Differential activation of innate immune responses by adenovirus and adeno-associated virus vectors

AK Zaiss, Q Liu, GP Bowen, NCW Wong… - Journal of …, 2002 - Am Soc Microbiol
AK Zaiss, Q Liu, GP Bowen, NCW Wong, JS Bartlett, DA Muruve
Journal of virology, 2002Am Soc Microbiol
Adenovirus vectors induce acute inflammation of infected tissues due to activation of the
innate immune system and expression of numerous chemokines and cytokines in
transduced target cells. In contrast, adeno-associated virus (AAV) vectors are not associated
with significant inflammation experimentally or clinically. We tested the ability of AAV vectors
to induce the expression of chemokines in vitro and to activate the innate immune system in
vivo. In human HeLa cells and murine renal epithelium-derived cells (REC cells) the …
Abstract
Adenovirus vectors induce acute inflammation of infected tissues due to activation of the innate immune system and expression of numerous chemokines and cytokines in transduced target cells. In contrast, adeno-associated virus (AAV) vectors are not associated with significant inflammation experimentally or clinically. We tested the ability of AAV vectors to induce the expression of chemokines in vitro and to activate the innate immune system in vivo. In human HeLa cells and murine renal epithelium-derived cells (REC cells) the adenovirus vector AdlacZ induced the expression of multiple inflammatory chemokines including RANTES, interferon-inducible protein 10 (IP-10), interleukin-8 (IL-8), MIP-1β, and MIP-2 in a dose-dependent manner. The use of AAVlacZ did not induce the expression of these chemokines above baseline levels despite 40-fold-greater titers than AdlacZ and greater amounts of intracellular AAVlacZ genomes according to Southern and slot blot analysis. This finding confirmed that the lack of AAVlacZ induction of chemokine was not due to reduced transduction. In DBA/2 mice, the intravenous administration of 2.5 ื 1011 particles of AAVlacZ resulted in the rapid induction of liver tumor necrosis factor alpha (TNF-α), RANTES, IP-10, MIP-1β, MCP-1, and MIP-2 mRNAs. However, 6 h following injection, chemokine mRNA levels returned to baseline. As expected, administration of 10-fold less AdlacZ caused an induction of liver TNF-α and chemokine mRNAs that persisted for more than 24 h posttransduction. Whereas intravenous administration of 2.5 ื 1011 particles of AAVlacZ triggered a transient infiltration of neutrophils and CD11b+ cells into liver, this response stood in contrast to widespread inflammation and toxicity induced by AdlacZ. Kupffer cell depletion abolished AAVlacZ but not AdlacZ-induced chemokine expression and neutrophil infiltration. In summary, these results show that AAV vectors activate the innate immune system to a lesser extent than do adenovirus vectors and offer a possible explanation for the reduced inflammatory properties of AAV compared to adenovirus vectors.
American Society for Microbiology