Virus-Encoded Complement Regulators: Current Status

Abstract

Viruses require a host for replication and survival and hence are subjected to host immunological pressures. The complement system, a crucial first response of the host immune system, is effective in targeting viruses and virus-infected cells, and boosting the antiviral innate and acquired immune responses. Thus, the system imposes a strong selection pressure on viruses. Consequently, viruses have evolved multiple countermeasures against host complement. A major mechanism employed by viruses to subvert the complement system is encoding proteins that target complement. Since viruses have limited genome size, most of these proteins are multifunctional in nature. In this review, we provide up to date information on the structure and complement regulatory functions of various viral proteins.

Keywords: CD59; Herpesvirus; Poxvirus; RCA; complement; innate immunity; pathogenesis; viral RCA; viral immune evasion.

Figure 1

Timeline of identification of virally encoded complement regulators. Abbreviations: HSV gC, Herpes simplex virus glycoprotein C; VCP, Vaccinia virus complement control protein; RCA, regulator of complement activation; HVS, Herpesvirus saimiri; KSHV, Kaposi’s sarcoma-associated herpesvirus; Kaposica, KSHV inhibitor of complement activation; KCP, KSHV complement control protein; NS1, Non-structural protein; HAstV coat protein, Human astrovirus coat protein; HCV NS5A, Hepatitis C virus non-structural 5A protein; HCV NS3/4A, Hepatitis C virus non-structural 3/4A protease; NiV, Nipah virus.

Figure 2

Complement activation and its regulation by host regulators and virally encoded molecules. Viruses can activate the host complement system by three major pathways: classical pathway (CP), lectin pathway (LP), and alternative pathway (AP). (1) In CP activation, viruses are known to be recognized by C1q and antibody. (2) In LP activation, viruses are recognized by the Ficolin/MBL-MASP complex. (3) Recognition is followed by activation of C1 and Ficolin/MBL complexes, in CP and LP respectively, which results in the cleavage of C4 and C2 and formation of C3 convertase C4b2a. The convertase then cleaves C3 into C3a and C3b. The latter opsonizes viral particles. (4) In AP, viruses are recognized directly by C3b molecules, which are generated by the initial C3 convertase C3(H2O)Bb. (5) The surface-bound C3b molecules then trigger the formation of C3 convertase C3bBb with the help of factors B and D, which is stabilized by properdin (P). The C3 convertases formed then cleaves more C3 to opsonize viral particles. (6) When C3b is attached to the preformed C3 convertase (C4b2a or C3bBbP), it is converted into C5 convertase (C4b2a3b or C3b2BbP) which is capable of cleaving C5 into C5a and C5b. (7) The newly formed C5b combines C6 and C7 to form a C5b-7 trimer that can attach to the viral surface. (8) Binding of the trimer to C8 and C9 followed by polymerization of C9 results in the formation of the membrane attack complex (MAC) that induces virolysis. These pathways are regulated at various steps by host complement regulators like C1 inhibitor, C4b-binding protein (C4BP), complement receptor 1 (CR1; CD35), membrane cofactor protein (MCP; CD46), decay-accelerating factor (DAF; CD55), factor H (FH) and CD59. Viral complement regulators that target complement proteins, enzymes, and complexes are shown in red text, whereas those that inhibit complement proteins’ expression are shown in blue text. Some viral complement regulators enhance the expression of host complement regulators. These are identified in green text, and green arrows mark the regulator they upregulate. Abbreviations: CaPt, Astrovirus capsid protein; M1, Influenza virus matrix protein 1; NS1, Flavivirus non-structural protein 1; NS3/4A, Hepatitis C virus non-structural 3/4A protease; HCV-CP, Hepatitis C virus core protein; NS5A, Hepatitis C virus non-structural 5A protein; VCP, Vaccinia virus complement control protein; SPICE, Smallpox inhibitor of complement enzymes; Kaposica, KSHV inhibitor of complement activation; γHV-68 RCA, Murine gammaherpesvirus 68 regulator of complement activation; HVS CCPH, Herpesvirus saimiri complement control protein homolog; EMICE, Ectromelia virus inhibitor of complement enzymes; MOPICE, Monkeypox inhibitor of complement enzymes; RCP-H, Rhesus rhadinovirus complement control protein H; RCP-1, Rhesus rhadinovirus complement control protein-1; gC1, Herpes simplex virus glycoprotein C-1; E protein, Zika virus E protein, HVS CD59, Herpesvirus saimiri CD59; HBx, Hepatitis B virus X protein.