent prolonged expression seems very relevant. 25 Although in that study some loss corrected cells was seen, silencing of transgene expression due to the inflammatory response appeared to be the main cause of the loss of correction. The mild and transient increase in liver enzymes observed a week after injection of Adenovirus, would be in agreement with such a mechanism (not shown).…”