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1 Department of Therapeutic Gene Modulation, Groningen University Institute for Drug Exploration, University of Groningen, The Netherlands
2 Department of Pathology and Laboratory Medicine, Medical Biology Section, University Medical Center Groningen (UMCG), University of Groningen, The Netherlands
Correspondence
Hidde J. Haisma
h.j.haisma{at}rug.nl
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Published online ahead of print on 15 February 2008 as DOI 10.1099/vir.0.83495-0.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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; Muruve, 2004; Muruve et al., 1999; Zhang et al., 2001). Hepatic Kupffer cells (KCs) have been shown to contribute to the inflammatory response, and to be responsible for the short half-life of the circulating viral particles and indirectly for the lower transgene expression in other cell types (Alemany et al., 2000; Lieber et al., 1997; Smith et al., 2008; Wolff et al., 1997). Elimination of viruses by KCs results in a non-linear correlation between low doses of injected viruses and transgene expression (Fechner et al., 1999; Tao et al., 2001; Ziegler et al., 2002). Administration of sufficient numbers of viral particles to exceed a threshold level necessary to saturate the uptake by KCs can produce a linear correlation with transgene expression (Fechner et al., 1999; Tao et al., 2001; Ziegler et al., 2002).
The development of systemically deliverable adenoviral vectors requires two main conditions: targeting of the virus to selected cells and detargeting of the virus from native receptors, especially those present in the liver, which sequesters the majority of intravenously injected virus via KCs, sinusoidal liver endothelial cells and hepatocytes. From in vitro studies, it was found that adenovirus infection starts by a high-affinity interaction of the viral fiber knob with the coxsackievirus–adenovirus receptor (CAR) (Bergelson et al., 1997; Tomko et al., 1997). Subsequently, internalization of the virus occurs via binding of the RGD motif in the penton base protein to cellular v3β3 and v5β5 integrins (Wickham et al., 1993). Furthermore, heparan sulfate glycosaminoglycans have been shown to provide a third cell-surface interaction with adenovirus particles (Dechecchi et al., 2000; Smith et al., 2003a).
A number of strategies to alter adenovirus tropism have been used to eliminate adenovirus–receptor interactions (Bangari & Mittal, 2006; Glasgow et al., 2006; Mizuguchi & Hayakawa, 2004; Nicklin et al., 2005). Initial attempts to detarget the liver have been made by ablating the CAR- and integrin-based interactions (Akiyama et al., 2004; Koizumi et al., 2003; Martin et al., 2003; Nakamura et al., 2003). Also, fiber-shaft modifications have been introduced to eliminate virus interactions with native receptors (Bayo-Puxan et al., 2006; Breidenbach et al., 2004; Nicol et al., 2004; Shayakhmetov et al., 2004; Smith et al., 2003b; Vigne et al., 2003). However, the results are variable. Some animal studies showed reduced transduction of the liver, whilst in others, liver uptake was not affected by these modifications. Smith et al. (2003b) examined the role of heparan sulfate proteoglycans (HSPGs) in liver adenovirus uptake in vivo by replacing a putative HSPG-binding motif (KKTK) in the fiber shaft with an irrelevant peptide sequence, and observed a reduction in liver transgene expression of 90 %. However, Di Paolo et al. (2007) demonstrated recently that the KKTK motif plays only a minimal role in hepatic infectivity in vivo.
Chemical methods have also been used to detarget adenovirus. These methods include PEGylation (Croyle et al., 2000, 2002; Fisher et al., 2001; Lanciotti et al., 2003; Ogawara et al., 2004; O'Riordan et al., 1999) or polymer coating of the adenovirus (Green et al., 2004), which resulted in decreased toxicity and increased plasma half-life of adenovirus, allowing site-specific targeting.
Specific strategies aimed at preventing the interaction of adenovirus with KCs have been devised based on the selective depletion of KCs or pre-dosing of animals with transcriptionally inactive adenovirus (Alemany et al., 2000; Lieber et al., 1997; Schiedner et al., 2003b; Wolff et al., 1997). Scavenger receptors on KCs are responsible for the elimination of blood-borne pathogens and polyanionic macromolecules, such as modified lipoproteins and modified albumins (Gordon, 2002; Gough & Gordon, 2000; Krieger, 1997; Mukhopadhyay & Gordon, 2004; Peiser et al., 2002; Platt & Gordon, 2001; Platt et al., 2002; Shirai et al., 1999; Swart et al., 1999; Taylor et al., 2005; Yamada et al., 1998).
