2. 四川农业大学动物医学院预防兽医研究所，成都 611130;
3. 四川农业大学动物疫病与人类健康四川省重点实验室，成都 611130
2. Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China;
3. Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
疱疹病毒科依据生物学特性和基因结构分成3个亚科：甲型疱疹病毒亚科、乙型疱疹病毒亚科和丙型疱疹病毒亚科。病毒粒子由外至内依次为囊膜(envelope)、皮层(tegument)、衣壳(capsid)、含双链DNA基因组的核心(core)[1-2]。甲型疱疹病毒亚科成员众多，宿主广泛，能感染哺乳类、两栖类和禽类，主要侵害宿主的皮肤、黏膜和神经组织，病毒还会在宿主神经组织潜伏感染，既没有临床症状也不会向外排毒，一旦感染之后，难以彻底清除，在宿主免疫力低下时潜伏病毒又被重新激活。gC是甲型疱疹病毒亚科病毒的多功能跨膜糖蛋白，由UL44基因编码，具有硫酸乙酰肝素受体功能，能促进病毒的吸附[3-4]。此外，还能介导病毒在低pH条件下进入上皮细胞、参与病毒的水平传播、与补体结合帮助病毒进行免疫逃避等。本文主要综述了gC在促进病毒复制方面的重要作用，以期能为深入研究甲型疱疹病毒亚科病毒的生命周期和开发gC相关的亚单位疫苗与mRNA疫苗提供参考。
1 gC的基本特性 1.1 UL44基因的保守性甲型疱疹病毒亚科的病毒基因组由共价连接的独特长区(unique long，UL)、独特短区(unique short，US)和重复序列所组成(repeat sequence，RS)，大部分病毒的基因组长度在150 kb左右，直径为150~200 nm，包含70以上个基因。其中，常见的甲型疱疹病毒亚科的成员包括伪狂犬病病毒(pseudorabies virus, PRV)、牛疱疹病毒Ⅰ型(bovine herpes virus 1, BHV-1)、猫疱疹病毒Ⅰ型(feline herpes virus 1, FHV-1)、鸡传染性喉气管炎病毒(infectious laryngotracheitis virus, ILTV)、马立克病毒(Marek's disease virus, MDV)、鸭肠炎病毒(duck enteritis virus, DEV)、人单纯疱疹病毒1型(herpes simplex virus 1, HSV-1)、人单纯疱疹病毒2型(herpes simplex virus 2，HSV-2)和水泡带状疱疹病毒(varicella zoster virus, VZV)。对这些病毒编码gC蛋白的UL44基因进行多序列比对，结果见表 1。以上基因序列来源于NCBI[5-13]。
|
表 1 甲型疱疹病毒亚科的病毒UL44基因序列相似性比对 Table 1 Alignment of alpha herpes virus UL44 gene sequence similarity |
不同的甲型疱疹病毒亚科病毒UL44基因的序列相似度从25.71%到77.55%，其中以HSV-1 gC与HSV-2 gC基因全序列相似度最高，达到77.55%(表 1)。UL44基因的序列相似度普遍在30%以上，揭示了不同甲型疱疹病毒亚科成员的gC蛋白之间可能存在功能的相似。
1.2 UL44基因类型甲型疱疹病毒亚科的病毒基因转录遵循级联瀑布式规律，根据基因转录的先后顺序，分为立即早期α(immediate early, IE)、早期β(early, E)和晚期γ(late, L)基因。IE基因的转录出现在病毒DNA复制之前，因此其表达不依赖病毒蛋白质的合成。UL48基因是IE基因的转录激活因子，诱导IE基因转录激活，部分E基因参与核苷酸代谢和DNA合成，如编码合成胸苷激酶(thymidine kinase, TK)、DNA聚合酶等。L基因主要编码衣壳蛋白、主要皮层蛋白和囊膜糖蛋白[14]。甲型疱疹病毒亚科病毒的UL44基因属于L基因，L基因的表达依赖IE基因，并受到IE基因的调控[14-15]。
2 gC参与病毒吸附 2.1 gC与糖胺聚糖结合促进病毒吸附感染在病毒的生命周期中，病毒首先通过与宿主细胞表面的受体结合从而吸附到细胞上。在甲型疱疹病毒亚科中，囊膜糖蛋白gC、gB与宿主细胞表面受体硫酸乙酰肝素结合[16-17]，介导病毒吸附至宿主细胞上[18-20]。随后gD能与细胞表面受体HVEM、nectin-1、nectin-2和3-O-HS特异性结合，与受体结合后gD构象发生变化，以此作为信号传递给gH/gL异二聚体，在gH/gL的协助下，gB以预融合状态进行病毒包膜与细胞膜的融合[21-22]。此外gB、gD、gH和gL是甲型疱疹病毒亚科的病毒侵入细胞的必须蛋白，gC是参与入侵的重要蛋白，但非必须蛋白，它们参与了病毒在不同pH条件下进入不同类型细胞的过程[23](图 1)。
|
图 1 gC参与HSV-1吸附和融合宿主细胞膜的过程 Fig. 1 gC participates in the process of HSV-1 adsorption and fusion host cell membrane |
在多数甲型疱疹病毒亚科的病毒中，如HSV-1[24]、EHV-4[25]、PRV[26]中gC与宿主细胞表面受体糖胺聚糖(glycosaminoglycans, GAGs)结合，以达到病毒附着在宿主细胞上的目的，但DEV、ILTV gC没有此功能[27-28]。与gC结合的GAGs主要是硫酸肝素(heparin sulfate, HS)和硫酸软骨素(chondroitin sulfate, CS)，硫酸软骨素通常是在硫酸肝素缺失时作为一种辅助受体与gC结合。此外，gC的N糖基化也可导致gC与宿主的结合受体由HS变为CS[29]。gC的硫酸肝素结合区域(heparin sulfate binding region, HBD)是gC与HS的结合位点，在HSV-1中，gC的HBD分布在其N端，主要位于gC 127—144位半胱氨酸[30]形成的环形结构间[31]。最少由10~12个糖单元组成，其中，一个2-O和一个6-O硫酸盐基团是必须结构单元[4]。HBD中带正电荷氨基残基能与HS中带负电荷的氨基残基结合，达到吸附在细胞表面的目的[32]。
gC与GAGs的结合受到gC黏液样区域(mucin-like region，MLR)的调控。MLR是高度O糖基化的区域，位于gC与GAGs结合位点附近[33]。缺失gC黏液性区域的HSV-1吸附到细胞膜的能力降低，宿主细胞表面释放的病毒粒子减少[34]。总的看来gC能够介导病毒吸附，不过并不是介导吸附的唯一蛋白，gB同样在病毒吸附过程中发挥重要作用，此外，MLR能够调控gC的吸附作用。
2.2 gC促进低pH途径中HSV的进入HSV进入细胞具有中性pH和低pH两种机制，HSV利用低pH机制进入上皮细胞，利用中性pH机制进入神经细胞[35-36]。HSV利用不同的途径来感染重要的靶细胞，gC在病毒通过内吞途径进入上皮细胞时起促进作用，gC存在时可增加病毒的融合，提高HSV的入胞效率，在gC缺失之后HSV-1进入CHO-HVEM和HEKa等上皮细胞的效率相较于野毒有明显的降低，HSV-1缺失gC后进入CHO-HVEM的效率下降50%，进入HEKa细胞的效率下降35%，而gC对病毒进入如Vero细胞等非上皮细胞效率无明显影响[37]。
gC促进病毒吸附的另一重要因素是gC能调节低pH诱导的gB构象变化。gB属于III类融合蛋白家族的成员，在疱疹病毒中是保守的，gB通过构象变化来介导病毒的融合和进入宿主细胞。这种构象的改变最近发现是由gC参与调节的，gC调节低pH诱导的gB构象变化，促进gB在低pH途径中与细胞膜的融合。在gC存在的情况下，gB的变构所需的低pH可上升0.4~0.7个pH单位，使得gB可以在较高的pH条件下发生变构，降低了gB变构的低pH要求，而gC缺失病毒gB的变构需要转移至pH更低的隔室，gB与细胞膜发生融合的时间增加，其中gC主要影响gB发挥膜融合重要作用的结构域I、II和V的变构[37-39]。这些变化对于gB是可逆的，且对病毒的进入十分重要[40]。gC能够调节低pH诱导的gB构象变化，来影响病毒与细胞膜的融合，但对gC能促进低pH条件下病毒感染上皮细胞的机理尚不明确，推测可能与不同种类细胞内的pH环境有关。
