title: Functional activity of the complement regulator encoded by Kaposi's sarcoma-associated herpesvirus.
abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) is closely associated with Kaposi's sarcoma and certain B-cell lymphomas. The fourth open reading frame of the KSHV genome encodes a protein (KSHV complement control protein (KCP, previously termed ORF4)) predicted to have complement-regulating activity. Here, we show that soluble KCP strongly enhanced the decay of classical C3-convertase but not the alternative pathway C3-convertase, when compared with the host complement regulators: factor H, C4b-binding protein, and decay-accelerating factor. The equilibrium affinity constant (KD) of KCP for C3b and C4b was determined by surface plasmon resonance analysis to range between 0.47-10 microM and 0.025-6.1 microM, respectively, depending on NaCl concentration and cation presence. Soluble and cell-associated KCP acted as a cofactor for factor I (FI)-mediated cleavage of both C4b and C3b and induced the cleavage products C4d and iC3b, respectively. In the presence of KCP, FI further cleaved iC3b to C3d, which has never been described before as complement receptor 1 only mediates the production of C3dg by FI. KCP would enhance virus pathogenesis through evading complement attack, opsonization, and anaphylaxis but may also aid in targeting KSHV to one of its host reservoirs since C3d is a ligand for complement receptor 2 on B-cells.
authors.affiliation: University of Wales College of Medicine, Virus Receptor and Immune Evasion Group, Department of Medical Biochemistry, Heath Park, Cardiff CF14 4XX, United Kingdom.
authors.forename: O Brad
authors.initials: OB
authors.lastname: Spiller
authors.forename: David J
authors.initials: DJ
authors.lastname: Blackbourn
authors.forename: Linda
authors.initials: L
authors.lastname: Mark
authors.forename: David G
authors.initials: DG
authors.lastname: Proctor
authors.forename: Anna M
authors.initials: AM
authors.lastname: Blom
mesh_terms: D017398:Alternative Splicing; D003167:Complement Activation; D003179:Complement C3b / Q000737:chemistry; D015935:Complement C4b / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D019288:Herpesvirus 8, Human / Q000235:genetics*; D006801:Humans; D007700:Kinetics; D008024:Ligands; D016366:Open Reading Frames; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D020349:Surface Plasmon Resonance; D014764:Viral Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: C473771:KSHV complement control protein, Herpesvirus 8; D008024:Ligands; D014764:Viral Proteins; D003179:Complement C3b; D015935:Complement C4b