In this study, we hypothesized that the scavenger receptors present on KCs may serve as a receptor for adenovirus. To investigate this hypothesis, we isolated KCs and hepatocytes and infected them with an adenoviral vector expressing a reporter gene. Specific inhibition of gene expression was observed when a scavenger receptor A ligand, polyinosinic acid [poly(I)], was applied to the cells prior to adenovirus administration. In vivo, pre-administration of poly(I) in mice and rats resulted in a higher level of transgene expression with no effect on toxicity. Overall, these findings suggest that this approach will be useful for increasing the selectivity and efficiency of gene transfer in gene-therapy applications.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Rat hepatocytes and KCs were isolated from male Wag/Rij rats (200–250 g; Harlan CPB) after collagenase perfusion of the liver, followed by centrifugation and counterflow centrifugal elutriation as described previously (Kamps et al., 1997). After isolation, hepatocytes were cultured in 24-well plates in Williams E medium (Gibco Invitrogen) supplemented with 10 % heat-inactivated FBS, 2 mM L-glutamine, 100 U penicillin ml–1 and 100 µg streptomycin ml–1. KCs were grown in 24-well plates in RPMI 1640 medium (Gibco Invitrogen) supplemented with 20 % FBS, 2 mM L-glutamine, 100 U penicillin ml–1 and 100 µg streptomycin ml–1. The purity of KCs was controlled by immunocytochemistry using the ED2 antibody and by staining for endogenous peroxidase activity, for which KCs are positive and endothelial cells are negative. The purity was >80 %.
Inhibitors.
The following scavenger receptor-effective and -ineffective ligands were used: poly(I) and polycytidylic acid [poly(C)] potassium salts (both from Sigma) and plasmid DNA.
Adenoviral vector.
AdTL is an E1- and E3-deleted recombinant serotype 5 adenovirus (He et al., 1998) that contains a green fluorescent protein (GFP) and luciferase gene-expression cassette, each under the control of a cytomegalovirus promoter (Alemany & Curiel, 2001). The virus was grown in 293 cells and purified in HEPES/sucrose buffer (pH 8.0) according to a conventional double CsCl gradient centrifugation method (Becker et al., 1994), and the number of viral particles (vp) was calculated from the OD260. The number of p.f.u. was determined by plaque-forming assay. The ratio vp : p.f.u. ratio was determined to be 1 : 18.7.
In vitro infection and reporter-gene expression analysis.
J774 and HepG2 cells were seeded into 96-well culture plates at a density of 10 000 cells per well for viral transduction experiments. After 24 h, cells were first incubated for 1 h at 37 °C in the presence or absence of scavenger-receptor inhibitors [poly(I), poly(C) or plasmid DNA] as indicated in the experiments. After 1 h, AdTL was added at a concentration of 1000 vp per cell in DMEM containing 2 % FBS (infection medium). One hour after infection, the infection medium was replaced by normal culture medium and cells were incubated for 48 h before performing the luciferase assay. The cells were lysed with cell-culture lysis buffer (Promega) and the lysates were analysed with the luciferase assay system (Promega) on a LumiCount luminometer (Packard). All data are expressed as relative light units (RLU).
Adenovirus infection of freshly isolated hepatocytes and KCs was performed as described above in the presence or absence of poly(I). Forty-eight hours post-infection, cells were analysed for expression of the GFP reporter protein by using fluorescence microscopy.
Animal infection and transgene-expression analysis.
The effect of scavenger receptor A blockade on liver transgene levels and adenovirus blood circulation times were determined in C57/Bl mice or WagRij rats (Harlan CPB). Animals were anaesthetized (isoflurane/N2O/O2 inhalation) and the indicated amount of vp diluted in HEPES/sucrose buffer (pH 8.0) was injected intravenously via the orbital plexus (mice) or penis vein (rats). When indicated, 4.0 or 0.2 mg poly(I) in PBS was injected into rats or mice, respectively, 5 min prior to injection of the virus. An aliquot of blood was collected by orbital puncture 5, 30, 60 and 120 min after intravenous administration. The blood samples were then centrifuged to collect plasma and the numbers of vp in the plasma samples were subsequently measured by serial dilution and infection of 293 cells based on a conventional plaque-forming assay. In brief, each plasma sample was diluted serially in DMEM/F-12 supplemented with 2 % heat-inactivated FBS and added to 293 cells plated in 96-well tissue-culture plates (10 000 cells per well). After 14 days, cells were analysed for GFP expression and cytopathic effect. To estimate the number of vp in the plasma sample, this limiting-dilution assay was performed in parallel with the original solution of virus constructs injected into the animal.
For detection of transgene levels, animals were sacrificed 48 h after viral injection and organs were excised and frozen in liquid N2. Tissue samples were ground into a fine powder with a pestle and mortar in an ethanol/dry ice bath. The tissue powders were consequently lysed with cell-culture lysis buffer (Promega) and, after three cycles of freeze–thawing, centrifuged and the recovered supernatants were analysed with the luciferase assay system (Promega) on a LumiCount luminometer (Packard). Protein concentration was based on the assumption that one-third of the total tissue wet mass is protein, to normalize the RLU values.