2.3 gC能介导病毒水平传播MDV是甲型疱疹病毒亚科的成员，感染宿主后能导致宿主产生肿瘤，MDV能够通过水平传播感染易感动物，其gC、US2和UL13参与MDV的水平传播[41]，其中，gC、UL13和UL47是必须的，US2是非必须的[42-43]。甲型疱疹病毒亚科的病毒的gC是I型膜蛋白，其跨膜结构域锚定在细胞膜上，但大部分的MDV gC是通过体外分泌的，通过逆转录分析鉴定出2种缺失跨膜结构域的gC mRNA剪接变体，其缺少了gC全长的104对碱基和145对碱基，分别称为gC104和gC145, 与野生型MDV或回复株相比，当只允许表达单个gC剪接变体时，MDV的水平传播会减少，这表明了gC、gC104和gC145都是MDV在水平传播中所必须的[44]。此外，gC表达剪接变体还受到UL47和ICP27的调控，在UL47缺失时，利用RT-PCR对gC转录物丰度进行检测时，gC全长的转录物数量可增加84%，但gC104和gC145的剪接转录物数量下降45%和33%[43]。ICP27可以抑制剪接变体，调节mRNA[45-46]，在ICP27存在的情况下gC145转录物表达量下降58%，gC全长转录物表达量增加22%[43]。
gC的水平传播功能是相对保守的，Gallid alphaherpesvirus 3的gC缺失后病毒的水平传播能力丧失，但在插入MDV gC替换Gallid alphaherpesvirus 3 gC后发现，Gallid alphaherpesvirus 3仍能在鸡群中水平传播[47]。但并非所有甲型疱疹病毒亚科的病毒gC都具有水平传播功能，在将ILTV gC替换MDV gC后，MDV无法实现个体间的水平传播，而Mardivirus属的病毒gC则能够相互替换而均能实现水平传播功能，证明gC的水平传播功能在Mardivirus属内是保守的[48]。总之，虽然对gC是如何影响MDV水平传播的机制尚不清楚，但可以确定的是缺失gC后MDV的复制功能受到损害，不能正常释放具有传染性的正常病毒粒子。
3 gC介导病毒的免疫逃避gC能够与补体C3结合且已经发生能够屏蔽gB特异性抗体对gB的识别中和。这对于病毒感染之初，有效地抵抗了补体与抗体对病毒的中和，使病毒逃避了宿主的免疫，促进了病毒的感染吸附。
3.1 gC抑制补体介导的中和反应进行免疫逃避gC具有补体C3b受体功能，能与C3b相结合抑制补体介导的中和作用以及扰乱补体系统正常功能，达到免疫逃避的目的，帮助病毒潜伏在宿主体内，这是甲型疱疹病毒亚科病毒的免疫逃避策略之一[49-50]。
在激活补体的旁路途径中，B因子与固相如微生物或外源性异物表面C3b结合为C3bB，在D因子、P因子(Properdin)作用下，形成C3转化酶C3bBb，并通过C3正反馈放大环路，产生更多的C3转化酶(C3bBb)和C5转化酶(C3bBb3b)，攻膜复合物(membrane attack complex, MAC)在末端通路过程中形成。补体成分C3b可介导调理作用，C3b的裂解产物iC3b、C3dg均为重要的调理素，通过与吞噬细胞表面的CR1、CR3结合促进吞噬细胞吞噬病原微生物。此外，C3b还可共价结合免疫复合物，C3b黏附在红细胞、血小板后将免疫复合物运送至肝或脾被吞噬细胞吞噬清除；MAC可溶解病毒包膜，参与抗病毒防御机制[51-55]。补体还可通过调节体液免疫和细胞免疫来参与机体内的免疫应答。C3b的裂解产物iC3b、C3d作用于B细胞的受体复合物(CR2-CD19-CD81)来降低活化B细胞的阈值；C3a或C5a可促进抗原呈递细胞的成熟来刺激T细胞的活化[56-57]。
HSV-1感染宿主细胞后gC可与补体C3b结合，干扰补体系统功能发挥[50]。gC还具有加速C3、C5转换酶复合物衰减功能，但gC对C3转化酶的加速衰减作用呈剂量依赖性，且gC的加速C3转化酶的衰减仅仅只针对旁路途径产生的C3bB，并非是经典途径产生的C3转化酶(C4b2a)，此外，gC可以降低旁路途径介导的细胞裂解的总效率，这表明gC可以影响C5/C5b与C3b的相互作用[58]。HSV-1 gC还抑制C5和P因子与C3b的结合，这种抑制作用是通过gC在空间上阻碍了P因子和C5进入C3b[59]。总的来说，gC通过抑制受感染细胞的补体激活，可以逃避补体介导的中和作用。通过构建gC重组蛋白，直接酶联免疫吸附法和竞争酶联免疫吸附法检测表达的蛋白与人C3和C3片段的结合情况，发现gC的重组蛋白能和C3、C3b、和C3c结合，并不与C3d结合，确定了gC与补体的结合位点在C3c上[59](图 2)。在探究gC抑制补体介导的中和作用时，将HSV-1 gC突变株与HSV野生株与非免疫血清进行孵育1 h，结果显示，gC突变株的病毒滴度最高可下降5 000倍，而野生株仅仅下降2倍。且用无HSV抗体的非免疫血清与HSV-1 gC缺失株和野生株进行孵育，也得到上述同样的结果，表明gC抑制补体介导的中和反应与抗体无关，且这种抑制作用发生在感染的早期[60]。
|
1.减少MAC合成；2.C3b介导的吞噬功能降低；3.加速C3/C5转化酶的衰变；4.免疫复合物清除率降低 1. Reduced MAC synthesis; 2. Reduced C3b-mediated phagocytosis; 3. Accelerated the decay of the C3/C5 convertase enzyme; 4. Reduced clearance rate of immune complexes 图 2 gC与C3b的结合对补体系统功能的影响 Fig. 2 The effect of the combination of gC and C3b on the function of the complement system |
HSV-1和HSV2 gC都可以与C3b结合[61-62]。PRV的糖蛋白III (gIII)能与补体的第3组分(C3)结合[63]。马疱疹病毒1型(EHV-1型)和4型(EHV-4型)的糖蛋白13(gp13, EHV-gC)能结合C3[64]。HSV-1 gC与C3的结合区域主要分为4个结构域，结构域I主要包含124—137氨基酸；结构域II主要包含276—292氨基酸；结构域III主要包含339—366氨基酸；结构域IV主要包含223—246氨基酸。gC抑制C5和备解素P的功能域在N端的33—123氨基酸[30, 65](图 3)。
综上所述，gC与补体激活途径的中枢成分C3b结合后导致正常C3b成分减少严重，影响了补体系统的细胞毒作用、调理作用、清除免疫复合物等正常功能的发挥。gC这一功能在病毒逃避宿主的免疫反应中起到至关重要的作用。因此，在后续甲型疱疹病毒疫苗的开发中gC作为重要的亚单位疫苗和其他诸如gD、gE蛋白亚单位疫苗一起发挥着重要作用[66-68]。此外，在经核苷修饰的mRNA在脂质纳米颗粒表达相同gC、gD和gE蛋白的mRNA疫苗的免疫效果更佳[69]。
3.2 gC通过屏蔽gB的原表位进行免疫逃避在病毒和宿主对抗的过程中，病毒已经进化出避免宿主抗体中和的策略。疱疹病毒gC和gE是介导病毒免疫逃避的主要蛋白，gE作为IgG Fc受体可以和IgG的Fc部分特异性结合，抑制IgG Fc参与补体激活和抗体依赖的细胞毒性作用[70-71]，gC除了与宿主补体C3b结合抑制补体介导的中和反应外，还可以保护gB免受抗体识别中和表位，此作为一种新的免疫逃避机制帮助病毒在宿主中持久感染[72]。gB作为甲型疱疹病毒亚科的病毒侵入的必须蛋白，参与病毒的吸附和膜融合，在所有甲型疱疹病毒亚科的病毒中都是保守的[73-74]。gC屏蔽gB抗原位点使gB特异性抗体无法准确识别gB，和野生株HSV相比缺失gC后的HSV更容易被gB抗体中和，且gD和gH的抗体的活性更高[75-77]。
