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PMID: 15113916 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Analysis of adenovirus sequestration in the liver, transduction of hepatic cells, and innate toxicity after injection of fiber-modified vectors.

Journal of virology ·Vol. 78 ·No. 10 ·2004-05-00 ·Pages 5368-81

Shayakhmetov DM, Li ZY, Ni S, Lieber A

Abstract

After intravenous administration, adenovirus (Ad) vectors are predominantly sequestered by the liver. Delineating the mechanisms for Ad accumulation in the liver is crucial for a better understanding of Ad clearance and Ad-associated innate toxicity. To help address these issues, in this study, we used Ad vectors with different fiber shaft lengths and either coxsackievirus-Ad receptor (CAR)-interacting Ad serotype 9 (Ad9) or non-CAR-interacting Ad35 fiber knob domains. We analyzed the kinetics of Ad vector accumulation in the liver, uptake into hepatocytes and Kupffer cells, and induction of cytokine expression and release in response to systemic vector application. Immediately after intravenous injection, all Ad vectors accumulated equally efficiently in the liver; however, only genomes of long-shafted Ads were maintained in the liver tissue over time. We found that Kupffer cell uptake of long-shafted Ads was mediated by the fiber knob domain and was CAR independent. The short-shafted Ads were unable to efficiently interact with hepatocellular receptors and were not taken up by Kupffer cells. Moreover, our studies indicated that Kupffer cells were not the major reservoir for the observed accumulation of Ads (used in this study) in the liver within the first 30 min after virus infusion. The lower level of liver cell transduction by short-shafted Ads correlated with a significantly reduced inflammatory anti-Ad response as well as liver damage induced by the systemic administration of these vectors. This study contributes to a better understanding of the biology of systemically applied Ad and will help in designing safer vectors that can efficiently transduce target tissues.

MeSH Terms
Adenoviridae/genetics,pathogenicity Alanine Transaminase/blood Animals Cytokines/genetics Genetic Vectors/genetics,toxicity Hepatocytes/virology Interleukin-6/blood Kupffer Cells/virology Liver/virology Mice Mice, Inbred C57BL Receptors, Virus/physiology Tumor Necrosis Factor-alpha/analysis
Chemicals
Cytokines Interleukin-6 Receptors, Virus Tumor Necrosis Factor-alpha Alanine Transaminase
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Shayakhmetov Dmitry M
Division of Medical Genetics, University of Washington, Seattle, WA 98195, USA.
Li Zong-Yi
Ni Shaoheng
Lieber André
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Article Info
Journal
Journal of virology
Abbr.
J Virol
ISSN
0022-538X
DOI
10.1128/jvi.78.10.5368-5381.2004
Published
2004-05-00
Pages
5368-81
Language
English
Region
United States
NLM ID
0113724
PMCID
PMC400378
Subset
IM
Grants
NCI NIH HHS · R01 CA 80192 · United States
NIDDK NIH HHS · P30 DK047754 · United States
NIDDK NIH HHS · P30 DK 47754 · United States
NCI NIH HHS · R01 CA080192 · United States
NHLBI NIH HHS · HL 00008 · United States
External Links
PubMed source DOI: 10.1128/jvi.78.10.5368-5381.2004 PMC Full Text View journal details
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