The experiments were performed according to the European ethical board statement. Approval and description of the experiments are contained in the D2772 and D4314A documents at the University of Groningen.
Quantitative real-time PCR.
DNA was isolated from liver tissue by using DNeasy Tissue kits (Qiagen) according to the manufacturer's protocol. DNA was purified by using minicolumns and dissolved in elution buffer, and its concentration was determined spectrophotometrically (A260/A280). The concentration of adenovirus DNA was determined by real-time PCR using the Applied Biosystems Prism 7900HT sequence detection system with SDS 2.1 software. Amplification was carried out in a total volume of 20 µl with SYBR Green PCR MasterMix (Applied Biosystems), forward (hexon; 5'-CTTCGATGATGCCGCAGTG-3') and reverse (5'-GGGCTCAGGTACTCCGAGG-3') primers and extracted DNA. The parameters used were one cycle of 95 °C for 10 min, then 40 cycles of 95 °C for 15 s, 56 °C for 15 s and 72 °C for 40 s. Adenovirus copy number was quantified by using a standard curve created from dilutions of adenovirus DNA from 1 500 000 copies to 15 copies in a background of mouse genomic DNA. Samples were amplified in duplicate and the mean total copy number was normalized to copies of viral DNA (µg DNA)–1.
Immunohistochemistry.
Immunohistochemistry was performed on frozen liver sections to locate KCs with the F4/80 antibody (Serotec). Livers were frozen in liquid N2 and 7 µm sections were cut, fixed with acetone, air-dried and rehydrated in PBS. Primary antibody was used at a 1 : 50 dilution, followed by rabbit anti-rat–biotin at a 1 : 100 dilution. Colour development was performed with 3-amino-9-ethylcarbazole (AEC; Sigma) dissolved in N,N-dimethylformamide (Merck)/0.5 M acetate buffer, pH 4.9. Slides were counterstained with Mayer's haematoxylin and mounted in Kaiser's glycerin.
Statistical analysis.
Differences in gene expression were analysed by using a one-sided paired Student's t-test, assuming equal variance. Differences were considered to be significant when P<0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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). We used a panel of these ligands to determine the role of scavenger receptors in adenovirus transduction. First, we compared the effect of these ligands on virus transduction in the J774 cell line (scavenger receptor A-positive and CAR-negative) and a cancer cell line, HepG2 (scavenger receptor A-negative and CAR-positive) (Choi et al., 2004; Hamblin et al., 2000; Rhainds et al., 1999) (Fig. 1). For infection, a basic adenoviral vector (AdTL) containing reporter genes was used. In J774 cells, poly(I), a scavenger receptor-effective ligand (Krieger & Herz, 1994; Platt & Gordon, 2001), reduced the transgene levels by 83 % when used at 25 µg ml–1, whereas poly(C) (25 µg ml–1) or plasmid DNA (10 µg ml–1), scavenger receptor-ineffective ligands (Krieger & Herz, 1994; Platt & Gordon, 2001), did not. In HepG2 cells, no reduction in transgene levels was measured when the cells were infected in the presence of the ligands, including poly(I). Poly(I) did not reduce GFP expression in freshly isolated rat hepatocytes when infected with adenovirus (Fig. 2), whereas expression in KCs was blocked almost completely (Fig. 2). As poly(I) is a selective ligand of scavenger receptors, these data suggest that scavenger receptors are involved in adenovirus uptake in macrophages.
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) and distribution changed from a patchy pattern to a regular diffuse pattern. Together, these results can be attributed to diminished uptake of virus by liver macrophages and an increase in infection and transduction in surrounding liver tissue, through the CAR receptor and/or HSPGs on hepatocytes (Smith et al., 2003a).
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). The higher luciferase activity, registered as a consequence of the use of poly(I), can be explained by a reduction of viral particles degraded by liver macrophages. This results in more viral particles being available to infect tissues expressing the virus native receptor.
Effects of poly(I) on adenovirus clearance from blood
To evaluate whether blockade of the scavenger receptors by poly(I) results in reduced clearance of adenovirus from the circulation, blood samples from mice were analysed for adenovirus levels by plaque-forming assays. At the low dose of adenovirus, 5x109 vp per mouse, which was selected to be below the threshold of KC saturation (Tao et al., 2001; Ziegler et al., 2002), we observed a rapid clearance of virus from the blood, with a maximum level of virus present in the blood of approximately 5x103 p.f.u. ml–1 at 5 min after virus administration. Pre-administration of poly(I) increased the maximum level by more than 10-fold. At the high dose of virus administration, 5x1010 vp per mouse, a similar increase in the maximum level of circulating virus was measured 30 min after the virus injection (Fig. 4). These data demonstrate that pre-administration of poly(I) to animals increased blood levels of adenovirus.
