丙型肝炎病毒高变区1中存在介导病毒入侵和免疫逃避的三个不同结构域
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摘要
丙型肝炎病毒(hepatitis C virus, HCV)属于黄病毒科、丙型肝炎病毒属,为有包膜的单正链RNA病毒。目前全球约有1.8亿人感染HCV,大多数为慢性感染,部分感染者可发展为肝硬化和肝细胞癌。HCV的RNA聚合酶缺少校对功能,致使HCV整个基因组具有很高的变异性,但HCV基因的变异呈不平衡分布.位于包膜蛋白2(E2)氨基端的27个氨基酸残基变异性最为突出,即HVRl。HIVR1高度暴露于包膜蛋白表面,其中含有中和抗体表位,可以诱导宿主产生针对该区域的抗体,产生的抗体可以高效中和HCV的感染,但HVR1的基因序列高度变异,先前由宿主免疫细胞产生的抗体不能识别变异后的HVRl,因此病毒得以逃避宿主细胞的免疫监控并在病人体内持续感染进而使感染慢性化。众多实验室都将HVR1作为HCV疫苗研发的重要靶标,但自1989年丙型肝炎病毒首次命名至今,仍没有一个真正有效的保护性疫苗问世。
HCV感染会引起肝内生化代谢紊乱,包括脂质代谢障碍和载脂蛋白合成异常,与其他病毒性肝炎相比,HCV感染慢性化后,中重度肝细胞脂肪变性包括胞质内脂滴聚集是其典型组织病理学特征。HCV是有包膜RNA病毒,其表面有不同数量的脂蛋白包裹,所以病人血清中纯化得到的HCV病毒颗粒呈现不同的密度分布,并且不同密度的病毒颗粒感染性也不同。有研究发现HVR1的删除会导致低密度病毒颗粒数目下降,也就是减弱了HCV的脂蛋白结合能力,可见HVR1在病毒与脂蛋白结合的过程中亦发挥重要的作用。多项研究证明HVR1同时还在与宿主SR-B1受体结合以及介导病毒入侵的过程中起关键作用,HVR1具有如此重要的生物学功能,那么其结构必然具有相对稳定性和保守性,虽然HVR1是HCV基因组中变异频率最高的部分之一,但对HCV一系列分离株的序列分析表明一些氨基酸残基的位点是高度、或者相对保守的。尽管人们已经发现HVR1同时行驶着诱导宿主免疫反应,脂蛋白结合以及介导病毒与受体结合的多重功能,但目前尚不清楚其结构与生物学功能的对应关系。
一、HCV高变区1中介导病毒细胞入侵关键氨基酸残基的鉴定
首先我们以HCVpp作为研究模型,以HCVla亚型的H77株为模式株,用单一氨基酸残基删除扫描的方法分析HVR1中27个氨基酸残基分别对HCV细胞入侵的影响,实验结果明确的鉴定出HVRl中介导HCV细胞入侵的关键氨基酸残基(Ala-14,Gly-15, Lys-25, Gln-26以及Asn-27),其中任意一个残基的删除对HCVpp感染性的影响都是致命的,相比之下,其他22个氨基酸残基的删除对HCVpp感染性并未造成明显影响。再用HCV入侵相关受体结合实验进行机制分析,我们证明这5位氨基酸残基介导了病毒包膜蛋白与宿主细胞SR-B1受体的结合。氨基酸残基合并删除实验进一步的证明了我们的结论,HVRl氨基端13个残基的删除以及第16-24位9个氨基酸残基的删除不会显著降低HCVpp的感染力。除了决定HCV细胞入侵的5个氨基酸残基之外,HVR1氨基端的13个氨基酸残基可以通过适当的突变,增强病毒与受体的结合能力从而增强病毒的细胞入侵能力,并且这一区域适当的突变还可以增强病毒的抗中和能力从而更利于病毒的免疫逃避和持续感染。
二、HCV高变区1中诱导中和抗体产生的抗原表位的鉴定
我们将HVR1分为氨基段,中段和羧基段三部分肽段分别与TRX融合表达后免疫家兔来检测HVR1的27个氨基酸残基在诱导宿主免疫反应过程中是否存在差异,我们发现HVRl的氨基端13个氨基酸残基不能诱导宿主产生抗体,而第16到24位的9个氨基酸残基是HVRl中唯一的中和表位,这9个氨基酸残基对于病毒细胞入侵无关紧要,但含有肝素结合位点,有利于HCV的粘附,更为重要的是,高密度脂蛋白(HDL)介导的HCV感染增强作用依赖于该9个氨基酸残基的存在,该九个残基还可通过与HDL的作用显著下调E2抗体的中和活性,小鼠DNA免疫试验也进一步验证了我们的结论。
三、HCV高变区1中介导病毒颗粒与脂蛋白结合关键区域的鉴定
