CD8~+T细胞免疫压力下丙型肝炎病毒的适应性变异
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摘要
目的
1.检测武汉人群中慢性HCV感染患者基因分型，分析基因分型分布及其临床意义；
2.扩增HCV1b型感染患者的HCV NS3区并进行测序，分析HCV NS3功能区氨基酸变异和CD8~+T细胞表位内外的变异；
3.比较中国武汉人群和德国人群HLA频率分布差异。检测HCV1b型感染患者HLA分型，并比较分析武汉HCV患者人群与武汉健康人群HLA频率分布；
4.分析HCV1b病毒株序列变异与宿主HLA-I限制性CD8~+T细胞表位变异的相关性，并针对NS3序列预测HLA-I限制性CD8~+T细胞表位。
方法
1.收集227例武汉慢性HCV感染患者血清和全血，抽提血清中HCV RNA，采用型特异性引物扩增法对HCV RNA进行基因分型，分析武汉人群中HCV基因型别分布，并分析HCV1b型的临床意义。
2.采用巢式PCR对HCV1b基因型的HCV NS3区进行扩增并测序，采用软件将HCV1b型患者的HCV NS3区序列进行序列比，分析HCV NS3功能区的变异和CD8~+T细胞表位内外的变异。
3. HLA频率分布网站中比较中国武汉人群和德国人群的HLA频率分布。采用型特异性引物PCR法检测中国武汉HCV1b型患者相应的HLA-I（A-和B-位点）等位基因，与武汉健康人群HLA-I等位基因频率相比较。
4.采用ALIGN、DNAMAN等软件分析武汉HCV1b感染患者中不同HLA-I限制性的CD8~+T细胞表位的变异频率。采用网络软件预测HCV1b型NS3区序列的HLA-I限制性CD8~+T细胞表位。
结果
1.227份武汉慢性丙肝患者中HCV基因1b型126例（63.6%），其他HCV基因型72例（36.4%），表明在我国慢性丙肝患者HCV主要型别是1b型。比较39例HCV1b型和19例HCV其他基因型别患者肝功能，发现HCV1b型感染者较其他HCV基因型感染者更容易出现肝功能异常，提示HCV1b型较其他HCV基因型更易造成肝脏损伤。
2.对30条HCV NS3区全长序列进行分析，发现决定HCV功能的氨基酸序列很难发生变异，表明HCV NS3功能区的氨基酸序列相对保守。而且HCV NS3区CD8~+T细胞表位内的氨基酸突变频率明显大于表位外（p<0.05，有统计学意义），提示CD8~+T细胞的免疫压力是导致HCV NS3变异的重要原因之一。
3.比较中国武汉人群和德国人群的HLA-A和HLA-B基因型频率分布，发现中国武汉人群中HLA-A02/11/24和HLA-B13/15/46频率较高。而且中国武汉和德国人群的HLA基因型频率分布有明显不同，在武汉人群中分布频率较高的HLA-A11、HLA-B46基因型频率在德国人群中明显较低；而在德国人群中分布频率较高的HLA-A01、HLA-A03、HLA-B07、HLA-B08基因型频率在中国武汉人群中较低。分析本研究中135例HCV患者的HLA-A基因型频率和134例HCV患者的HLA-B基因型频率，发现跟中国武汉健康人群的HLA基因型频率基本一致。
4.从群体水平上分析HCV1b型患者HLA-I限制性的HCV NS3区CD8~+T细胞表位突变，发现两个HLA-A02阳性的HCV NS3区CD8~+T细胞表位（NS31169-1177和NS31443-1451）突变频率，明显高于HLA-A02阴性的HCV NS3区CD8~+T细胞表位突变频率，有统计学意义（P<0.05）。将预测的HCV1b型患者中HLA-I限制性的HCVNS3区CD8~+T细胞表位与30条HCV NS3全长序列联合分析，发现四个预测的HCVNS3区CD8~+T细胞表位的变异与HLA-I限制性CD8~+T细胞免疫压力可能有关。
结论
1.武汉人群中主要的HCV病毒株型别是HCV1b型，并且HCV1b型较其他HCV基因型更易造成肝脏损伤。
2.决定HCV功能的NS3功能区氨基酸序列很难发生变异，而HCV NS3区CD8+T细胞表位内的氨基酸突变频率明显大于CD8~+T细胞表位外的氨基酸突变频率，提示CD8~+T细胞的免疫压力是导致HCV NS3变异的重要原因之一。
3.武汉和德国人群的HLA基因频率有明显不同，在武汉人群中HLA频率较高比如HLA-A11、HLA-B46在德国人群中明显较低。武汉人群中频率较高的HLA-I限制性的HCV CD8~+T细胞表位突变频率则相对较高。
4.两个NS3区CD8~+T细胞表位（NS31169-1177和NS31443-1451）跟HLA-A02相关，表明HCV NS3区CD8~+T细胞表位突变受到宿主HLA等位基因限制。
本研究的创新点
1.发现武汉和德国人群的HLA基因频率有明显不同，武汉人群中频率较高的HLA-I限制性的HCV CD8~+T细胞表位突变频率相对较高，为找出最佳的HCV抗原序列并研制预防性和治疗性疫苗提供了科学基础。
2.国内既往多项研究集中在HCV的异质性和HCV CD8~+T细胞表位预测，仅少数研究HLA-I类等位基因与HCV变异的关系。
本研究的意义
探讨HCV在CD8~+T细胞免疫压力下演化适应过程，测定HLA-I限制性HCV NS3区CD8~+T细胞表位序列多态性，明确不同人群中HCV在CD8~+T细胞免疫压力下演变规律，为寻找保护性CD8~+T细胞抗原表位和研制基于T细胞HCV疫苗提供科学基础。
Objective
1. To detect the HCV genotyping of chronic HCV patients in Wuhan population, toanalyze the distribution of HCV genotyping and its clinic significance.
2. To amplificate HCV NS3region (HCV genotype1b) and finish its sequencing, andanalyze the amino acid mutation of HCV NS3function region and CD8~+T cell epitope.