gC功能的总结见表 2。
|
|
表 2 gC功能总结 Table 2 Summary of gC functions |
gC是甲型疱疹病毒亚科病毒的多功能糖蛋白，近年来研究发现gC在病毒的生命周期中扮演重要的角色，能结合宿主细胞表面受体介导病毒的吸附，促进低pH条件下病毒感染上皮细胞，影响MDV的水平传播，此外还能作为补体受体干扰补体对病毒的中和，屏蔽gB的抗原位点阻碍gB抗体对gB的识别清除。gC的越来越多的功能被发现，不过其机制不是完全都清楚的。其中，gC免疫逃避功能受到了极大关注，gC能够与补体结合，但对于如PRV、BHV-1、EHV等病毒的gC与补体受体结合还停留在蛋白层面，对于gC上的具体功能域还知之甚少。此外，最近发现gC能够屏蔽gB的抗原表位，并且还能降低其他糖蛋白的抗体效果，gC是否也屏蔽了其他糖蛋白的抗原位点还不得而知，gC与gB无空间上的结合，对于gC对gB抗原位点的屏蔽作用目前也没有合理的解析。目前，gC在亚单位疫苗和mRNA疫苗的研发中受到热捧，对gC的免疫逃避功能进行深入的研究对于疫苗的研发和甲型疱疹病毒亚科的病毒生命周期的解析具有重要意义。
| [1] |
MCGEOCH D J, RIXON F J, DAVISON A J. Topics in herpesvirus genomics and evolution[J]. Virus Res, 2006, 117(1): 90-104. DOI:10.1016/j.virusres.2006.01.002 |
| [2] |
METTENLEITER T C, KLUPP B G, GRANZOW H. Herpesvirus assembly: a tale of two membranes[J]. Curr Opin Microbiol, 2006, 9(4): 423-429. DOI:10.1016/j.mib.2006.06.013 |
| [3] |
LAQUERRE S, ARGNANI R, ANDERSON D B, et al. Heparan sulfate proteoglycan binding by herpes simplex virus type 1 glycoproteins B and C, which differ in their contributions to virus attachment, penetration, and cell-to-cell spread[J]. J Virol, 1998, 72(7): 6119-6130. DOI:10.1128/JVI.72.7.6119-6130.1998 |
| [4] |
FEYZI E, TRYBALA E, BERGSTRÖM T, et al. Structural requirement of heparan sulfate for interaction with herpes simplex virus type 1 virions and isolated glycoprotein C[J]. J Biol Chem, 1997, 272(40): 24850-24857. DOI:10.1074/jbc.272.40.24850 |
| [5] |
THUREEN D R, KEELER C L JR. Psittacid herpesvirus 1 and infectious laryngotracheitis virus: Comparative genome sequence analysis of two avian alphaherpesviruses[J]. J Virol, 2006, 80(16): 7863-7872. DOI:10.1128/JVI.00134-06 |
| [6] |
TRYBALA E, ROTH A, JOHANSSON M, et al. Glycosaminoglycan-binding ability is a feature of wild-type strains of herpes simplex virus Type 1[J]. Virology, 2002, 302(2): 413-419. DOI:10.1006/viro.2002.1639 |
| [7] |
DAVISON A J. Evolution of sexually transmitted and sexually transmissible human herpesviruses[J]. Ann NY Acad Sci, 2011, 1230(1): E37-E49. DOI:10.1111/j.1749-6632.2011.06358.x |
| [8] |
SCHWYZER M, ACKERMANN M. Molecular virology of ruminant herpesviruses[J]. Vet Microbiol, 1996, 53(1-2): 17-29. DOI:10.1016/S0378-1135(96)01231-X |
| [9] |
KLUPP B G, HENGARTNER C J, METTENLEITER T C, et al. Complete, annotated sequence of the pseudorabies virus genome[J]. J Virol, 2004, 78(1): 424-440. DOI:10.1128/JVI.78.1.424-440.2004 |
| [10] |
TULMAN E R, AFONSO C L, LU Z, et al. The genome of a very virulent Marek's disease virus[J]. J Virol, 2000, 74(17): 7980-7988. DOI:10.1128/JVI.74.17.7980-7988.2000 |
| [11] |
YING W, CHENG A C, WANG M S, et al. Comparative genomic analysis of duck enteritis virus strains[J]. J Virol, 2012, 86(24): 13841-13842. DOI:10.1128/JVI.01517-12 |
| [12] |
TAI S H S, NⅡKURA M, CHENG H H, et al. Complete genomic sequence and an infectious BAC clone of feline herpesvirus-1 (FHV-1)[J]. Virology, 2010, 401(2): 215-227. DOI:10.1016/j.virol.2010.02.021 |
| [13] |
DAVISON A J, SCOTT J E. The complete DNA sequence of varicella-zoster virus[J]. J Gen Virol, 1986, 67(Pt 9): 1759-1816. |
| [14] |
TAL-SINGER R, PENG C, PONCE DE LEON M, et al. Interaction of herpes simplex virus glycoprotein gC with mammalian cell surface molecules[J]. J Virol, 1995, 69(7): 4471-4483. DOI:10.1128/jvi.69.7.4471-4483.1995 |