将浓缩的HCVcc进行碘克沙醇密度梯度离心,发现密度偏低的病毒颗粒具有强感染性,而随着HCVcc病毒颗粒密度的升高,其感染性也逐渐降低。此外,HDL对不同密度HCVcc感染的促进作用差异显著,其对低密度以及中等密度HCVcc感染的促进作用不明显,却显著增强高密度HCVcc的感染性。先前我们已证明HVRl中存在一个由9个氨基酸残基组成的功能结构域是诱导宿主产生抗体的主要抗原表位,并且HDL介导的HCV感染增强作用依赖于该9个氨基酸残基的存在,本部分实验我们发现删除了这9个氨基酸残基后,HCVcc病毒颗粒的密度分布曲线发生了明显改变,低密度的病毒颗粒数目明显下降,并且感染性也显著降低,而更多的病毒颗粒则集中在密度偏高几层,这和删除了整个HVRl的HCVcc所呈现出的病毒密度曲线趋势几乎是一致,这说明在HVRl中,决定HCV病毒颗粒与脂蛋白结合的关键部位恰恰就是这个由9个氨基酸残基组成的抗原决定区。在HDL对不同密度病毒颗粒的感染增强试验中,删除了9个氨基酸残基的任何密度层病毒颗粒的感染性均不再被HDL所增强。
小结
我们鉴定出HVR1中至少存在三个功能结构域,它们之间相互协调发挥着微妙的作用：HVR1的抗原决定区在病毒颗粒表面形成一个高度凸起,在脂蛋白结合过程中行驶一个非特异性“脂抓手”作用,结合在病毒颗粒表面的脂蛋白又通过与宿主SR-BI受体的结合拉近病毒颗粒与靶细胞的空间距离,使得抗原决定区两侧的SR-BI结合位点更易于与SR-BI受体结合并启动HCV细胞入侵的一系列步骤；更为有意思的是抗原决定区的空间凸起又是诱导宿主产生抗体的关键抗原表位,但其自身又呈现了高度的变异,使得宿主产生的抗体不能识别宿主体内新释放出的病毒颗粒,从而达到免疫逃避和持续感染的目的；而恰恰也是这样一个抗原表位,因为其自身的空间高度凸起,使得HCV病毒颗粒表面包裹着大量的脂蛋白,脂蛋白覆盖住了HCV病毒颗粒表面其他真正意义上的保守中和抗体表位,使得宿主细胞不能大量产生可以识别病毒颗粒表面保守位点的中和抗体,我们认为这个“脂抓手”同时又起到了“免疫诱饵”的作用。人们往往将HVR1的27个氨基端残基作为一个整体进行研究,我们的实验对HVR1的功能意义进行了深刻的剖析与阐释,并精确地鉴定出HVR1结构与功能之间的对应关系,这为今后保护性疫苗以及抗病毒药物的研发都提供了重要的启示。
Hepatitis C virus (HCV), an enveloped single-stranded positive-sense RNA virus in the family Flaviviridae, infects more than180million individuals worldwide and in most cases, patients with acute HCV infection will progress towards chronic infection, and some of them process to liver cirrhosis and hepatocellular carcinoma. HCV genome has a high mutation rate resulting from an error-prone RNA polymerase. These sequence variations are concentrated in some special regions of the genome and the best-characterized hypervariable region of HCV is the27amino acid residues located at the N-terminal part of the envelope protein E2(hypervariable region1, HVR1). HVR1exposes on the surface of viral particles, and contains dominant neutralizing epitopes. Its variation may lead to virus escape from pre-existing neutralizing antibodies. Mutation of HVR1has been proposed to be driven by immune pressure and play an important role in the establishment of persistent infection and disease progression. HVR1is used to be a target for the development of prophylactic vaccine. But from HCV was named in1989, a vaccine is not available presently.