3. Compare the HLA phenotypic frequence distribution between Wuhan and German.To detect HLA typing of HCV1b isolates, and compare the HLA phenotypic frequencedistribution between Wuhan HCV patient population and German healthy population.
4. To analyze the sequence variation of peripheral circulating HCV isolates and itscorrelation with the HLA-I alleles, and predict HLA-I restricted CD8~+T cell epitope.
Methods
1. We collected the serum and whole blood from227patients. The genotyping afterextracting the HCV RNA from the serum is detected for analyzing the distribution of HCVgenotyping in Wuhan patients and the clinical significance of HCV genotype1b.
2. HCV NS3(HCV genotype1b) will be amplified by a nested RT-PCR assay withtype specific primers and sequenced. Software for sequence analysis is used for analyzing thesequence of the function region and identified the mutation according to their location insideor outside previously described CD8~+T cell epitope.
3. We compared HLA phenotypic frequence distribution which was obtained from HLA phenotypic frequence web between Wuhan population and German population. HLAphenotypic frequence of HLA-class I alleles (A-and HLA-B locus) in patients with HCVgenotype1b was performed for comparing with the HLA-Alleles of Wuhan healthy patients.
4. Analyzing HCV NS3(HCV genotype1b) CD8~+T cell epitope mutation withrespect to the host’s HLA-type with ALIGN software. We also predicted the HLA-Irestricting CD8~+T cell epitope with HCV genotype1b by web software.
Results
1. There were126cases of HCV genotype1b in227Wuhan HCV patients whose ratiowas63.6%, whereas the other HCV genotype had72cases whose ratio was36.4%, whichindicated the major genotype in Chinses HCV patients is genotype1b. Comparing the liverfunction of39cases with HCV genotype1b and19cases with other HCV genotype, we foundthat the liver disfunction of HCV genotype1b happened more easily than other HCVgenotype, that is to say the disease with HCV genotype1b is sicker than HCV other genotype.
2. After30HCV NS3sequence were analyzed, it is indicated that the amino acidsequence of HCV NS3function region was difficult to mutate with relatively conservative. Inaddition, the amino acid mutations frequency of inside previously described CD8~+T cellepitope was significantly higher compared with the outside region, which had statisticsignificance (P<0.05). It is indicated that the immune pressure of CD8~+T cell is one of theimportant reason for HCV NS3mutation.