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). This resulted in an accompanying higher gene-expression level, as determined by luciferase measurements (Fig. 5b). The pre-virus injection of poly(I) results in a reduced clearance of adenovirus, with a consequent enhancement of viral particles and an increase in transgene levels in the liver.
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; Manickan et al., 2006; Schiedner et al., 2003a; Shayakhmetov et al., 2004). Mouse liver sections were stained for KCs 48 h after administration of AdTL and KC numbers were quantified. With the low dose of adenovirus (5x109 vp), KC numbers remained unchanged (data not shown). At the high dose of virus (5x1010 vp), a reduction in KC count was observed in animals injected with AdTL only, but not in mice pre-injected with poly(I) (Fig. 6a, b). The levels of the liver enzymes aspartate aminotransferase and alanine aminotransferase in serum obtained 48 h after injection of AdTL only or AdTL in combination with poly(I) are low and very similar, indicating no toxicity from treatment with either adenovirus or virus combined with poly(I) (Fig. 7) at this time point. However, to study the direct effect of poly(I) on the toxicity caused by uptake by KCs, a similar experiment should be performed within 24 h of adenovirus administration.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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; Hodges et al., 2005; Lievens et al., 2004; Nicol et al., 2004; Park et al., 2005; Smith et al., 2002).
Shayakhmetov et al. (2004) demonstrated that coagulation factor IX and the complement component C4-binding protein can bind the adenovirus fiber-knob domain and provide a bridge for virus uptake through cell-surface HSPGs and low-density lipoprotein receptor-related protein. An adenoviral vector that contained mutations in the fiber-knob domain that ablated blood-factor binding demonstrated significantly reduced infection of liver cells and liver toxicity in vivo (Shayakhmetov et al., 2005). Intravenous delivery of adenovirus results in interaction of the virus with circulating platelets (Stone et al., 2007). Virus–platelet aggregates are then taken up by KCs and degraded. Depletion of platelets prior to virus infection could improve levels of target-cell transduction at a lower vector dose (Stone et al., 2007).
The ability of KCs to take up large particles, such as adenovirus, is well established (Smith et al., 2008). In these studies, we show that poly(I), a scavenger receptor A inhibitor, has a profound effect on the sequestration of adenovirus by KCs.
We demonstrated previously (Kamps et al., 1997) that poly(I) inhibited the uptake of negatively charged liposomes by KCs efficiently, indicating that scavenger receptors are involved in the uptake of these liposomes. Scavenger-receptor binding is thought to result from the intrinsic negative charge of the binding ligand. Although the fiber of Ad5 is positively charged to promote binding to target cells, the rest of the capsid displays predominantly negatively charged residues (Mei & Wadell, 1995). Also, serum proteins associated on the surface may play an important role in hepatic uptake of negatively charged particles via scavenger receptors (Furumoto et al., 2004). Here, we show that binding of adenovirus to KCs can be abolished by pre-treatment with poly(I). The reduced liver sequestration of adenovirus observed after pre-treatment with poly(I) allows lower doses to be used with similar transgene-expression levels.
In our study, we did not attempt to detarget the adenovirus from its natural receptor (CAR) and, thus, we observed increased hepatic expression after pre-treatment with poly(I). This may be a feasible approach for treating liver or metabolic diseases, but may not be desirable for other gene-therapy applications. Detargeting hepatocytes may be accomplished by genetic CAR ablation of adenovirus, with concomitant introduction of targeting ligands into the adenovirus capsid by chemical modification (Ogawara et al., 2004) or by using bifunctional ligands, such as bispecific antibodies (Haisma et al., 2000).
The results indicate that blocking of scavenger receptor A by administration of poly(I) prior to adenovirus injection can be used to reduce the clearance of virus by KCs and is a feasible approach to increase the availability of adenovirus without affecting toxicity. Higher availability of adenoviral particles for specific targeting will increase the efficiency of gene therapy. Poly(I) combined with targeted viral vector is a powerful tool for gene-therapy applications.
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ACKNOWLEDGEMENTS |
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REFERENCES |
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Alemany, R. & Curiel, D. T. (2001). CAR-binding ablation does not change biodistribution and toxicity of adenoviral vectors. Gene Ther 8, 1347–1353.[CrossRef][Medline]
Alemany, R., Suzuki, K. & Curiel, D. T. (2000). Blood clearance rates of adenovirus type 5 in mice. J Gen Virol 81, 2605–2609.
Bangari, D. S. & Mittal, S. K. (2006). Current strategies and future directions for eluding adenoviral vector immunity. Curr Gene Ther 6, 215–226.[CrossRef][Medline]
Bayo-Puxan, N., Cascallo, M., Gros, A., Huch, M., Fillat, C. & Alemany, R. (2006). Role of the putative heparan sulfate glycosaminoglycan-binding site of the adenovirus type 5 fiber shaft on liver detargeting and knob-mediated retargeting. J Gen Virol 87, 2487–2495.
