人乳头瘤病毒假病毒制备方法的优化以及高通量中和实验检测系统的建立
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摘要
人乳头瘤病毒(HPV)能够引起包括宫颈癌在内的多种生殖道疾病,严重危害人类健康。HPV具有严格的宿主特异性和组织分化依赖性,难以通过常规组织培养方法扩增,也难以从病变组织中分离获得足够的病毒。因此建立简便、高效的HPV体外感染模型是发展HPV预防疫苗与治疗药物的迫切需要。近来研究发现HPV假病毒可用于在体外有效模拟HPV的感染,以此基础建立的中和实验方法具有较突出准确、便捷的优点,在HPV预防疫苗、中和抗体研究中显示出巨大的应用潜力。HPV假病毒中和实验方法的广泛使用需要进一步提高假病毒构建效率,同时能够满足高通量检测的需要。本实验室已应用磷酸钙多质粒共转染方法在293FT细胞中建立了构建HPV假病毒的方法,本研究以此为基础,进一步对HPV假病毒构建体系进行系统改进和优化,建立了更为高效且适合高通量检测的HPV中和实验方法。
建立简便高效、高通量的假病毒中和实验检测方法对提高实验效率,满足大规模抗体检测的需要具有十分重要的意义。同时,建立多个型别的HPV假病毒中和实验模型为具有高保护力的多价疫苗的开发提供了全面的中和抗体评价体系。
本研究首先探讨了在HPV假病毒构建体系中优化质粒转染比例以及磷酸钙转染条件对假病毒构建效率的影响。结果显示,在该体系中不同的HPV结构蛋白表达质粒转染比例对于假病毒构建效率有显著影响,HPV主要结构蛋白L1的表达水平是影响构建效率的主要因素,L2表达质粒的用量过高或过低均不利于假病毒的构建。报告质粒的用量对假病毒构建效率的影响相对较小。综合比较显示,在该体系中L1和L2表达质粒和报告质粒以合适比例(1:1/10:1/2)进行共转染可获得较理想的构建效率。同时通过优化磷酸钙转染试剂的用量和DNA在磷酸钙溶液中浓度获得了较优的转染条件。通过优化改进,本研究建立了更为高效的HPV假病毒大量制备方法,在HPV16、HPV18、HPV6、HPV11假病毒构建中的应用结果显示相比原方法可显著提高构建效率10～20倍。为HPV假病毒中和实验的规模化应用提供了有利条件。
为适应高通量检测的需要,本研究通过改进报告基因及检测方法建立了新型的HPV假病毒中和实验体系。本研究选择半乳糖苷酶作为报告基因,构建了携带优化后的半乳糖苷酶表达元件的HPV假病毒,研究结果显示,假病毒感染后的细胞加入显色底物后可呈现显著的蓝色,并且该标记可为酶联免疫图像分析系统(Elispot)所检测。酶联免疫图像分析系统可对显色后的96孔细胞培养板进行连续快速的自动扫描并计数,满足了高通量检测的需要。本研究进一步对显色方法进行优化,提高了检测效率。通过综合应用优化的半乳糖苷酶报告基因表达元件与酶联免疫图像分析系统,本研究建立新型的可满足高通量检测要求的HPV假病毒中和实验方法。本研究应用该方法对四型HPV中和单抗的鉴定结果表明,半乳糖苷酶假病毒中和实验方法与目前应用的EGFP假病毒中和实验方法的检测灵敏度相当,同时新方法还具有可自动连续检测、操作简便、结果显示直观的优点,可更好地满足大规模中和抗体检测实验的需要。本研究应用该方法鉴定获得了2株HPV16中和单抗,3株HPV18中和单抗,以及HPV6和HPV11中和单抗各5株;同时对本中心生产的HPV16、HPV18、HPV6和HPV11四价VLP疫苗的抗体保护性进行了评价,为临床实验阶段所需疫苗的合适剂量提供了参考。
HPV58和HPV52是中国较为流行的高危HPV型别,但一直以来研究较少。建立HPV58和HPV52假病毒中和实验模型对于研究HPV58和HPV52以及预防疫苗的开发具有重要意义。我们将HPV58和HPV52的衣壳蛋白表达序列进行密码子人源化优化后,克隆到表达载体上,与报告质粒分别共转染293FT获得了感染性的HPV58和HPV52假病毒。将质粒通过尾静脉高压注射方式免疫小鼠,成功在小鼠体内诱导了高滴度的HPV58和HPV52的中和性抗体。Western blotting结果显示这两型假病毒在约55KD处均具有L1蛋白活性。多抗血清交叉中和实验表明HPV58和HPV52、HPV16和HPV58之间存在一定水平的抗体交叉保护,而HPV16和HPV52之间没有可检测的抗体交叉保护性。
Infection of Human papillomavirus(HPV) is the cause of various diseases of genital tract,including cervix cancer,which is the second most common cancer leading to death in women.HPV's infection has host specificity,moreover,completed life cycle of HPV relays on differentiation of epithelial cells.Absence of applicable cell culture systems for infectious virus and limited virus particles obtained from patients' tissues restrict research on HPV and development of HPV vaccine. Convenient and efficient infection models of HPV in vitro are necessary for development of prophylactic vaccine and therapeutic agents of HPV.In recent years, people use pseudovirus to imitate HPV and construct pseudovirus-based neutralization assay for HPV,which displays a enormous applied potential in detection of neutralizing antibodys and development of prophylactic vaccine.