HCV infection in hepatic cell disturbs cellular biochemistry, including lipid metabolism and apolipoprotein synthesis. Therefore, moderate to severe hepatic steatosis symptoms, including lipid droplet aggregation in plasma, are typical histopathology features distinctive in HCV chronic infection. HCV is an enveloped RNA virus, which is usually wrapped in vivo with a lipoprotein covering. HCV particles purified from patient serum subjected todensity gradient centrifugation show up in different layers, with each layer exhibiting different levels of infectivity. It is reported that deletion of HVR1reduces the number of low-density virus particles, that is, impaired the virus binding with lipoproteins. Hence, HVR1has important functions also in the association between viral particles and lipoproteins. HVR1is notably responsible for the interaction between HCV envelope glycoproteins and SR-BI and plays an important role in HCV cell entry. Although HVR1is highly variable, its importance in virus entry suggests that structural constraints might be present within this region. In this context, it has been suggested that the variability of HVR1is no random, as its chemicophysical properties and conformation are conserved. Despite these observations, the relevance between the structure and function of HVR1remains to be defined.
I. Identification of key residues mediating HCV cell entry within HVR1
We used HCVpp model, and investigated27residues within HVR1of H77isolate. Using deletion mutagenesis and function analyses, we found that five residues (A14, G15, K25, Q26and N27) within HVR1of H77isolate play a key role in HCVpp cell entry. Deletion of any a single residue in these five amino acids led to significant loss of pseudoparticle infectivity, while deletion of any a single residue in other regions only led to slight effect on infectivity of pseudoparticles. In this study, binding of envelope mutants to SR-BI directly correlated with the entry efficiency of the corresponding pseudoparticles, suggesting that the five key residues mediate entry predominantly through regulation of interaction between envelope proteins and SR-BI. The importance of these five residues is further supported by the findings that deletion of aa1-13(△1-13) attenuated HCVpp infectivity slightly, whereas deletion of aa16-24(△16-24) did not decrease infectivity of the resulting HCVpp. Furthermore, the amino terminal region of HVR1may regulate the infectivity of the virus and in turn to protect the virus from neutralizing antibodies targeting to the epitope within the carboxyl terminus of HVR1.
Ⅱ. Identification of antigenic epitopes within HVR1
To identify antigenic epitopes within HVR1, HVR1-specific antibodies were raised by immunizing rabbits with thioredoxin-HVR1peptide fusion proteins. It seems that, the N-terminal13amino acids and middle13amino acids do not contain an epitope. Our data provide evidence that neutralizing epitope in H77HVR1is located in region across aa16-24. This9residues exist in HVR1is dispensable for HCV entry, but play an important role in HCV envelope-heparin binding, and this region is necessary for enhancement of HCV infection by HDL and conferring HCV resistant to neutralizing antibodies targeted to epitope outside of HVR1. The result was further supported by antibody binding assay using sera from mice that received DNA vaccines carrying HBsAg and HVR1fusion gene.
Ⅲ. Identification of key region mediating lipoprotein binding within HVR1
The concentrated HCVcc were separated by overnight centrifugation through a iodixanol gradients, compared with fractions with higher density, fractions with lower density contained more infective particles, and enhancement by HDL was only restricted to infectivity of HCV viral particles with higher density, but no enhancement to viral particles with low density. We have identified a sole neutralizing epitope comprising aa16-24in HVR1of H77isolate of genotype la, and this region is necessary for enhancement of HCV infection by HDL. We found the populations of△16-24HCVcc were characterized by decrease of particles with low buoyant density ranging and increase of high density particles, and△HVR1exhibited the similar tendency. It demonstrated this neutralizing epitope acts as a key microdomain to modulate the association between viral particles and lipoprotein, and we found HDL could not enhance infectivity of△16-24particles of each density fraction.