Becker, T. C., Noel, R. J., Coats, W. S., Gomez-Foix, A. M., Alam, T., Gerard, R. D. & Newgard, C. B. (1994). Use of recombinant adenovirus for metabolic engineering of mammalian cells. Methods Cell Biol 43, 161–189.[Medline]
Bergelson, J. M., Cunningham, J. A., Droguett, G., Kurt-Jones, E. A., Krithivas, A., Hong, J. S., Horwitz, M. S., Crowell, R. L. & Finberg, R. W. (1997). Isolation of a common receptor for coxsackie B viruses and adenoviruses 2 and 5. Science 275, 1320–1323.
Breidenbach, M., Rein, D. T., Wang, M., Nettelbeck, D. M., Hemminki, A., Ulasov, I., Rivera, A. R., Everts, M., Alvarez, R. D. & other authors (2004). Genetic replacement of the adenovirus shaft fiber reduces liver tropism in ovarian cancer gene therapy. Hum Gene Ther 15, 509–518.[CrossRef][Medline]
Brunetti-Pierri, N., Palmer, D. J., Beaudet, A. L., Carey, K. D., Finegold, M. & Ng, P. (2004). Acute toxicity after high-dose systemic injection of helper-dependent adenoviral vectors into nonhuman primates. Hum Gene Ther 15, 35–46.[CrossRef][Medline]
Choi, C. F., Tsang, P. T., Huang, J. D., Chan, E. Y., Ko, W. H., Fong, W. P. & Ng, D. K. (2004). Synthesis and in vitro photodynamic activity of new hexadeca-carboxy phthalocyanines. Chem Commun (Camb) 2236–2237.
Cotter, M. J. & Muruve, D. A. (2005). The induction of inflammation by adenovirus vectors used for gene therapy. Front Biosci 10, 1098–1105.[Medline]
Croyle, M. A., Yu, Q. C. & Wilson, J. M. (2000). Development of a rapid method for the PEGylation of adenoviruses with enhanced transduction and improved stability under harsh storage conditions. Hum Gene Ther 11, 1713–1722.[CrossRef][Medline]
Croyle, M. A., Chirmule, N., Zhang, Y. & Wilson, J. M. (2002). PEGylation of E1-deleted adenovirus vectors allows significant gene expression on readministration to liver. Hum Gene Ther 13, 1887–1900.[CrossRef][Medline]
Dechecchi, M. C., Tamanini, A., Bonizzato, A. & Cabrini, G. (2000). Heparan sulfate glycosaminoglycans are involved in adenovirus type 5 and 2-host cell interactions. Virology 268, 382–390.[CrossRef][Medline]
Di Paolo, N. C., Kalyuzhniy, O. & Shayakhmetov, D. M. (2007). Fiber shaft-chimeric adenovirus vectors lacking the KKTK motif efficiently infect liver cells in vivo. J Virol 81, 12249–12259.
Fechner, H., Haack, A., Wang, H., Wang, X., Eizema, K., Pauschinger, M., Schoemaker, R., Veghel, R., Houtsmuller, A. & other authors (1999). Expression of coxsackie adenovirus receptor and alphav-integrin does not correlate with adenovector targeting in vivo indicating anatomical vector barriers. Gene Ther 6, 1520–1535.[CrossRef][Medline]
Fisher, K. D., Stallwood, Y., Green, N. K., Ulbrich, K., Mautner, V. & Seymour, L. W. (2001). Polymer-coated adenovirus permits efficient retargeting and evades neutralising antibodies. Gene Ther 8, 341–348.[CrossRef][Medline]
Furumoto, K., Nagayama, S., Ogawara, K., Takakura, Y., Hashida, M., Higaki, K. & Kimura, T. (2004). Hepatic uptake of negatively charged particles in rats: possible involvement of serum proteins in recognition by scavenger receptor. J Control Release 97, 133–141.[CrossRef][Medline]
Glasgow, J. N., Everts, M. & Curiel, D. T. (2006). Transductional targeting of adenovirus vectors for gene therapy. Cancer Gene Ther 13, 830–844.[CrossRef][Medline]
Gordon, S. (2002). Pattern recognition receptors: doubling up for the innate immune response. Cell 111, 927–930.[CrossRef][Medline]
Gough, P. J. & Gordon, S. (2000). The role of scavenger receptors in the innate immune system. Microbes Infect 2, 305–311.[CrossRef][Medline]
Green, N. K., Herbert, C. W., Hale, S. J., Hale, A. B., Mautner, V., Harkins, R., Hermiston, T., Ulbrich, K., Fisher, K. D. & Seymour, L. W. (2004). Extended plasma circulation time and decreased toxicity of polymer-coated adenovirus. Gene Ther 11, 1256–1263.[CrossRef][Medline]
Haisma, H. J., Grill, J., Curiel, D. T., Hoogeland, S., van Beusechem, V. W., Pinedo, H. M. & Gerritsen, W. R. (2000). Targeting of adenoviral vectors through a bispecific single-chain antibody. Cancer Gene Ther 7, 901–904.[CrossRef][Medline]
Hamblin, M. R., Miller, J. L. & Ortel, B. (2000). Scavenger-receptor targeted photodynamic therapy. Photochem Photobiol 72, 533–540.[CrossRef][Medline]
He, T. C., Zhou, S., da Costa, L. T., Yu, J., Kinzler, K. W. & Vogelstein, B. (1998). A simplified system for generating recombinant adenoviruses. Proc Natl Acad Sci U S A 95, 2509–2514.