3. It is indicated that the HLA-A02/11/24and HLA-B13/15/46frequence was higher inWuhan population than in German population. The HLA phenotypic frequence distributionbetween Wuhan population and German population was different obviously. HLA-A11orHLA-B46frequence which was high in Wuhan population was lower in Germany population,whereas the frequence of HLA-A01/03or HLA-B07/08which is high in German populationis lower in Wuhan population. HLA genotypes of HCV patients population being analyzedand compared with Wuhan healthy population, it is suggested that the HLA phenotypicfrequency of HCV patients population and healthy population is basically the same.
4. HLA-I restricted NS3CD8~+T epitope mutation frequence analyzed in a populationlevel (HCV1b) indicated two HLA-A02positive associated NS3CD8~+T cell epitopemutation frequence was higher than HLA-A02negative, which had statistical significance(P<0.05). In another words, in two previously described CD8~+T cell epitope mutations werehighly reproducible in patients sharing the relevant HLA-Alleles in a population level. HLA-Irestriced NS3region CD8~+T cell epitope (HCV1b) were predicted and analyzed with30NS3sequence with HLA data, which suggested predicted four HLA-I positive NS3region CD8~+Tcell epitope mutation frequence have higher tendency than HLA-I negative.
Conclusion
1. The major genotype in Chinses HCV patients is genotype1b, and the disease ofwhich is worese than HCV other genotype.
2. The amino acid sequence of HCV NS3function region was difficult to mutate orrelatively conservative. The amino acid mutations frequency of inside previously describedCD8~+T cell epitope was significantly higher compared to the outside region, which suggestedthe immune pressure of CD8~+T cell is one of the important reasons for HCV NS3mutation.
3. The HLA phenotypic frequence between Wuhan healthy population and Germanhealthy population was different obviously. The frequence of HLA-A11or HLA-B46whichwas high in Wuhan healthy population was lower in German healthy population. The HCVCD8~+T cell epitope mutation frequence which is restricted by HLA with higher phenotypicfrequence is relatively higher in wuhan population.
4. Two HCV NS3region (HCV genotype1b) CD8~+T cell epitope mutation wasrestricted with HLA-A02, which indicated HLA-I associated CD8~+T cell pressure was themajor driving force for viral evolution of. HLA-I restriced HCV NS3region CD8~+T cellepitope (HCV genotype1b) were predicted and predicted four HLA-I positive HCV NS3region CD8~+T cell epitope mutation frequence have higher tendency than HLA-I negative.
1.检测武汉人群中慢性HCV感染患者基因分型，分析基因分型分布及其临床意义；
2.扩增HCV1b型感染患者的HCV NS3区并进行测序，分析HCV NS3功能区氨基酸变异和CD8~+T细胞表位内外的变异；
3.比较中国武汉人群和德国人群HLA频率分布差异。检测HCV1b型感染患者HLA分型，并比较分析武汉HCV患者人群与武汉健康人群HLA频率分布；