Cotransfection of plasmids with condon-optimized genes is proved more convenient and higher-yield in producing pseudovirion than other systems,which has been constructed in our lab.To evaluate the protection providing by HPV prophylactic vaccine to animals or human,a great deal pseudovirion and a rapid, simple and convenient,high-throughput neutralization assay is required.To satisfy need of development of multivalent HPV vaccine,developing pseudovirus-based neutralization assay for other HPV types is necessary.
In construction of pseudovirus by cotransfection of plasmids,appropriately lowering transfected mole ratio of L2 expression plasmid and reporter plasmid enhances expression of L1,which is positive correlative to construction efficiency of pseudovirus under certain conditions.The optimized transfected ratio may be 1:1/10:1/2 of L1、L2 expression plasmids and reporter plasmid.Modified transfected mole ratios of plasmids、optimal DNA concentration in calcium phosphate solution and appropriate volume of calcium phosphate solution contribute to a 10～20 times higher efficiency in construction of HPV16、HPV18、HPV6 and HPV11 pseudovirion.
To satisfy the need of high-throughput assay for neutralizing antibodies, considerring the conditions in our lab,we constructed a new neutralization assay based on pseudovirion encapsidatingβ-gal expression plasmid.We utilized Elispot reader to scan 96 wells cell culture plates and display automatic counting result of cells transducted by pseudovirion every well,what remarkably enhance efficiency of neutralization assay for HPV.The method of x-gal stainning was improved to further enhance the efficiency.The new neutralization assay for HPV has high specificity,a wide detection range and similar sensitivity comparing to that of EGFP pseudovirus -based neutralization assay,moreover,it's low-cost in reagents and easy to operate.
The neutralization efficiency of HPV16,HPV18,HPV6 and HPV11 monoclonal antibodies generated in our lab were then evaluated by the new pseudovirus-base neutralization assay.All these neutralizing mAbs can be used to thoroughly elucidate the neutralizing eptitopes of HPV and evaluate the quality of HPV vaccines.To investigate a suitable dose of candidate VLP-mixed vaccine of HPV16/18/6/11,sixty mice were vaccinated with serial diluted HPV16/18/6/11 VLP mix and the ED50 was identified to be HPV16 0.017μg/mL、HPV18 0.017μg/mL、HPV6 0.025μg/mL、HPV11 0.067μg/mL,which will guide us in the determination of an appropriate dose of mix vaccine in clinical trial studies.