Hodges, B. L., Taylor, K. M., Chu, Q., Scull, S. E., Serriello, R. G., Anderson, S. C., Wang, F. & Scheule, R. K. (2005). Local delivery of a viral vector mitigates neutralization by antiviral antibodies and results in efficient transduction of rabbit liver. Mol Ther 12, 1043–1051.[CrossRef][Medline]
Kamps, J. A., Morselt, H. W., Swart, P. J., Meijer, D. K. & Scherphof, G. L. (1997). Massive targeting of liposomes, surface-modified with anionized albumins, to hepatic endothelial cells. Proc Natl Acad Sci U S A 94, 11681–11685.
Koizumi, N., Mizuguchi, H., Sakurai, F., Yamaguchi, T., Watanabe, Y. & Hayakawa, T. (2003). Reduction of natural adenovirus tropism to mouse liver by fiber-shaft exchange in combination with both CAR- and alphav integrin-binding ablation. J Virol 77, 13062–13072.
Krieger, M. (1997). The other side of scavenger receptors: pattern recognition for host defense. Curr Opin Lipidol 8, 275–280.[Medline]
Krieger, M. & Herz, J. (1994). Structures and functions of multiligand lipoprotein receptors: macrophage scavenger receptors and LDL receptor-related protein (LRP). Annu Rev Biochem 63, 601–637.[Medline]
Lanciotti, J., Song, A., Doukas, J., Sosnowski, B., Pierce, G., Gregory, R., Wadsworth, S. & O'Riordan, C. (2003). Targeting adenoviral vectors using heterofunctional polyethylene glycol FGF2 conjugates. Mol Ther 8, 99–107.[CrossRef][Medline]
Lieber, A., He, C. Y., Meuse, L., Schowalter, D., Kirillova, I., Winther, B. & Kay, M. A. (1997). The role of Kupffer cell activation and viral gene expression in early liver toxicity after infusion of recombinant adenovirus vectors. J Virol 71, 8798–8807.[Abstract]
Lievens, J., Snoeys, J., Vekemans, K., Van Linthout, S., de Zanger, R., Collen, D., Wisse, E. & De Geest, B. (2004). The size of sinusoidal fenestrae is a critical determinant of hepatocyte transduction after adenoviral gene transfer. Gene Ther 11, 1523–1531.[CrossRef][Medline]
Liu, Q., Zaiss, A. K., Colarusso, P., Patel, K., Haljan, G., Wickham, T. J. & Muruve, D. A. (2003). The role of capsid-endothelial interactions in the innate immune response to adenovirus vectors. Hum Gene Ther 14, 627–643.[CrossRef][Medline]
Manickan, E., Smith, J. S., Tian, J., Eggerman, T. L., Lozier, J. N., Muller, J. & Byrnes, A. P. (2006). Rapid Kupffer cell death after intravenous injection of adenovirus vectors. Mol Ther 13, 108–117.[CrossRef][Medline]
Martin, K., Brie, A., Saulnier, P., Perricaudet, M., Yeh, P. & Vigne, E. (2003). Simultaneous CAR- and alpha V integrin-binding ablation fails to reduce Ad5 liver tropism. Mol Ther 8, 485–494.[CrossRef][Medline]
Mei, Y. F. & Wadell, G. (1995). Molecular determinants of adenovirus tropism. Curr Top Microbiol Immunol 199, 213–228.[Medline]
Mizuguchi, H. & Hayakawa, T. (2004). Targeted adenovirus vectors. Hum Gene Ther 15, 1034–1044.[CrossRef][Medline]
Mukhopadhyay, S. & Gordon, S. (2004). The role of scavenger receptors in pathogen recognition and innate immunity. Immunobiology 209, 39–49.[CrossRef][Medline]
Muruve, D. A. (2004). The innate immune response to adenovirus vectors. Hum Gene Ther 15, 1157–1166.[CrossRef][Medline]
Muruve, D. A., Barnes, M. J., Stillman, I. E. & Libermann, T. A. (1999). Adenoviral gene therapy leads to rapid induction of multiple chemokines and acute neutrophil-dependent hepatic injury in vivo. Hum Gene Ther 10, 965–976.[CrossRef][Medline]
Nakamura, T., Sato, K. & Hamada, H. (2003). Reduction of natural adenovirus tropism to the liver by both ablation of fiber-coxsackievirus and adenovirus receptor interaction and use of replaceable short fiber. J Virol 77, 2512–2521.