| [15] |
SEDLACKOVA L, PERKINS K D, MEYER J, et al. Identification of an ICP27-responsive element in the coding region of a herpes simplex virus type 1 late gene[J]. J Virol, 2010, 84(6): 2707-2718. DOI:10.1128/JVI.02005-09 |
| [16] |
SARRAZIN S, LAMANNA W C, ESKO J D. Heparan sulfate proteoglycans[J]. Cold Spring Harb Perspect Biol, 2011, 3(7): a004952. |
| [17] |
HEROLD B C, VISALLI R J, SUSMARSKI N, et al. Glycoprotein C-independent binding of herpes simplex virus to cells requires cell surface heparan sulphate and glycoprotein B[J]. J Gen Viroly, 1994, 75(Pt 6): 1211-1222. |
| [18] |
LEMBO D, DONALISIO M, LAINE C, et al. Auto-associative heparin nanoassemblies: a biomimetic platform against the heparan sulfate-dependent viruses HSV-1, HSV-2, HPV-16 and RSV[J]. Eur J Pharmaceut Biopharmaceut, 2014, 88(1): 275-282. DOI:10.1016/j.ejpb.2014.05.007 |
| [19] |
IMAMURA J, SUZUKI Y, GONDA K, et al. Single particle tracking confirms that multivalent Tat protein transduction domain-induced heparan sulfate proteoglycan cross-linkage activates Rac1 for internalization[J]. J Biol Chem, 2011, 286(12): 10581-10592. DOI:10.1074/jbc.M110.187450 |
| [20] |
SHUKLA D, SPEAR P G. Herpesviruses and heparan sulfate: an intimate relationship in aid of viral entry[J]. J Clin Invest, 2001, 108(4): 503-510. DOI:10.1172/JCI200113799 |
| [21] |
WIRTZ L, MÖCKEL M, KNEBEL-MÖRSDORF D. Invasion of herpes simplex Virus 1 into murine dermis: role of Nectin-1 and herpesvirus entry mediator as cellular receptors during aging[J]. J Virol, 2020, 94(5): e02046-19. |
| [22] |
MONTGOMERY R I, WARNER M S, LUM B J, et al. Herpes simplex virus-1 entry into cells mediated by a novel member of the TNF/NGF receptor family[J]. Cell, 1996, 87(3): 427-436. DOI:10.1016/S0092-8674(00)81363-X |
| [23] |
EISENBERG R J, ATANASIU D, CAIRNS T M, et al. Herpes virus fusion and entry: a story with many characters[J]. Viruses, 2012, 4(5): 800-832. DOI:10.3390/v4050800 |
| [24] |
HEROLD B C, WUDUNN D, SOLTYS N, et al. Glycoprotein C of herpes simplex virus type 1 plays a principal role in the adsorption of virus to cells and in infectivity[J]. J Virol, 1991, 65(3): 1090-1098. DOI:10.1128/jvi.65.3.1090-1098.1991 |
| [25] |
AZAB W, TSUJIMURA K, MAEDA K, et al. Glycoprotein C of equine herpesvirus 4 plays a role in viral binding to cell surface heparan sulfate[J]. Virus Res, 2010, 151(1): 1-9. DOI:10.1016/j.virusres.2010.03.003 |
| [26] |
RUE C A, RYAN P. A role for glycoprotein C in pseudorabies virus entry that is independent of virus attachment to heparan sulfate and which involves the actin cytoskeleton[J]. Virology, 2003, 307(1): 12-21. DOI:10.1016/S0042-6822(02)00024-7 |
| [27] |
HU Y, LIU X K, ZOU Z, et al. Glycoprotein C plays a role in the adsorption of duck enteritis virus to chicken embryo fibroblasts cells and in infectivity[J]. Virus Res, 2013, 174(1-2): 1-7. DOI:10.1016/j.virusres.2013.01.015 |
| [28] |
KINGSLEY D H, KEELER C L JR. Infectious laryngotracheitis virus, an alpha herpesvirus that does not interact with cell surface heparan sulfate[J]. Virology, 1999, 256(2): 213-219. DOI:10.1006/viro.1999.9609 |
| [29] |
MÅRDBERG K, NYSTRÖM K, TARP M A, et al. Basic amino acids as modulators of an O-linked glycosylation signal of the herpes simplex virus type 1 glycoprotein gC: functional roles in viral infectivity[J]. Glycobiology, 2004, 14(7): 571-581. DOI:10.1093/glycob/cwh075 |