Summary
Our data showed that HCV HVR1contains three different functional microdomains that cooperate to confer HCV cell entry and immune evasion:The antigenic determinant region (aal6-25) shape a "Lipo-claw" on the surface of viral particle to modulate the association with lipoprotein, and this "Lipo-claw" can bind lipoprotein and promote HCV cell entry by more prone to be recognized by SR-BI receptor. Furthermore, it also can conceal other conserved neutralizing epitopes on the surface of envelope to evade immune response. This "Lipo-claw" rears on the surface of viral particles, and acts as an "immune decoy" to constantly evade immune clearance by its own highly heterogeneity. People are used to targeting HVR1as a whole region. These findings provide novel insights into understanding the exact role of HVR1in mediating HCV cell entry, immune evasion and antibody-mediated neutralization, and will thus contribute to the development of entry inhibitors or a protective vaccine that targets the interaction between HVR1and cell entry factors.
HCV感染会引起肝内生化代谢紊乱,包括脂质代谢障碍和载脂蛋白合成异常,与其他病毒性肝炎相比,HCV感染慢性化后,中重度肝细胞脂肪变性包括胞质内脂滴聚集是其典型组织病理学特征。HCV是有包膜RNA病毒,其表面有不同数量的脂蛋白包裹,所以病人血清中纯化得到的HCV病毒颗粒呈现不同的密度分布,并且不同密度的病毒颗粒感染性也不同。有研究发现HVR1的删除会导致低密度病毒颗粒数目下降,也就是减弱了HCV的脂蛋白结合能力,可见HVR1在病毒与脂蛋白结合的过程中亦发挥重要的作用。多项研究证明HVR1同时还在与宿主SR-B1受体结合以及介导病毒入侵的过程中起关键作用,HVR1具有如此重要的生物学功能,那么其结构必然具有相对稳定性和保守性,虽然HVR1是HCV基因组中变异频率最高的部分之一,但对HCV一系列分离株的序列分析表明一些氨基酸残基的位点是高度、或者相对保守的。尽管人们已经发现HVR1同时行驶着诱导宿主免疫反应,脂蛋白结合以及介导病毒与受体结合的多重功能,但目前尚不清楚其结构与生物学功能的对应关系。
一、HCV高变区1中介导病毒细胞入侵关键氨基酸残基的鉴定
首先我们以HCVpp作为研究模型,以HCVla亚型的H77株为模式株,用单一氨基酸残基删除扫描的方法分析HVR1中27个氨基酸残基分别对HCV细胞入侵的影响,实验结果明确的鉴定出HVRl中介导HCV细胞入侵的关键氨基酸残基(Ala-14,Gly-15, Lys-25, Gln-26以及Asn-27),其中任意一个残基的删除对HCVpp感染性的影响都是致命的,相比之下,其他22个氨基酸残基的删除对HCVpp感染性并未造成明显影响。再用HCV入侵相关受体结合实验进行机制分析,我们证明这5位氨基酸残基介导了病毒包膜蛋白与宿主细胞SR-B1受体的结合。氨基酸残基合并删除实验进一步的证明了我们的结论,HVRl氨基端13个残基的删除以及第16-24位9个氨基酸残基的删除不会显著降低HCVpp的感染力。除了决定HCV细胞入侵的5个氨基酸残基之外,HVR1氨基端的13个氨基酸残基可以通过适当的突变,增强病毒与受体的结合能力从而增强病毒的细胞入侵能力,并且这一区域适当的突变还可以增强病毒的抗中和能力从而更利于病毒的免疫逃避和持续感染。
二、HCV高变区1中诱导中和抗体产生的抗原表位的鉴定
我们将HVR1分为氨基段,中段和羧基段三部分肽段分别与TRX融合表达后免疫家兔来检测HVR1的27个氨基酸残基在诱导宿主免疫反应过程中是否存在差异,我们发现HVRl的氨基端13个氨基酸残基不能诱导宿主产生抗体,而第16到24位的9个氨基酸残基是HVRl中唯一的中和表位,这9个氨基酸残基对于病毒细胞入侵无关紧要,但含有肝素结合位点,有利于HCV的粘附,更为重要的是,高密度脂蛋白(HDL)介导的HCV感染增强作用依赖于该9个氨基酸残基的存在,该九个残基还可通过与HDL的作用显著下调E2抗体的中和活性,小鼠DNA免疫试验也进一步验证了我们的结论。
