Bioluminescence imaging reveals a significant role for complement in liver transduction following intravenous delivery of adenovirus

Bioluminescence imaging reveals a significant role for complement in liver transduction following intravenous delivery of adenovirus

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ABSTRACT The effect of complement on transgene expression was evaluated _in vivo_ and _in vitro_ using mice lacking complement components. Complement component 3 (C3) deficient mice (C3−/−)


and appropriate wild-type controls were intravenously injected with a replication incompetent, luciferase-expressing normal Ad5 (Ad5Luc1), or fibritin-fiber Ad5 (Ad5FFLuc1). Repeated,


noninvasive bioluminescence imaging was conducted over 35 days. Our data show for the first time that C3 facilitates both short- and long-term hepatic expression of luciferase following


systemic delivery. C3−/− mice showed significantly less (P<0.05) luciferase expression in their liver than treatment-matched wild-type mice when 2.3 × 109 (Ad5Luc1) and 4.0 × 109 (Ad5Luc1


or Ad5FFLuc1) viral particles (v.p.) were infused. The maximal difference in luciferase activity between C3−/− and wild-type mice was 99-fold difference at 3 days for the 2.3 × 109 v.p.


dose (Ad5Luc1), 35-fold at 13 days for the 4.0 × 109 v.p. dose (Ad5Luc1), and 22-fold at 13 days for the 4.0 × 109 v.p. dose (Ad5FFLuc1). Preincubation of Ad5Luc1 with wild-type, C1q−/−, or


factor B (FB) deficient mouse sera for 5 min significantly (P<0.05) increased transduction of mouse liver cells, as compared to preincubation with C3−/− sera or PBS. These results suggest


the classical or alternate complement pathway enhances Ad5-mediated liver transduction. Access through your institution Buy or subscribe This is a preview of subscription content, access


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Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS IMPACT OF LIVER FIBROSIS ON AAV-MEDIATED GENE TRANSFER TO


MOUSE HEPATOCYTES Article Open access 10 March 2025 HARNESSING WHOLE HUMAN LIVER EX SITU NORMOTHERMIC PERFUSION FOR PRECLINICAL AAV VECTOR EVALUATION Article Open access 14 March 2024 A


HUMANIZED MOUSE MODEL FOR ADENO-ASSOCIATED VIRAL GENE THERAPY Article Open access 04 March 2024 REFERENCES * Jooss K, Chirmule N . Immunity to adenovirus and adeno-associated viral vectors:


implications for gene therapy. _Gene Ther_ 2003; 10: 955–963. Article  CAS  PubMed  Google Scholar  * Zaiss AK et al. Differential activation of innate immune responses by adenovirus and


adeno-associated virus vectors. _J Virol_ 2002; 76: 4580–4590. Article  CAS  PubMed  PubMed Central  Google Scholar  * Walport MJ . Complement. First of two parts. _N Engl J Med_ 2001; 344:


1058–1066. Article  CAS  PubMed  Google Scholar  * Walport MJ . Complement. Second of two parts. _N Engl J Med_ 2001; 344: 1140–1144. Article  CAS  PubMed  Google Scholar  * Cichon G et al.


Complement activation by recombinant adenoviruses. _Gene Ther_ 2001; 8: 1794–1800. Article  CAS  PubMed  Google Scholar  * Tao N et al. Sequestration of adenoviral vector by Kupffer cells


leads to a nonlinear dose response of transduction in liver. _Mol Ther_ 2001; 3: 28–35. Article  CAS  PubMed  Google Scholar  * Einfeld DA et al. Reducing the native tropism of adenovirus


vectors requires removal of both CAR and integrin interactions. _J Virol_ 2001; 75: 11284–11291. Article  CAS  PubMed  PubMed Central  Google Scholar  * Kirby I et al. Identification of


contact residues and definition of the CAR-binding site of adenovirus type 5 fiber protein. _J Virol_ 2000; 74: 2804–2813. Article  CAS  PubMed  PubMed Central  Google Scholar  * Kirby I et


al. Mutations in the DG loop of adenovirus type 5 fiber knob protein abolish high-affinity binding to its cellular receptor CAR. _J Virol_ 1999; 73: 9508–9514. CAS  PubMed  PubMed Central 


Google Scholar  * Santis G et al. Molecular determinants of adenovirus serotype 5 fibre binding to its cellular receptor CAR. _J Gen Virol_ 1999; 80 (Part 6): 1519–1527. Article  CAS  PubMed


  Google Scholar  * Nakamura T, Sato K, Hamada H . 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_ 2003; 77: 2512–2521. Article  CAS  PubMed  PubMed Central  Google Scholar  * Dechecchi MC, Tamanini A, Bonizzato A, Cabrini G . Heparan sulfate


glycosaminoglycans are involved in adenovirus type 5 and 2-host cell interactions. _Virology_ 2000; 268: 382–390. Article  CAS  PubMed  Google Scholar  * Shayakhmetov DM et al. Binding of


adenovirus fiber knob to blood coagulation factors mediates CAR-independent liver tropism. _Mol Ther_ 2003; 7: S165. Google Scholar  * Circolo A et al. Genetic disruption of the murine


complement C3 promoter region generates deficient mice with extrahepatic expression of C3 mRNA. _Immunopharmacology_ 1999; 42: 135–149. Article  CAS  PubMed  Google Scholar  * Statistical


Analyses System (SAS). _Release 8.0_. SAS Institute Inc.: Cary, NC, 1999. * Krasnykh V et al. Genetic targeting of an adenovirus vector via replacement of the fiber protein with the phage T4


fibritin. _J Virol_ 2001; 75: 4176–4183. Article  CAS  PubMed  PubMed Central  Google Scholar  * Gaggar A, Shayakhmetov DM, Lieber A . CD46 is a cellular receptor for group B adenoviruses.