| [30] |
RUX A H, MOORE W T, LAMBRIS J D, et al. Disulfide bond structure determination and biochemical analysis of glycoprotein C from herpes simplex virus[J]. J Virol, 1996, 70(8): 5455-5465. DOI:10.1128/jvi.70.8.5455-5465.1996 |
| [31] |
MåRDBERG K, TRYBALA E, GLORIOSO J C, et al. Mutational analysis of the major heparan sulfate-binding domain of herpes simplex virus type 1 glycoprotein C[J]. J Gen Virol, 2001, 82(8): 1941-1950. DOI:10.1099/0022-1317-82-8-1941 |
| [32] |
FLYNN S J, RYAN P. The receptor-binding domain of pseudorabies virus glycoprotein gC is composed of multiple discrete units that are functionally redundant[J]. J Virol, 1996, 70(3): 1355-1364. DOI:10.1128/jvi.70.3.1355-1364.1996 |
| [33] |
JENTOFT N. Why are proteins O-glycosylated?[J]. Trends Biochem Sci, 1990, 15(8): 291-294. DOI:10.1016/0968-0004(90)90014-3 |
| [34] |
DELGUSTE M, PEERBOOM N, LE BRUN G, et al. Regulatory mechanisms of the mucin-like region on herpes simplex virus during cellular attachment[J]. ACS Chem Biol, 2019, 14(3): 534-542. DOI:10.1021/acschembio.9b00064 |
| [35] |
NICOLA A V, HOU J, MAJOR E O, et al. Herpes simplex virus type 1 enters human epidermal keratinocytes, but not neurons, via a pH-dependent endocytic pathway[J]. J Virol, 2005, 79(12): 7609-7616. DOI:10.1128/JVI.79.12.7609-7616.2005 |
| [36] |
NICOLA A V, MCEVOY A M, STRAUS S E. Roles for endocytosis and low pH in herpes simplex virus entry into HeLa and Chinese hamster ovary cells[J]. J Virol, 2003, 77(9): 5324-5332. DOI:10.1128/JVI.77.9.5324-5332.2003 |
| [37] |
SARI T K, GIANOPULOS K A, WEED D J, et al. Herpes simplex virus glycoprotein C regulates Low-pH entry[J]. mSphere, 2020, 5(1): e00826-19. |
| [38] |
WEED D J, DOLLERY S J, KOMALA SARI T, et al. Acidic pH mediates changes in antigenic and oligomeric conformation of herpes simplex virus gB and is a determinant of cell-specific entry[J]. J Virol, 2018, 92(17): e01034-18. |
| [39] |
WEED D J, PRITCHARD S M, GONZALEZ F, et al. Mildly acidic pH triggers an irreversible conformational change in the fusion domain of herpes simplex virus 1 glycoprotein B and inactivation of viral entry[J]. J Virol, 2017, 91(5): e02123-16. |
| [40] |
DOLLERY S J, DELBOY M G, NICOLA A V. Low pH-induced conformational change in herpes simplex virus glycoprotein B[J]. J Virol, 2010, 84(8): 3759-3766. DOI:10.1128/JVI.02573-09 |
| [41] |
JAROSINSKI K W, MARGULIS N G, KAMIL J P, et al. Horizontal transmission of Marek's disease virus requires US2, the UL13 protein kinase, and gC[J]. J Virol, 2007, 81(19): 10575-10587. DOI:10.1128/JVI.01065-07 |
| [42] |
JAROSINSKI K W, OSTERRIEDER N. Further analysis of Marek's disease virus horizontal transmission confirms that UL44 (gC) and UL13 protein kinase activity are essential, while US2 is nonessential[J]. J Virol, 2010, 84(15): 7911-7916. DOI:10.1128/JVI.00433-10 |
| [43] |
CHUARD A, COURVOISIER-GUYADER K, RÉMY S, et al. The tegument protein pUL47 of Marek's disease virus is necessary for horizontal transmission and is important for expression of glycoprotein gC[J]. J Virol, 2020, 95(2): e01645-20. |
| [44] |
JAROSINSKI K W, OSTERRIEDER N. Marek's disease virus expresses multiple UL44 (gC) variants through mRNA splicing that are all required for efficient horizontal transmission[J]. J Virol, 2012, 86(15): 7896-7906. DOI:10.1128/JVI.00908-12 |
| [45] |