Nicklin, S. A., Wu, E., Nemerow, G. R. & Baker, A. H. (2005). The influence of adenovirus fiber structure and function on vector development for gene therapy. Mol Ther 12, 384–393.[CrossRef][Medline]
Nicol, C. G., Graham, D., Miller, W. H., White, S. J., Smith, T. A., Nicklin, S. A., Stevenson, S. C. & Baker, A. H. (2004). Effect of adenovirus serotype 5 fiber and penton modifications on in vivo tropism in rats. Mol Ther 10, 344–354.[CrossRef][Medline]
Ogawara, K., Rots, M. G., Kok, R. J., Moorlag, H. E., Van Loenen, A. M., Meijer, D. K., Haisma, H. J. & Molema, G. (2004). A novel strategy to modify adenovirus tropism and enhance transgene delivery to activated vascular endothelial cells in vitro and in vivo. Hum Gene Ther 15, 433–443.[CrossRef][Medline]
O'Riordan, C. R., Lachapelle, A., Delgado, C., Parkes, V., Wadsworth, S. C., Smith, A. E. & Francis, G. E. (1999). PEGylation of adenovirus with retention of infectivity and protection from neutralizing antibody in vitro and in vivo. Hum Gene Ther 10, 1349–1358.[CrossRef][Medline]
Park, B. H., Lee, J. H., Jeong, J. S., Rha, S. H., Kim, S. E., Kim, J. S., Kim, J. M. & Hwang, T. H. (2005). Vascular administration of adenoviral vector soaked in absorbable gelatin sponge particles (GSP) prolongs the transgene expression in hepatocytes. Cancer Gene Ther 12, 116–121.[CrossRef][Medline]
Peiser, L., Mukhopadhyay, S. & Gordon, S. (2002). Scavenger receptors in innate immunity. Curr Opin Immunol 14, 123–128.[CrossRef][Medline]
Platt, N. & Gordon, S. (2001). Is the class A macrophage scavenger receptor (SR-A) multifunctional? – The mouse's tale. J Clin Invest 108, 649–654.[CrossRef][Medline]
Platt, N., Haworth, R., Darley, L. & Gordon, S. (2002). The many roles of the class A macrophage scavenger receptor. Int Rev Cytol 212, 1–40.[Medline]
Rhainds, D., Falstrault, L., Tremblay, C. & Brissette, L. (1999). Uptake and fate of class B scavenger receptor ligands in HepG2 cells. Eur J Biochem 261, 227–235.[Medline]
Schiedner, G., Bloch, W., Hertel, S., Johnston, M., Molojavyi, A., Dries, V., Varga, G., van Rooijen, N. & Kochanek, S. (2003a). A hemodynamic response to intravenous adenovirus vector particles is caused by systemic Kupffer cell-mediated activation of endothelial cells. Hum Gene Ther 14, 1631–1641.[CrossRef][Medline]
Schiedner, G., Hertel, S., Johnston, M., Dries, V., van Rooijen, N. & Kochanek, S. (2003b). Selective depletion or blockade of Kupffer cells leads to enhanced and prolonged hepatic transgene expression using high-capacity adenoviral vectors. Mol Ther 7, 35–43.[CrossRef][Medline]
Shayakhmetov, D. M., Li, Z. Y., Ni, S. & Lieber, A. (2004). Analysis of adenovirus sequestration in the liver, transduction of hepatic cells, and innate toxicity after injection of fiber-modified vectors. J Virol 78, 5368–5381.
Shayakhmetov, D. M., Gaggar, A., Ni, S., Li, Z. Y. & Lieber, A. (2005). Adenovirus binding to blood factors results in liver cell infection and hepatotoxicity. J Virol 79, 7478–7491.