_Nat Med_ 2003; 9: 1408–1412. Article  CAS  PubMed  Google Scholar  * Fernie-King B, Seilly DJ, Davies A, Lachmann PJ . Subversion of the innate immune response by micro-organisms. _Ann


Rheum Dis_ 2002; 61 (Suppl 2): ii8–ii12. Article  PubMed  PubMed Central  Google Scholar  * Fernie-King BA, Seilly DJ, Davies A, Lachmann PJ . Streptococcal inhibitor of complement inhibits


two additional components of the mucosal innate immune system: secretory leukocyte proteinase inhibitor and lysozyme. _Infect Immun_ 2002; 70: 4908–4916. Article  CAS  PubMed  PubMed Central


  Google Scholar  * Lachmann PJ . Microbial subversion of the immune response. _Proc Natl Acad Sci USA_ 2002; 99: 8461–8462. Article  CAS  PubMed  PubMed Central  Google Scholar  * Duthy TG


et al. The human complement regulator factor H binds pneumococcal surface protein PspC via short consensus repeats 13 to 15. _Infect Immun_ 2002; 70: 5604–5611. Article  CAS  PubMed  PubMed


Central  Google Scholar  * Meri T et al. The yeast _Candida albicans_ binds complement regulators factor H and FHL-1. _Infect Immun_ 2002; 70: 5185–5192. Article  CAS  PubMed  PubMed Central


  Google Scholar  * Meri T et al. _Onchocerca volvulus_ microfilariae avoid complement attack by direct binding of factor H. _J Infect Dis_ 2002; 185: 1786–1793. Article  CAS  PubMed  Google


Scholar  * Stoiber H, Speth C, Dierich MP . Role of complement in the control of HIV dynamics and pathogenesis. _Vaccine_ 2003; 21 (Suppl 2): S77–S82. Article  PubMed  Google Scholar  *


Ikeda K et al. Oncolytic virus therapy of multiple tumors in the brain requires suppression of innate and elicited antiviral responses. _Nat Med_ 1999; 5: 881–887. Article  CAS  PubMed 


Google Scholar  * Ikeda K _et al_ Complement depletion facilitates the infection of multiple brain tumors by an intravascular, replication-conditional herpes simplex virus mutant. _J Virol_


2000; 74: 4765–4775. Article  CAS  PubMed  PubMed Central  Google Scholar  * Suresh M et al. Complement component 3 is required for optimal expansion of CD8T cells during a systemic viral


infection. _J Immunol_ 2003; 170: 788–794. Article  CAS  PubMed  Google Scholar  * Dmitriev IP, Kashentseva EA, Curiel DT . Engineering of adenovirus vectors containing heterologous peptide


sequences in the C terminus of capsid protein IX. _J Virol_ 2002; 76: 6893–6899. Article  CAS  PubMed  PubMed Central  Google Scholar  * Vanderkwaak TJ et al. An advanced generation of


adenoviral vectors selectively enhances gene transfer for ovarian cancer gene therapy approaches. _Gynecol Oncol_ 1999; 74: 227–234. Article  CAS  PubMed  Google Scholar  * Yull FE et al.


Bioluminescent detection of endotoxin effects on HIV-1 LTR-driven transcription _in vivo_. _J Histochem Cytochem_ 2003; 51: 741–749. Article  CAS  PubMed  Google Scholar  Download references


ACKNOWLEDGEMENTS Research support was derived from NIH Grant Numbers CA80104 and 5P50CA089019, as well as DAMD17-02-01-0266. We thank Glorisa Reason for assistance with liver assays. AUTHOR


INFORMATION AUTHORS AND AFFILIATIONS * Department of Medicine, University of Alabama at Birmingham, Birmingham, 35294, AL, USA KR Zinn & AJ Szalai * Department of Radiology, University


of Alabama at Birmingham, Birmingham, 35294, AL, USA KR Zinn & TR Chaudhuri * The Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, 35294, AL, USA KR Zinn, A


Stargel & TR Chaudhuri * Department of Experimental Diagnostic Imaging, MD Anderson Cancer Center, University of Texas, Houston, 77030, TX, USA V Krasnykh Authors * KR Zinn View author


publications You can also search for this author inPubMed Google Scholar * AJ Szalai View author publications You can also search for this author inPubMed Google Scholar * A Stargel View


author publications You can also search for this author inPubMed Google Scholar * V Krasnykh View author publications You can also search for this author inPubMed Google Scholar * TR


Chaudhuri View author publications You can also search for this author inPubMed Google Scholar RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Zinn, K.,


Szalai, A., Stargel, A. _et al._ Bioluminescence imaging reveals a significant role for complement in liver transduction following intravenous delivery of adenovirus. _Gene Ther_ 11,


1482–1486 (2004). https://doi.org/10.1038/sj.gt.3302331 Download citation * Received: 10 July 2003 * Accepted: 18 May 2004 * Published: 05 August 2004 * Issue Date: 01 October 2004 * DOI:


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currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * luciferase * adenovirus * innate immunity * gene


therapy * inflammation * complement