4.分析HCV1b病毒株序列变异与宿主HLA-I限制性CD8~+T细胞表位变异的相关性，并针对NS3序列预测HLA-I限制性CD8~+T细胞表位。
方法
1.收集227例武汉慢性HCV感染患者血清和全血，抽提血清中HCV RNA，采用型特异性引物扩增法对HCV RNA进行基因分型，分析武汉人群中HCV基因型别分布，并分析HCV1b型的临床意义。
2.采用巢式PCR对HCV1b基因型的HCV NS3区进行扩增并测序，采用软件将HCV1b型患者的HCV NS3区序列进行序列比，分析HCV NS3功能区的变异和CD8~+T细胞表位内外的变异。
3. HLA频率分布网站中比较中国武汉人群和德国人群的HLA频率分布。采用型特异性引物PCR法检测中国武汉HCV1b型患者相应的HLA-I（A-和B-位点）等位基因，与武汉健康人群HLA-I等位基因频率相比较。
4.采用ALIGN、DNAMAN等软件分析武汉HCV1b感染患者中不同HLA-I限制性的CD8~+T细胞表位的变异频率。采用网络软件预测HCV1b型NS3区序列的HLA-I限制性CD8~+T细胞表位。
结果
1.227份武汉慢性丙肝患者中HCV基因1b型126例（63.6%），其他HCV基因型72例（36.4%），表明在我国慢性丙肝患者HCV主要型别是1b型。比较39例HCV1b型和19例HCV其他基因型别患者肝功能，发现HCV1b型感染者较其他HCV基因型感染者更容易出现肝功能异常，提示HCV1b型较其他HCV基因型更易造成肝脏损伤。
2.对30条HCV NS3区全长序列进行分析，发现决定HCV功能的氨基酸序列很难发生变异，表明HCV NS3功能区的氨基酸序列相对保守。而且HCV NS3区CD8~+T细胞表位内的氨基酸突变频率明显大于表位外（p<0.05，有统计学意义），提示CD8~+T细胞的免疫压力是导致HCV NS3变异的重要原因之一。
3.比较中国武汉人群和德国人群的HLA-A和HLA-B基因型频率分布，发现中国武汉人群中HLA-A02/11/24和HLA-B13/15/46频率较高。而且中国武汉和德国人群的HLA基因型频率分布有明显不同，在武汉人群中分布频率较高的HLA-A11、HLA-B46基因型频率在德国人群中明显较低；而在德国人群中分布频率较高的HLA-A01、HLA-A03、HLA-B07、HLA-B08基因型频率在中国武汉人群中较低。分析本研究中135例HCV患者的HLA-A基因型频率和134例HCV患者的HLA-B基因型频率，发现跟中国武汉健康人群的HLA基因型频率基本一致。
4.从群体水平上分析HCV1b型患者HLA-I限制性的HCV NS3区CD8~+T细胞表位突变，发现两个HLA-A02阳性的HCV NS3区CD8~+T细胞表位（NS31169-1177和NS31443-1451）突变频率，明显高于HLA-A02阴性的HCV NS3区CD8~+T细胞表位突变频率，有统计学意义（P<0.05）。将预测的HCV1b型患者中HLA-I限制性的HCVNS3区CD8~+T细胞表位与30条HCV NS3全长序列联合分析，发现四个预测的HCVNS3区CD8~+T细胞表位的变异与HLA-I限制性CD8~+T细胞免疫压力可能有关。
结论
1.武汉人群中主要的HCV病毒株型别是HCV1b型，并且HCV1b型较其他HCV基因型更易造成肝脏损伤。
2.决定HCV功能的NS3功能区氨基酸序列很难发生变异，而HCV NS3区CD8+T细胞表位内的氨基酸突变频率明显大于CD8~+T细胞表位外的氨基酸突变频率，提示CD8~+T细胞的免疫压力是导致HCV NS3变异的重要原因之一。
3.武汉和德国人群的HLA基因频率有明显不同，在武汉人群中HLA频率较高比如HLA-A11、HLA-B46在德国人群中明显较低。武汉人群中频率较高的HLA-I限制性的HCV CD8~+T细胞表位突变频率则相对较高。
4.两个NS3区CD8~+T细胞表位（NS31169-1177和NS31443-1451）跟HLA-A02相关，表明HCV NS3区CD8~+T细胞表位突变受到宿主HLA等位基因限制。
本研究的创新点
1.发现武汉和德国人群的HLA基因频率有明显不同，武汉人群中频率较高的HLA-I限制性的HCV CD8~+T细胞表位突变频率相对较高，为找出最佳的HCV抗原序列并研制预防性和治疗性疫苗提供了科学基础。
2.国内既往多项研究集中在HCV的异质性和HCV CD8~+T细胞表位预测，仅少数研究HLA-I类等位基因与HCV变异的关系。
本研究的意义
探讨HCV在CD8~+T细胞免疫压力下演化适应过程，测定HLA-I限制性HCV NS3区CD8~+T细胞表位序列多态性，明确不同人群中HCV在CD8~+T细胞免疫压力下演变规律，为寻找保护性CD8~+T细胞抗原表位和研制基于T细胞HCV疫苗提供科学基础。
Objective
1. To detect the HCV genotyping of chronic HCV patients in Wuhan population, toanalyze the distribution of HCV genotyping and its clinic significance.
2. To amplificate HCV NS3region (HCV genotype1b) and finish its sequencing, andanalyze the amino acid mutation of HCV NS3function region and CD8~+T cell epitope.
3. Compare the HLA phenotypic frequence distribution between Wuhan and German.To detect HLA typing of HCV1b isolates, and compare the HLA phenotypic frequencedistribution between Wuhan HCV patient population and German healthy population.
4. To analyze the sequence variation of peripheral circulating HCV isolates and itscorrelation with the HLA-I alleles, and predict HLA-I restricted CD8~+T cell epitope.
