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Updated: Jul 5, 2026
Combined Genetic and Chemical Capsid Modifications of Adenovirus-Based Gene Transfer Vectors for Shielding and Targeting
Published on: October 26, 2018
Interaction of systemically delivered adenovirus vectors with Kupffer cells in mouse liver
Jeffrey S Smith1, Zhili Xu, Jie Tian
1Division of Cellular and Gene Therapies, Food and Drug Administration Center for Biologics Evaluation and Research, Bethesda, MD 20892, USA.
Abstract:
When adenovirus (Ad) vectors are injected intravenously they are rapidly taken up by Kupffer cells (KCs) in the liver. This results in massive KC necrosis within minutes, followed by a more gradual disappearance of KCs from the liver. It is not known how KCs recognize Ad, or why Ad kills KCs. We used a variety of mutated and fiber-pseudotyped Ad vectors to evaluate how capsid proteins influence Ad uptake by KCs and to define the viral proteins that are involved in the destruction of KCs. We found that depletion of KCs from the liver was partially dependent on interactions between Ad and integrins, but was independent of the coxsackievirus and Ad receptor. The Ad5 fiber shaft was proven to be a particularly important contributory factor, because vectors with the shorter Ad35 shaft were not as effective at depleting KCs. In contrast, the fiber head played no discernible role. Variations in the ability of Ad vectors to deplete KCs could not be explained by differences in the amount of Ad that reached KCs, because all mutant Ads were accumulated by KCs at similar levels. Interestingly, we found that the Ad mutant ts1 did not cause KC death; this virus is known to bind and enter cells normally, but the capsid is unable to disassemble or lyse membranes. We conclude that Ad vectors kill KCs at a postbinding step and that this cell death can be mitigated if downstream events in viral entry are blocked.
Insights
Adenovirus (Ad) vectors kill liver Kupffer cells (KCs) through a post-binding mechanism. Blocking downstream viral entry events can mitigate this Ad-induced KC death.
Area of Science:
- * Hepatology and Virology
- * Immunology and Cell Biology
Background:
- * Intravenous adenovirus (Ad) vector administration leads to rapid Kupffer cell (KC) uptake and necrosis in the liver.
- * The mechanisms by which KCs recognize Ad and the viral components responsible for KC death remain unclear.
Purpose of the Study:
- * To investigate how Ad capsid proteins influence KC uptake.
- * To identify viral proteins involved in Ad-induced KC destruction.
Main Methods:
- * Utilized mutated and fiber-pseudotyped Ad vectors.
- * Assessed KC depletion and Ad uptake by KCs.
- * Examined the role of Ad5 and Ad35 fiber shafts and heads, integrins, and the coxsackievirus and Ad receptor (CAR).
Main Results:
- * KC depletion was partially dependent on Ad-integrin interactions but independent of CAR.
- * The Ad5 fiber shaft significantly contributed to KC depletion, more so than the Ad35 shaft; the fiber head had no role.
- * An Ad mutant (ts1) that cannot disassemble its capsid or lyse membranes did not induce KC death, despite normal binding and entry.
Conclusions:
- * Ad vectors induce KC death at a post-binding stage of viral entry.
- * Inhibiting downstream viral entry events can reduce Ad-mediated KC cytotoxicity.