Shirai, H., Murakami, T., Yamada, Y., Doi, T., Hamakubo, T. & Kodama, T. (1999). Structure and function of type I and II macrophage scavenger receptors. Mech Ageing Dev 111, 107–121.[CrossRef][Medline]
Smith, T., Idamakanti, N., Kylefjord, H., Rollence, M., King, L., Kaloss, M., Kaleko, M. & Stevenson, S. C. (2002). In vivo hepatic adenoviral gene delivery occurs independently of the coxsackievirus-adenovirus receptor. Mol Ther 5, 770–779.[CrossRef][Medline]
Smith, T. A., Idamakanti, N., Marshall-Neff, J., Rollence, M. L., Wright, P., Kaloss, M., King, L., Mech, C., Dinges, L. & other authors (2003a). Receptor interactions involved in adenoviral-mediated gene delivery after systemic administration in non-human primates. Hum Gene Ther 14, 1595–1604.[CrossRef][Medline]
Smith, T. A., Idamakanti, N., Rollence, M. L., Marshall-Neff, J., Kim, J., Mulgrew, K., Nemerow, G. R., Kaleko, M. & Stevenson, S. C. (2003b). Adenovirus serotype 5 fiber shaft influences in vivo gene transfer in mice. Hum Gene Ther 14, 777–787.[CrossRef][Medline]
Smith, J. S., Xu, Z. & Byrnes, A. P. (2008). A quantitative assay for measuring clearance of adenovirus vectors by Kupffer cells. J Virol Methods 147, 54–60.[CrossRef][Medline]
Stone, D., Liu, Y., Shayakhmetov, D., Li, Z. Y., Ni, S. & Lieber, A. (2007). Adenovirus-platelet interaction in blood causes virus sequestration to the reticuloendothelial system of the liver. J Virol 81, 4866–4871.
Swart, P. J., Harmsen, M. C., Kuipers, M. E., Van Dijk, A. A., Van Der Strate, B. W., Van Berkel, P. H., Nuijens, J. H., Smit, C., Witvrouw, M. & other authors (1999). Charge modification of plasma and milk proteins results in antiviral active compounds. J Pept Sci 5, 563–576.[CrossRef][Medline]
Tao, N., Gao, G. P., Parr, M., Johnston, J., Baradet, T., Wilson, J. M., Barsoum, J. & Fawell, S. E. (2001). Sequestration of adenoviral vector by Kupffer cells leads to a nonlinear dose response of transduction in liver. Mol Ther 3, 28–35.[CrossRef][Medline]
Taylor, P. R., Martinez-Pomares, L., Stacey, M., Lin, H. H., Brown, G. D. & Gordon, S. (2005). Macrophage receptors and immune recognition. Annu Rev Immunol 23, 901–944.[CrossRef][Medline]
Tomko, R. P., Xu, R. & Philipson, L. (1997). HCAR and MCAR: the human and mouse cellular receptors for subgroup C adenoviruses and group B coxsackieviruses. Proc Natl Acad Sci U S A 94, 3352–3356.
Vigne, E., Dedieu, J. F., Brie, A., Gillardeaux, A., Briot, D., Benihoud, K., Latta-Mahieu, M., Saulnier, P., Perricaudet, M. & Yeh, P. (2003). Genetic manipulations of adenovirus type 5 fiber resulting in liver tropism attenuation. Gene Ther 10, 153–162.[CrossRef][Medline]
Wickham, T. J., Mathias, P., Cheresh, D. A. & Nemerow, G. R. (1993). Integrins 
vβ3 and vβ5 promote adenovirus internalization but not virus attachment. Cell 73, 309–319.[CrossRef][Medline]
Wolff, G., Worgall, S., van Rooijen, N., Song, W. R., Harvey, B. G. & Crystal, R. G. (1997). Enhancement of in vivo adenovirus-mediated gene transfer and expression by prior depletion of tissue macrophages in the target organ. J Virol 71, 624–629.[Abstract]
Yamada, Y., Doi, T., Hamakubo, T. & Kodama, T. (1998). Scavenger receptor family proteins: roles for atherosclerosis, host defence and disorders of the central nervous system. Cell Mol Life Sci 54, 628–640.[CrossRef][Medline]
Zhang, Y., Chirmule, N., Gao, G. P., Qian, R., Croyle, M., Joshi, B., Tazelaar, J. & Wilson, J. M. (2001). Acute cytokine response to systemic adenoviral vectors in mice is mediated by dendritic cells and macrophages. Mol Ther 3, 697–707.[CrossRef][Medline]
Ziegler, R. J., Li, C., Cherry, M., Zhu, Y., Hempel, D., van Rooijen, N., Ioannou, Y. A., Desnick, R. J., Goldberg, M. A. & other authors (2002). Correction of the nonlinear dose response improves the viability of adenoviral vectors for gene therapy of Fabry disease. Hum Gene Ther 13, 935–945.[CrossRef][Medline]
Received 3 October 2007;
accepted 1 February 2008.
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, 5x109 vp AdTL; 
, poly(I)+5x109 vp AdTL; 
, 5x1010 vp AdTL; 
, poly(I)+5x1010 vp AdTL. Results are expressed as the mean of results from three rats.