HARDY W R, SANDRI-GOLDIN R M. Herpes simplex virus inhibits host cell splicing, and regulatory protein ICP27 is required for this effect[J]. J Virol, 1994, 68(12): 7790-7799. DOI:10.1128/jvi.68.12.7790-7799.1994 |
| [46] |
PONNURAJ N, TIEN Y T, VEGA-RODRIGUEZ W, et al. The herpesviridae conserved multifunctional infected-cell protein 27 (ICP27) is important but not required for replication and oncogenicity of Marek's disease alphaherpesvirus[J]. J Virol, 2019, 93(4): e01903-18. |
| [47] |
VEGA-RODRIGUEZ W, XU H, PONNURAJ N, et al. The requirement of glycoprotein C (gC) for interindividual spread is a conserved function of gC for avian herpesviruses[J]. Sci Rep, 2021, 11(1): 7753. DOI:10.1038/s41598-021-87400-x |
| [48] |
VEGA-RODRIGUEZ W, PONNURAJ N, GARCIA M, et al. The requirement of glycoprotein c for interindividual spread is functionally conserved within the alphaherpesvirus genus (Mardivirus), but Not the Host (Gallid)[J]. Viruses, 2021, 13(8): 1419. DOI:10.3390/v13081419 |
| [49] |
LUBINSKI J M, WANG L Y, SOULIKA A M, et al. Herpes simplex virus type 1 glycoprotein gC mediates immune evasion in vivo[J]. J Virol, 1998, 72(10): 8257-8263. DOI:10.1128/JVI.72.10.8257-8263.1998 |
| [50] |
FRIEDMAN H M, COHEN G H, EISENBERG R J, et al. Glycoprotein C of herpes simplex virus 1 acts as a receptor for the C3b complement component on infected cells[J]. Nature, 1984, 309(5969): 633-635. DOI:10.1038/309633a0 |
| [51] |
HARRISON R A. The properdin pathway: an "alternative activation pathway" or a "critical amplification loop" for C3 and C5 activation?[J]. Semin Immunopathol, 2018, 40(1): 15-35. DOI:10.1007/s00281-017-0661-x |
| [52] |
NILSSON B, EKDAHL K N. The tick-over theory revisited: is C3 a contact-activated protein?[J]. Immunobiology, 2012, 217(11): 1106-1110. DOI:10.1016/j.imbio.2012.07.008 |
| [53] |
MERLE N S, CHURCH S E, FREMEAUX-BACCHI V, et al. Complement system Part I-molecular mechanisms of activation and regulation[J]. Front Immunol, 2015, 6: 262. |
| [54] |
ARBORE G, KEMPER C, KOLEV M. Intracellular complement-the complosome-in immune cell regulation[J]. Mol Immunol, 2017, 89: 2-9. DOI:10.1016/j.molimm.2017.05.012 |
| [55] |
RICKLIN D, REIS E S, LAMBRIS J D. Complement in disease: a defence system turning offensive[J]. Nat Rev Nephrol, 2016, 12(7): 383-401. DOI:10.1038/nrneph.2016.70 |
| [56] |
DEMPSEY P W, ALLISON M E, AKKARAJU S, et al. C3 d of complement as a molecular adjuvant: bridging innate and acquired immunity[J]. Science, 1996, 271(5247): 348-350. DOI:10.1126/science.271.5247.348 |
| [57] |
MAYILYAN K R. Complement genetics, deficiencies, and disease associations[J]. Protein Cell, 2012, 3(7): 487-496. DOI:10.1007/s13238-012-2924-6 |
| [58] |
FRIES L F, FRIEDMAN H M, COHEN G H, et al. Glycoprotein C of Herpes simplex virus 1 is an inhibitor of the complement cascade[J]. J Immunol, 1986, 137(5): 1636-1641. |
| [59] |
KOSTAVASILI I, SAHU A, FRIEDMAN H M, et al. Mechanism of complement inactivation by glycoprotein C of herpes simplex virus[J]. J Immunol, 1997, 158(4): 1763-1771. |
| [60] |
FRIEDMAN H M, WANG L, FISHMAN N O, et al. Immune evasion properties of herpes simplex virus type 1 glycoprotein gC[J]. J Virol, 1996, 70(7): 4253-4260. DOI:10.1128/jvi.70.7.4253-4260.1996 |
| [61] |
LUBINSKI J, WANG L Y, MASTELLOS D, et al. In vivo role of complement-interacting domains of herpes simplex virus type 1 glycoprotein gC[J]. J Exp Med, 1999, 190(11): 1637-1646. DOI:10.1084/jem.190.11.1637 |
