Complement C4 Prevents Viral Infection through Capsid Inactivation

Area of Science:

• Immunology
• Virology

Background:

• The complement system is crucial for innate immunity and pathogen clearance.
• The classical complement pathway, initiated by antibody-antigen complexes, involves sequential cleavage of C1, C4, C2, C3, and C5.

Purpose of the Study:

• To investigate a novel antiviral mechanism mediated by the complement system.
• To elucidate the role of complement component C4 in inhibiting adenovirus infection.
• To explore the potential of complement modulation for antiviral therapies and gene therapy enhancement.

Main Methods:

• Demonstration of C4-dependent antiviral activity.
• Investigation of C4 activation and deposition on viral capsids.
• Assessment of C4b's inhibitory effect on viral disassembly and endosomal escape.
• Evaluation of viral burdens in C4-deficient mice.
• Analysis of complement synergy with TRIM21 in adenovirus gene therapy vectors.

Main Results:

• Complement component C4 inhibits human adenovirus infection by directly inactivating the virus capsid.
• C4 activation and C4b deposition on the capsid are antibody-dependent via the classical pathway.
• C4b-mediated neutralization is independent of C2 and C3 but requires C1q and antibody engagement.
• C4b inhibits capsid disassembly, preventing viral endosomal escape and cytosolic entry.
• C4-deficient mice show increased viral loads, and complement enhances adenovirus gene therapy efficacy.

Conclusions:

• A novel C4-dependent antiviral mechanism is identified, independent of downstream complement components.
• Complement component C4 directly inactivates adenovirus by inhibiting capsid disassembly.
• Targeting the complement system offers a promising strategy for preventing viral infections and improving gene therapy outcomes.