HPV58 and HPV52 are popular high-risk HPV in China,popularity of HPV58 is second to that of HPV18,but little has been studied about the two types since always.Construction of HPV58 and HPV52 pseudovirion help to research on HPV58、HPV52 and development of corresponding vaccine.Codon-optimized expression plasmids of capsid protein and reporter plasmid are cotransfected to 293FT cells, successfully generating high titer infectious pseudovirion of HPV58 and HPV52 respectively.Expression of 58L1 and 52L1 in cells was detected by Western blotting. Immunizing codon-optimized 58L1 and 52L1 expression plasmids induced neutralizing antibody in mice which can neutralize infection of pseudovirion respectively.We found cross neutralization phenomena exists between HPV16 and HPV58,HPV58 and HPV52,but not between HPV52 and HPV16.
建立简便高效、高通量的假病毒中和实验检测方法对提高实验效率,满足大规模抗体检测的需要具有十分重要的意义。同时,建立多个型别的HPV假病毒中和实验模型为具有高保护力的多价疫苗的开发提供了全面的中和抗体评价体系。
本研究首先探讨了在HPV假病毒构建体系中优化质粒转染比例以及磷酸钙转染条件对假病毒构建效率的影响。结果显示,在该体系中不同的HPV结构蛋白表达质粒转染比例对于假病毒构建效率有显著影响,HPV主要结构蛋白L1的表达水平是影响构建效率的主要因素,L2表达质粒的用量过高或过低均不利于假病毒的构建。报告质粒的用量对假病毒构建效率的影响相对较小。综合比较显示,在该体系中L1和L2表达质粒和报告质粒以合适比例(1:1/10:1/2)进行共转染可获得较理想的构建效率。同时通过优化磷酸钙转染试剂的用量和DNA在磷酸钙溶液中浓度获得了较优的转染条件。通过优化改进,本研究建立了更为高效的HPV假病毒大量制备方法,在HPV16、HPV18、HPV6、HPV11假病毒构建中的应用结果显示相比原方法可显著提高构建效率10～20倍。为HPV假病毒中和实验的规模化应用提供了有利条件。
为适应高通量检测的需要,本研究通过改进报告基因及检测方法建立了新型的HPV假病毒中和实验体系。本研究选择半乳糖苷酶作为报告基因,构建了携带优化后的半乳糖苷酶表达元件的HPV假病毒,研究结果显示,假病毒感染后的细胞加入显色底物后可呈现显著的蓝色,并且该标记可为酶联免疫图像分析系统(Elispot)所检测。酶联免疫图像分析系统可对显色后的96孔细胞培养板进行连续快速的自动扫描并计数,满足了高通量检测的需要。本研究进一步对显色方法进行优化,提高了检测效率。通过综合应用优化的半乳糖苷酶报告基因表达元件与酶联免疫图像分析系统,本研究建立新型的可满足高通量检测要求的HPV假病毒中和实验方法。本研究应用该方法对四型HPV中和单抗的鉴定结果表明,半乳糖苷酶假病毒中和实验方法与目前应用的EGFP假病毒中和实验方法的检测灵敏度相当,同时新方法还具有可自动连续检测、操作简便、结果显示直观的优点,可更好地满足大规模中和抗体检测实验的需要。本研究应用该方法鉴定获得了2株HPV16中和单抗,3株HPV18中和单抗,以及HPV6和HPV11中和单抗各5株;同时对本中心生产的HPV16、HPV18、HPV6和HPV11四价VLP疫苗的抗体保护性进行了评价,为临床实验阶段所需疫苗的合适剂量提供了参考。
HPV58和HPV52是中国较为流行的高危HPV型别,但一直以来研究较少。建立HPV58和HPV52假病毒中和实验模型对于研究HPV58和HPV52以及预防疫苗的开发具有重要意义。我们将HPV58和HPV52的衣壳蛋白表达序列进行密码子人源化优化后,克隆到表达载体上,与报告质粒分别共转染293FT获得了感染性的HPV58和HPV52假病毒。将质粒通过尾静脉高压注射方式免疫小鼠,成功在小鼠体内诱导了高滴度的HPV58和HPV52的中和性抗体。Western blotting结果显示这两型假病毒在约55KD处均具有L1蛋白活性。多抗血清交叉中和实验表明HPV58和HPV52、HPV16和HPV58之间存在一定水平的抗体交叉保护,而HPV16和HPV52之间没有可检测的抗体交叉保护性。
Infection of Human papillomavirus(HPV) is the cause of various diseases of genital tract,including cervix cancer,which is the second most common cancer leading to death in women.HPV's infection has host specificity,moreover,completed life cycle of HPV relays on differentiation of epithelial cells.Absence of applicable cell culture systems for infectious virus and limited virus particles obtained from patients' tissues restrict research on HPV and development of HPV vaccine. Convenient and efficient infection models of HPV in vitro are necessary for development of prophylactic vaccine and therapeutic agents of HPV.In recent years, people use pseudovirus to imitate HPV and construct pseudovirus-based neutralization assay for HPV,which displays a enormous applied potential in detection of neutralizing antibodys and development of prophylactic vaccine.
