Spiller O B, Mark L, Blue C E, Proctor D G, Aitken J A, Blom A M, Blackbourn D J
Department of Child Health, Cardiff University, Wales College of Medicine, United Kingdom.
J Virol. 2006 Apr;80(8):4068-78. doi: 10.1128/JVI.80.8.4068-4078.2006.
Complement, which bridges innate and adaptive immune responses as well as humoral and cell-mediated immunity, is antiviral. Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a lytic cycle protein called KSHV complement control protein (KCP) that inhibits activation of the complement cascade. It does so by regulating C3 convertases, accelerating their decay, and acting as a cofactor for factor I degradation of C4b and C3b, two components of the C3 and C5 convertases. These complement regulatory activities require the short consensus repeat (SCR) motifs, of which KCP has four (SCRs 1 to 4). We found that in addition to KCP being expressed on the surfaces of experimentally infected endothelial cells, it is associated with the envelope of purified KSHV virions, potentially protecting them from complement-mediated immunity. Furthermore, recombinant KCP binds heparin, an analogue of the known KSHV cell attachment receptor heparan sulfate, facilitating infection. Treating virus with an anti-KCP monoclonal antibody (MAb), BSF8, inhibited KSHV infection of cells by 35%. Epitope mapping of MAb BSF8 revealed that it binds within SCR domains 1 and 2, also the region of the protein involved in heparin binding. This MAb strongly inhibited classical C3 convertase decay acceleration by KCP and cofactor activity for C4b cleavage but not C3b cleavage. Our data suggest similar topological requirements for cell binding by KSHV, heparin binding, and regulation of C4b-containing C3 convertases but not for factor I-mediated cleavage of C3b. Importantly, they suggest KCP confers at least two functions on the virion: cell binding with concomitant infection and immune evasion.
补体可连接先天性免疫和适应性免疫以及体液免疫和细胞介导的免疫,具有抗病毒作用。卡波西肉瘤相关疱疹病毒(KSHV)编码一种裂解周期蛋白,称为KSHV补体控制蛋白(KCP),它可抑制补体级联反应的激活。其作用方式是调节C3转化酶,加速其衰变,并作为I因子降解C4b和C3b(C3和C5转化酶的两个组分)的辅因子。这些补体调节活性需要短共有重复序列(SCR)基序,KCP有四个这样的基序(SCR 1至4)。我们发现,除了在实验感染的内皮细胞表面表达外,KCP还与纯化的KSHV病毒粒子的包膜相关,可能保护它们免受补体介导的免疫。此外,重组KCP可结合肝素,这是已知的KSHV细胞附着受体硫酸乙酰肝素的类似物,有助于感染。用抗KCP单克隆抗体(MAb)BSF8处理病毒,可使KSHV对细胞的感染减少35%。MAb BSF8的表位作图显示,它结合在SCR结构域1和2内,这也是该蛋白参与肝素结合的区域。该单克隆抗体强烈抑制KCP介导的经典C3转化酶衰变加速以及C4b裂解的辅因子活性,但不抑制C3b裂解。我们的数据表明,KSHV的细胞结合、肝素结合以及含C4b的C3转化酶的调节具有相似的拓扑学要求,但I因子介导的C3b裂解则不然。重要的是,这些数据表明KCP赋予病毒粒子至少两种功能:伴随感染的细胞结合和免疫逃避。