| [62] |
TAL-SINGER R, SEIDEL-DUGAN C, FRIES L, et al. Herpes simplex virus glycoprotein C is a receptor for complement component iC3b[J]. J Infect Dis, 1991, 164(4): 750-753. DOI:10.1093/infdis/164.4.750 |
| [63] |
HUEMER H P, LARCHER C, COE N E. Pseudorabies virus glycoprotein Ⅲ derived from virions and infected cells binds to the third component of complement[J]. Virus Res, 1992, 23(3): 271-280. DOI:10.1016/0168-1702(92)90113-N |
| [64] |
HUEMER H P, NOWOTNY N, CRABB B S, et al. gp13 (EHV-gC): a complement receptor induced by equine herpesviruses[J]. Virus Res, 1995, 37(2): 113-126. DOI:10.1016/0168-1702(95)00027-N |
| [65] |
HUNG S L, PENG C R L N, KOSTAVASILI I, et al. The interaction of glycoprotein C of herpes simplex virus types 1 and 2 with the alternative complement pathway[J]. Virology, 1994, 203(2): 299-312. DOI:10.1006/viro.1994.1488 |
| [66] |
AWASTHI S, BALLIET J W, FLYNN J A, et al. Protection provided by a herpes simplex virus 2 (HSV-2) glycoprotein C and D subunit antigen vaccine against genital HSV-2 infection in HSV-1-seropositive guinea pigs[J]. J Virol, 2014, 88(4): 2000-2010. DOI:10.1128/JVI.03163-13 |
| [67] |
AWASTHI S, MAHAIRAS G G, SHAW C E, et al. A dual-modality herpes simplex virus 2 vaccine for preventing genital herpes by using glycoprotein C and D subunit antigens to induce potent antibody responses and adenovirus vectors containing capsid and tegument proteins as T Cell immunogens[J]. J Virol, 2015, 89(16): 8497-8509. DOI:10.1128/JVI.01089-15 |
| [68] |
AWASTHI S, HOOK L M, SHAW C E, et al. A trivalent subunit antigen glycoprotein vaccine as immunotherapy for genital herpes in the guinea pig genital infection model[J]. Hum Vacc Immun, 2017, 13(12): 2785-2793. DOI:10.1080/21645515.2017.1323604 |
| [69] |
AWASTHI S, HOOK L M, PARDI N, et al. Nucleoside-modified mRNA encoding HSV-2 glycoproteins C, D, and E prevents clinical and subclinical genital herpes[J]. Sci Immunol, 2019, 4(39): eaaw7083. DOI:10.1126/sciimmunol.aaw7083 |
| [70] |
EGAN K, HOOK L M, NAUGHTON A, et al. Herpes simplex virus type 2 trivalent protein vaccine containing glycoproteins C, D and E protects guinea pigs against HSV-1 genital infection[J]. Hum Vacc Immun, 2020, 16(9): 2109-2113. DOI:10.1080/21645515.2020.1749509 |
| [71] |
LUBINSKI J M, LAZEAR H M, AWASTHI S, et al. The herpes simplex virus 1 IgG fc receptor blocks antibody-mediated complement activation and antibody-dependent cellular cytotoxicity in vivo[J]. J Virol, 2011, 85(7): 3239-3249. DOI:10.1128/JVI.02509-10 |
| [72] |
SARI T K, GIANOPULOS K A, NICOLA A V. Glycoprotein C of herpes simplex Virus 1 shields glycoprotein B from antibody neutralization[J]. J Virol, 2020, 94(5): e01852-19. |
| [73] |
HELDWEIN E E, LOU H, BENDER F C, et al. Crystal structure of glycoprotein B from herpes simplex virus 1[J]. Science, 2006, 313(5784): 217-220. DOI:10.1126/science.1126548 |
| [74] |
COOPER R S, HELDWEIN E E. Herpesvirus gB: a finely tuned fusion machine[J]. Viruses, 2015, 7(12): 6552-6569. DOI:10.3390/v7122957 |
| [75] |
AWASTHI S, LUBINSKI J M, FRIEDMAN H M. Immunization with HSV-1 glycoprotein C prevents immune evasion from complement and enhances the efficacy of an HSV-1 glycoprotein D subunit vaccine[J]. Vaccine, 2009, 27(49): 6845-6853. DOI:10.1016/j.vaccine.2009.09.017 |