Cotransfection of plasmids with condon-optimized genes is proved more convenient and higher-yield in producing pseudovirion than other systems,which has been constructed in our lab.To evaluate the protection providing by HPV prophylactic vaccine to animals or human,a great deal pseudovirion and a rapid, simple and convenient,high-throughput neutralization assay is required.To satisfy need of development of multivalent HPV vaccine,developing pseudovirus-based neutralization assay for other HPV types is necessary.
In construction of pseudovirus by cotransfection of plasmids,appropriately lowering transfected mole ratio of L2 expression plasmid and reporter plasmid enhances expression of L1,which is positive correlative to construction efficiency of pseudovirus under certain conditions.The optimized transfected ratio may be 1:1/10:1/2 of L1、L2 expression plasmids and reporter plasmid.Modified transfected mole ratios of plasmids、optimal DNA concentration in calcium phosphate solution and appropriate volume of calcium phosphate solution contribute to a 10～20 times higher efficiency in construction of HPV16、HPV18、HPV6 and HPV11 pseudovirion.
To satisfy the need of high-throughput assay for neutralizing antibodies, considerring the conditions in our lab,we constructed a new neutralization assay based on pseudovirion encapsidatingβ-gal expression plasmid.We utilized Elispot reader to scan 96 wells cell culture plates and display automatic counting result of cells transducted by pseudovirion every well,what remarkably enhance efficiency of neutralization assay for HPV.The method of x-gal stainning was improved to further enhance the efficiency.The new neutralization assay for HPV has high specificity,a wide detection range and similar sensitivity comparing to that of EGFP pseudovirus -based neutralization assay,moreover,it's low-cost in reagents and easy to operate.
The neutralization efficiency of HPV16,HPV18,HPV6 and HPV11 monoclonal antibodies generated in our lab were then evaluated by the new pseudovirus-base neutralization assay.All these neutralizing mAbs can be used to thoroughly elucidate the neutralizing eptitopes of HPV and evaluate the quality of HPV vaccines.To investigate a suitable dose of candidate VLP-mixed vaccine of HPV16/18/6/11,sixty mice were vaccinated with serial diluted HPV16/18/6/11 VLP mix and the ED50 was identified to be HPV16 0.017μg/mL、HPV18 0.017μg/mL、HPV6 0.025μg/mL、HPV11 0.067μg/mL,which will guide us in the determination of an appropriate dose of mix vaccine in clinical trial studies.
HPV58 and HPV52 are popular high-risk HPV in China,popularity of HPV58 is second to that of HPV18,but little has been studied about the two types since always.Construction of HPV58 and HPV52 pseudovirion help to research on HPV58、HPV52 and development of corresponding vaccine.Codon-optimized expression plasmids of capsid protein and reporter plasmid are cotransfected to 293FT cells, successfully generating high titer infectious pseudovirion of HPV58 and HPV52 respectively.Expression of 58L1 and 52L1 in cells was detected by Western blotting. Immunizing codon-optimized 58L1 and 52L1 expression plasmids induced neutralizing antibody in mice which can neutralize infection of pseudovirion respectively.We found cross neutralization phenomena exists between HPV16 and HPV58,HPV58 and HPV52,but not between HPV52 and HPV16.
引文
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