三、HCV高变区1中介导病毒颗粒与脂蛋白结合关键区域的鉴定
将浓缩的HCVcc进行碘克沙醇密度梯度离心,发现密度偏低的病毒颗粒具有强感染性,而随着HCVcc病毒颗粒密度的升高,其感染性也逐渐降低。此外,HDL对不同密度HCVcc感染的促进作用差异显著,其对低密度以及中等密度HCVcc感染的促进作用不明显,却显著增强高密度HCVcc的感染性。先前我们已证明HVRl中存在一个由9个氨基酸残基组成的功能结构域是诱导宿主产生抗体的主要抗原表位,并且HDL介导的HCV感染增强作用依赖于该9个氨基酸残基的存在,本部分实验我们发现删除了这9个氨基酸残基后,HCVcc病毒颗粒的密度分布曲线发生了明显改变,低密度的病毒颗粒数目明显下降,并且感染性也显著降低,而更多的病毒颗粒则集中在密度偏高几层,这和删除了整个HVRl的HCVcc所呈现出的病毒密度曲线趋势几乎是一致,这说明在HVRl中,决定HCV病毒颗粒与脂蛋白结合的关键部位恰恰就是这个由9个氨基酸残基组成的抗原决定区。在HDL对不同密度病毒颗粒的感染增强试验中,删除了9个氨基酸残基的任何密度层病毒颗粒的感染性均不再被HDL所增强。
小结
我们鉴定出HVR1中至少存在三个功能结构域,它们之间相互协调发挥着微妙的作用：HVR1的抗原决定区在病毒颗粒表面形成一个高度凸起,在脂蛋白结合过程中行驶一个非特异性“脂抓手”作用,结合在病毒颗粒表面的脂蛋白又通过与宿主SR-BI受体的结合拉近病毒颗粒与靶细胞的空间距离,使得抗原决定区两侧的SR-BI结合位点更易于与SR-BI受体结合并启动HCV细胞入侵的一系列步骤；更为有意思的是抗原决定区的空间凸起又是诱导宿主产生抗体的关键抗原表位,但其自身又呈现了高度的变异,使得宿主产生的抗体不能识别宿主体内新释放出的病毒颗粒,从而达到免疫逃避和持续感染的目的；而恰恰也是这样一个抗原表位,因为其自身的空间高度凸起,使得HCV病毒颗粒表面包裹着大量的脂蛋白,脂蛋白覆盖住了HCV病毒颗粒表面其他真正意义上的保守中和抗体表位,使得宿主细胞不能大量产生可以识别病毒颗粒表面保守位点的中和抗体,我们认为这个“脂抓手”同时又起到了“免疫诱饵”的作用。人们往往将HVR1的27个氨基端残基作为一个整体进行研究,我们的实验对HVR1的功能意义进行了深刻的剖析与阐释,并精确地鉴定出HVR1结构与功能之间的对应关系,这为今后保护性疫苗以及抗病毒药物的研发都提供了重要的启示。
Hepatitis C virus (HCV), an enveloped single-stranded positive-sense RNA virus in the family Flaviviridae, infects more than180million individuals worldwide and in most cases, patients with acute HCV infection will progress towards chronic infection, and some of them process to liver cirrhosis and hepatocellular carcinoma. HCV genome has a high mutation rate resulting from an error-prone RNA polymerase. These sequence variations are concentrated in some special regions of the genome and the best-characterized hypervariable region of HCV is the27amino acid residues located at the N-terminal part of the envelope protein E2(hypervariable region1, HVR1). HVR1exposes on the surface of viral particles, and contains dominant neutralizing epitopes. Its variation may lead to virus escape from pre-existing neutralizing antibodies. Mutation of HVR1has been proposed to be driven by immune pressure and play an important role in the establishment of persistent infection and disease progression. HVR1is used to be a target for the development of prophylactic vaccine. But from HCV was named in1989, a vaccine is not available presently.