| [76] |
AWASTHI S, LUBINSKI J M, SHAW C E, et al. Immunization with a vaccine combining herpes simplex virus 2 (HSV-2) glycoprotein C (gC) and gD subunits improves the protection of dorsal root ganglia in mice and reduces the frequency of recurrent vaginal shedding of HSV-2 DNA in guinea pigs compared to immunization with gD alone[J]. J Virol, 2011, 85(20): 10472-10486. DOI:10.1128/JVI.00849-11 |
| [77] |
HOOK L M, HUANG J L, JIANG M, et al. Blocking antibody access to neutralizing domains on glycoproteins involved in entry as a novel mechanism of immune evasion by herpes simplex virus type 1 glycoproteins C and E[J]. J Virol, 2008, 82(14): 6935-6941. DOI:10.1128/JVI.02599-07 |
| [78] |
METTENLEITER T C, ZSAK L, ZUCKERMANN F, et al. Interaction of glycoprotein gⅢ with a cellular heparinlike substance mediates adsorption of pseudorabies virus[J]. J Virol, 1990, 64(1): 278-286. DOI:10.1128/jvi.64.1.278-286.1990 |
| [79] |
OKAZAKI K, MATSUZAKI T, SUGAHARA Y, et al. BHV-1 adsorption is mediated by the interaction of glycoprotein gⅢ with heparinlike moiety on the cell surface[J]. Virology, 1991, 181(2): 666-670. DOI:10.1016/0042-6822(91)90900-V |
| [80] |
OSTERRIEDER N. Construction and characterization of an equine herpesvirus 1 glycoprotein C negative mutant[J]. Virus Res, 1999, 59(2): 165-177. DOI:10.1016/S0168-1702(98)00134-8 |
| [81] |
MAEDA K, HAYASHI S, TANIOKA Y, et al. Pseudorabies virus (PRV) is protected from complement attack by cellular factors and glycoprotein C (gC)[J]. Virus Res, 2002, 84(1-2): 79-87. DOI:10.1016/S0168-1702(01)00417-8 |
| [82] |
HIDAKA Y, SAKAI Y, TOH Y, et al. Glycoprotein C of herpes simplex virus type 1 is essential for the virus to evade antibody-independent complement-mediated virus inactivation and lysis of virus-infected cells[J]. J Gen Virol, 1991, 72(Pt 4): 915-921. |
| [83] |
MACLEOD D T, NAKATSUJI T, YAMASAKI K, et al. HSV-1 exploits the innate immune scavenger receptor MARCO to enhance epithelial adsorption and infection[J]. Nat Commun, 2013, 4: 1963. DOI:10.1038/ncomms2963 |
| [84] |
GONZÁLEZ-MOTOS V, JVRGENS C, RITTER B, et al. Varicella zoster virus glycoprotein C increases chemokine-mediated leukocyte migration[J]. PLoS Pathog, 2017, 13(5): e1006346. DOI:10.1371/journal.ppat.1006346 |
| [85] |
MAEDA K, HORIMOTO T, MIKAMI T. Properties and functions of feline herpesvirus type 1 glycoproteins[J]. J Vet Med Sci, 1998, 60(8): 881-888. DOI:10.1292/jvms.60.881 |
| [86] |
TRYBALA E, SVENNERHOLM B, BERGSTRÖM T, et al. Herpes simplex virus type 1-induced hemagglutination: glycoprotein C mediates virus binding to erythrocyte surface heparan sulfate[J]. J Virol, 1993, 67(3): 1278-1285. DOI:10.1128/jvi.67.3.1278-1285.1993 |
| [87] |
OKAZAKI K, KANNO T, KIRIYA S, et al. Hemadsorptive activity of transfected COS-7 cells expressing BHV-1 glycoprotein gⅢ[J]. Virology, 1993, 193(2): 1024-1027. DOI:10.1006/viro.1993.1220 |
| [88] |
YAMADA S, IMADA T, SHIMIZU M, et al. A mutant of pseudorabies virus with deletion of glycoprotein gⅢ gene prepared from a Japanese isolate: it fails to agglutinate mouse erythrocytes[J]. Vet Microbiol, 1995, 45(2-3): 233-242. DOI:10.1016/0378-1135(94)00132-G |
| [89] |
ANDOH K, HATTORI S, MAHMOUD H Y A H, et al. The haemagglutination activity of equine herpesvirus type 1 glycoprotein C[J]. Virus Res, 2015, 195: 172-176. DOI:10.1016/j.virusres.2014.10.014 |
(编辑 白永平)