Methods
1. We collected the serum and whole blood from227patients. The genotyping afterextracting the HCV RNA from the serum is detected for analyzing the distribution of HCVgenotyping in Wuhan patients and the clinical significance of HCV genotype1b.
2. HCV NS3(HCV genotype1b) will be amplified by a nested RT-PCR assay withtype specific primers and sequenced. Software for sequence analysis is used for analyzing thesequence of the function region and identified the mutation according to their location insideor outside previously described CD8~+T cell epitope.
3. We compared HLA phenotypic frequence distribution which was obtained from HLA phenotypic frequence web between Wuhan population and German population. HLAphenotypic frequence of HLA-class I alleles (A-and HLA-B locus) in patients with HCVgenotype1b was performed for comparing with the HLA-Alleles of Wuhan healthy patients.
4. Analyzing HCV NS3(HCV genotype1b) CD8~+T cell epitope mutation withrespect to the host’s HLA-type with ALIGN software. We also predicted the HLA-Irestricting CD8~+T cell epitope with HCV genotype1b by web software.
Results
1. There were126cases of HCV genotype1b in227Wuhan HCV patients whose ratiowas63.6%, whereas the other HCV genotype had72cases whose ratio was36.4%, whichindicated the major genotype in Chinses HCV patients is genotype1b. Comparing the liverfunction of39cases with HCV genotype1b and19cases with other HCV genotype, we foundthat the liver disfunction of HCV genotype1b happened more easily than other HCVgenotype, that is to say the disease with HCV genotype1b is sicker than HCV other genotype.
2. After30HCV NS3sequence were analyzed, it is indicated that the amino acidsequence of HCV NS3function region was difficult to mutate with relatively conservative. Inaddition, the amino acid mutations frequency of inside previously described CD8~+T cellepitope was significantly higher compared with the outside region, which had statisticsignificance (P<0.05). It is indicated that the immune pressure of CD8~+T cell is one of theimportant reason for HCV NS3mutation.
3. It is indicated that the HLA-A02/11/24and HLA-B13/15/46frequence was higher inWuhan population than in German population. The HLA phenotypic frequence distributionbetween Wuhan population and German population was different obviously. HLA-A11orHLA-B46frequence which was high in Wuhan population was lower in Germany population,whereas the frequence of HLA-A01/03or HLA-B07/08which is high in German populationis lower in Wuhan population. HLA genotypes of HCV patients population being analyzedand compared with Wuhan healthy population, it is suggested that the HLA phenotypicfrequency of HCV patients population and healthy population is basically the same.
4. HLA-I restricted NS3CD8~+T epitope mutation frequence analyzed in a populationlevel (HCV1b) indicated two HLA-A02positive associated NS3CD8~+T cell epitopemutation frequence was higher than HLA-A02negative, which had statistical significance(P<0.05). In another words, in two previously described CD8~+T cell epitope mutations werehighly reproducible in patients sharing the relevant HLA-Alleles in a population level. HLA-Irestriced NS3region CD8~+T cell epitope (HCV1b) were predicted and analyzed with30NS3sequence with HLA data, which suggested predicted four HLA-I positive NS3region CD8~+Tcell epitope mutation frequence have higher tendency than HLA-I negative.
Conclusion
1. The major genotype in Chinses HCV patients is genotype1b, and the disease ofwhich is worese than HCV other genotype.
2. The amino acid sequence of HCV NS3function region was difficult to mutate orrelatively conservative. The amino acid mutations frequency of inside previously describedCD8~+T cell epitope was significantly higher compared to the outside region, which suggestedthe immune pressure of CD8~+T cell is one of the important reasons for HCV NS3mutation.
3. The HLA phenotypic frequence between Wuhan healthy population and Germanhealthy population was different obviously. The frequence of HLA-A11or HLA-B46whichwas high in Wuhan healthy population was lower in German healthy population. The HCVCD8~+T cell epitope mutation frequence which is restricted by HLA with higher phenotypicfrequence is relatively higher in wuhan population.
4. Two HCV NS3region (HCV genotype1b) CD8~+T cell epitope mutation wasrestricted with HLA-A02, which indicated HLA-I associated CD8~+T cell pressure was themajor driving force for viral evolution of. HLA-I restriced HCV NS3region CD8~+T cellepitope (HCV genotype1b) were predicted and predicted four HLA-I positive HCV NS3region CD8~+T cell epitope mutation frequence have higher tendency than HLA-I negative.
引文
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