HCV infection in hepatic cell disturbs cellular biochemistry, including lipid metabolism and apolipoprotein synthesis. Therefore, moderate to severe hepatic steatosis symptoms, including lipid droplet aggregation in plasma, are typical histopathology features distinctive in HCV chronic infection. HCV is an enveloped RNA virus, which is usually wrapped in vivo with a lipoprotein covering. HCV particles purified from patient serum subjected todensity gradient centrifugation show up in different layers, with each layer exhibiting different levels of infectivity. It is reported that deletion of HVR1reduces the number of low-density virus particles, that is, impaired the virus binding with lipoproteins. Hence, HVR1has important functions also in the association between viral particles and lipoproteins. HVR1is notably responsible for the interaction between HCV envelope glycoproteins and SR-BI and plays an important role in HCV cell entry. Although HVR1is highly variable, its importance in virus entry suggests that structural constraints might be present within this region. In this context, it has been suggested that the variability of HVR1is no random, as its chemicophysical properties and conformation are conserved. Despite these observations, the relevance between the structure and function of HVR1remains to be defined.
I. Identification of key residues mediating HCV cell entry within HVR1
We used HCVpp model, and investigated27residues within HVR1of H77isolate. Using deletion mutagenesis and function analyses, we found that five residues (A14, G15, K25, Q26and N27) within HVR1of H77isolate play a key role in HCVpp cell entry. Deletion of any a single residue in these five amino acids led to significant loss of pseudoparticle infectivity, while deletion of any a single residue in other regions only led to slight effect on infectivity of pseudoparticles. In this study, binding of envelope mutants to SR-BI directly correlated with the entry efficiency of the corresponding pseudoparticles, suggesting that the five key residues mediate entry predominantly through regulation of interaction between envelope proteins and SR-BI. The importance of these five residues is further supported by the findings that deletion of aa1-13(△1-13) attenuated HCVpp infectivity slightly, whereas deletion of aa16-24(△16-24) did not decrease infectivity of the resulting HCVpp. Furthermore, the amino terminal region of HVR1may regulate the infectivity of the virus and in turn to protect the virus from neutralizing antibodies targeting to the epitope within the carboxyl terminus of HVR1.
Ⅱ. Identification of antigenic epitopes within HVR1
To identify antigenic epitopes within HVR1, HVR1-specific antibodies were raised by immunizing rabbits with thioredoxin-HVR1peptide fusion proteins. It seems that, the N-terminal13amino acids and middle13amino acids do not contain an epitope. Our data provide evidence that neutralizing epitope in H77HVR1is located in region across aa16-24. This9residues exist in HVR1is dispensable for HCV entry, but play an important role in HCV envelope-heparin binding, and this region is necessary for enhancement of HCV infection by HDL and conferring HCV resistant to neutralizing antibodies targeted to epitope outside of HVR1. The result was further supported by antibody binding assay using sera from mice that received DNA vaccines carrying HBsAg and HVR1fusion gene.
Ⅲ. Identification of key region mediating lipoprotein binding within HVR1
The concentrated HCVcc were separated by overnight centrifugation through a iodixanol gradients, compared with fractions with higher density, fractions with lower density contained more infective particles, and enhancement by HDL was only restricted to infectivity of HCV viral particles with higher density, but no enhancement to viral particles with low density. We have identified a sole neutralizing epitope comprising aa16-24in HVR1of H77isolate of genotype la, and this region is necessary for enhancement of HCV infection by HDL. We found the populations of△16-24HCVcc were characterized by decrease of particles with low buoyant density ranging and increase of high density particles, and△HVR1exhibited the similar tendency. It demonstrated this neutralizing epitope acts as a key microdomain to modulate the association between viral particles and lipoprotein, and we found HDL could not enhance infectivity of△16-24particles of each density fraction.
Summary
Our data showed that HCV HVR1contains three different functional microdomains that cooperate to confer HCV cell entry and immune evasion:The antigenic determinant region (aal6-25) shape a "Lipo-claw" on the surface of viral particle to modulate the association with lipoprotein, and this "Lipo-claw" can bind lipoprotein and promote HCV cell entry by more prone to be recognized by SR-BI receptor. Furthermore, it also can conceal other conserved neutralizing epitopes on the surface of envelope to evade immune response. This "Lipo-claw" rears on the surface of viral particles, and acts as an "immune decoy" to constantly evade immune clearance by its own highly heterogeneity. People are used to targeting HVR1as a whole region. These findings provide novel insights into understanding the exact role of HVR1in mediating HCV cell entry, immune evasion and antibody-mediated neutralization, and will thus contribute to the development of entry inhibitors or a protective vaccine that targets the interaction between HVR1and cell entry factors.
引文
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