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

Area of Science:

• Virology
• Immunology
• Gene Therapy

Background:

• Adenovirus type 5 (Ad5) vectors are used for gene therapy.
• Coagulation factor X (FX) is essential for Ad5 liver transduction.
• The mechanism of FX's role in Ad5 transduction was unclear.

Purpose of the Study:

• To investigate the protective role of coagulation factor X (FX) against complement-mediated inactivation of Adenovirus type 5 (Ad5) vectors.
• To elucidate the mechanism by which FX enhances Ad5 liver transduction.

Main Methods:

• In vitro studies using naive mouse serum to assess Ad5 neutralization when FX binding was blocked.
• In vivo studies in wild-type mice and mice deficient in antibodies, C1q, or C4 to evaluate Ad5 liver transduction.
• Assessing the role of natural IgM and the classical complement pathway in Ad5 neutralization.

Main Results:

• Blocking FX binding to Ad5 in vitro led to neutralization by naive mouse serum, mediated by natural IgM and the classical complement pathway.
• In vivo, FX was essential for Ad5 liver transduction in wild-type mice.
• FX was not required for Ad5 liver transduction in mice lacking antibodies, C1q, or C4, indicating a complement-dependent protective mechanism.

Conclusions:

• Adenovirus type 5 (Ad5) actively recruits coagulation factor X (FX) to protect itself from inactivation by the classical complement pathway.
• The protective effect of FX is critical for efficient Ad5 liver transduction in vivo.
• The sensitivity of Ad5 to complement inactivation must be considered in the design of systemic gene therapy vectors.