Coagulation factor X shields adenovirus type 5 from attack by natural antibodies and complement

Xu, Zhili; Qiu, Qi Hong; Tian, Jie; Smith, Jeffrey S.; Conenello, Gina; Morita, Takashi; Byrnes, Andrew P.

doi:10.1038/nm.3107

Cited by 140 publications

(262 citation statements)

References 53 publications

Supporting

Mentioning

240

Contrasting

Order By: Relevance

“…Xu et al (47) suggest that FX is necessary to shield Ad5 from natural antibody and complement inactivation but may not be required for Ad5 liver transduction in vivo. In either immunodeficient Rag1 Ϫ/Ϫ mice or mice deficient in complement component C1q or C4, an Ad5 viral mutant in which FX binding is ablated showed only a modest reduction in transduction.…”

Section: Discussionmentioning

confidence: 99%

Hepatocyte Heparan Sulfate Is Required for Adeno-Associated Virus 2 but Dispensable for Adenovirus 5 Liver Transduction In Vivo

Zaiss

Foley

Lawrence

et al. 2016

J Virol

View full text Add to dashboard Cite

Adeno-associated virus 2 (AAV2) and adenovirus 5 (Ad5) are promising gene therapy vectors. Both display liver tropism and are currently thought to enter hepatocytes in vivo through cell surface heparan sulfate proteoglycans (HSPGs). To test directly this hypothesis, we created mice that lack Ext1, an enzyme required for heparan sulfate biosynthesis, in hepatocytes. A better understanding of how viral vectors enter cells in vivo is critical to improve their therapeutic use. Adeno-associated virus 2 (AAV2) and adenovirus 5 (Ad5) vectors have shown promise in clinical trials for treatment of a wide variety of diseases (1, 2). Both vectors, when injected intravenously into mice, exhibit transgene expression in liver (3-5). Heparan sulfate proteoglycans (HSPGs) are the primary receptors currently thought to facilitate AAV2 and Ad5 entry into hepatocytes (6-8).HSPGs are present both on the cell surface and in the extracellular matrix (9, 10). They consist of a protein core posttranslationally modified to contain heparan sulfate (HS) chains (11). HS biosynthesis occurs by polymerization of alternating glucuronic acid and N-acetylglucosamine residues (12-14), catalyzed by an enzyme complex composed of EXT1 and EXT2 (15). EXT1 and EXT2 are essential molecules required for HS synthesis; cells lacking either molecule do not synthesize HS (16,49).AAV2 binds directly to cell surface HSPGs via an HS-binding motif on the virus capsid (3,17,18). AAV capsid modifications that alter the cluster of positive amino acids that constitute the HS binding motif abrogate liver transduction (3,19,20), suggesting that the ability of the capsid to bind to HS is critical for AAV2 liver transduction in vivo. In contrast, Ad5 binding to HSPGs requires the presence of blood coagulation factor X (FX), which binds to the Ad5 hexon when the virus comes in contact with blood (7,(21)(22)(23). The interaction of Ad.FX and HS is mediated by electrostatic interactions between the heparin binding exosite of the FX serine protease domain and the sulfate groups of HS (6,(23)(24)(25). FX is required for Ad5 transduction in vivo in wild-type mice. In the absence of FX, or when viruses with mutant hexon proteins unable to bind FX are used, Ad5 liver transduction is essentially completely abrogated (7, 21-23, 26, 27).

show abstract

Section: Discussionmentioning

confidence: 99%

Hepatocyte Heparan Sulfate Is Required for Adeno-Associated Virus 2 but Dispensable for Adenovirus 5 Liver Transduction In Vivo

Zaiss

Foley

Lawrence

et al. 2016

J Virol

View full text Add to dashboard Cite

show abstract

“…It was recently reported that coagulation factor (F) X binds the hypervariable regions (HVR) of the hexon in an adenovirus, leading to liver infection [25,26]. The factor X enhances liver transduction by adenovirus vectors due to the protection of adenovirus from attack by the classical complementary pathway [27]. Therefore, a targeted adenovirus constructed on a mutant hypervariable region backbone to suppress a liver transduction may effectively allow for the development of vectors to specifically transduce certain tumors even through systemic administration [28].…”

Section: Discussionmentioning

confidence: 99%

A targeting ligand enhances infectivity and cytotoxicity of an oncolytic adenovirus in human pancreatic cancer tissues

Yamamoto

Hiraoka²,

Goto³

et al. 2014

Journal of Controlled Release

View full text Add to dashboard Cite

“…Natural IgM does not directly neutralize Ad5 in vitro (8), but natural IgM nevertheless inhibits liver transduction by Ad5 vectors in vivo (9,10). KCs are a major sink for Ad5 vectors (11)(12)(13)(14)(15).…”

mentioning

confidence: 99%

“…To determine whether the in vivo effect of IgM is specific or nonspecific, we tested whether liver transduction was inhibited by anti-HBV monoclonal IgM. To provide the most stringent test of the effect of IgM on liver transduction, we used the AdHVR7 Ad5 mutant vector, which is unable to bind FX and is extremely sensitive to inhibition by natural antibodies and complement (8). BALB/c natural IgM bound similarly both to the normal AdCMV-Luc Ad5 vector and to the AdHVR7 mutant vector (Fig.…”

mentioning

confidence: 99%

Impact of Natural IgM Concentration on Gene Therapy with Adenovirus Type 5 Vectors

Qiu

Tian

et al. 2015

J Virol

Self Cite

View full text Add to dashboard Cite

Coagulation factor X shields adenovirus type 5 from attack by natural antibodies and complement

Cited by 140 publications

References 53 publications

Hepatocyte Heparan Sulfate Is Required for Adeno-Associated Virus 2 but Dispensable for Adenovirus 5 Liver Transduction In Vivo

Hepatocyte Heparan Sulfate Is Required for Adeno-Associated Virus 2 but Dispensable for Adenovirus 5 Liver Transduction In Vivo

A targeting ligand enhances infectivity and cytotoxicity of an oncolytic adenovirus in human pancreatic cancer tissues

Impact of Natural IgM Concentration on Gene Therapy with Adenovirus Type 5 Vectors

Contact Info

Product

Resources

About