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Cell Host Microbe. 2019 Apr 10;25(4):617-629.e7. doi: 10.1016/j.chom.2019.02.016. Epub 2019 Mar 26.

Complement C4 Prevents Viral Infection through Capsid Inactivation.

Author information

1
Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.
2
Centre for Immune Regulation (CIR) and Department of Biosciences, University of Oslo, Oslo N-0316, Norway; CIR and Department of Immunology, Rikshospitalet, Oslo University Hospital, Oslo N-0372, Norway; Department of Pharmacology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, Oslo N-0372, Norway.
3
CIR and Department of Immunology, Rikshospitalet, Oslo University Hospital, Oslo N-0372, Norway; Department of Pharmacology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, Oslo N-0372, Norway.
4
CIR and Department of Immunology, Rikshospitalet, Oslo University Hospital, Oslo N-0372, Norway.
5
Centre for Immune Regulation (CIR) and Department of Biosciences, University of Oslo, Oslo N-0316, Norway; CIR and Department of Immunology, Rikshospitalet, Oslo University Hospital, Oslo N-0372, Norway.
6
Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, UK. Electronic address: lcj@mrc-lmb.cam.ac.uk.

Abstract

The complement system is vital for anti-microbial defense. In the classical pathway, pathogen-bound antibody recruits the C1 complex (C1qC1r2C1s2) that initiates a cleavage cascade involving C2, C3, C4, and C5 and triggering microbial clearance. We demonstrate a C4-dependent antiviral mechanism that is independent of downstream complement components. C4 inhibits human adenovirus infection by directly inactivating the virus capsid. Rapid C4 activation and capsid deposition of cleaved C4b are catalyzed by antibodies via the classical pathway. Capsid-deposited C4b neutralizes infection independent of C2 and C3 but requires C1q antibody engagement. C4b inhibits capsid disassembly, preventing endosomal escape and cytosolic access. C4-deficient mice exhibit heightened viral burdens. Additionally, complement synergizes with the Fc receptor TRIM21 to block transduction by an adenovirus gene therapy vector but is partially restored by Fab virus shielding. These results suggest that the complement system could be altered to prevent virus infection and enhance virus gene therapy efficacy.

KEYWORDS:

TRIM21; adenovirus; complement; complement C4; complement-mediated neutralization; gene therapy; host-pathogen; humoral immunity; neutralizing antibodies; non-enveloped virus

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