禽腺联病毒YZ-1株的分离、基因组克隆、基因表达及感染性病毒拯救
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摘要
腺联病毒(adeno-associated virus,AAV)属于细小病毒科、依赖病毒属成员,其复制需有腺病毒或疱疹病毒等辅助病毒的协助。AAV基因组长度约为4.7kb,其正股和负股单链DNA以等量比例存在病毒子中。作为基因导入载体,AAV具有无致病性、感染分裂及不分裂细胞和外源基因表达稳定等优点,在缺少辅助病毒情况下,AAV-2还能以定点方式整合于人19号染色体的q13.3-qter位点,因此AAV是很有前景的基因治疗载体。禽腺联病毒(avian adeno-associated virus,AAAV)的研究较少,现有的研究资料表明,AAAV具有其它AAV相似的生物学特性和基因结构,提示可作为禽源细胞基因导入载体。本研究在成功分离AAAV基础上,对其全基因组进行了克隆和序列分析,并对病毒蛋白基因进行了克隆和表达,为构建重组AAAV和进开展禽源细胞外源基因表达研究奠定了基础。
一、AAAV的分离与鉴定
从某健康鸡群采集泄殖腔棉拭样本10份,将无菌处理的粪便滤液与禽腺病毒1型鸡胚致死孤儿病毒(CELO)共接种11日龄SPF鸡胚,收集接种后72～120h死亡鸡胚尿囊液。根据已发表AAAV VR-865株Rep和Cap基因序列设计引物,用PCR对致死鸡胚尿囊液进行检测,结果从1份样品接种的鸡胚尿囊液中扩增到预期大小的Rep和Cap基因片段。将电泳分离的PCR产物切胶回收,序列测定结果显示与AAAV VR-865株Rep和Cap基因的核苷酸序列同源性分别为97.1%和94.6%。将PCR检测阳性尿囊液进行鸡胚传代,用PCR对不同代次死亡鸡胚尿囊液进行连续检测,结果均能扩增到预期大小的基因片段。从死亡鸡胚尿囊液中纯化病毒,经磷钨酸负染后在电子显微镜下观察,可见典型的AAAV病毒颗粒。用差速和超速离心分离病毒,提取的核酸电泳分析显示预期大小的4.7kb基因组DNA。这些结果表明,从1份健康鸡粪便样品中分离的病毒为AAAV,定名为YZ-1株。
二、AAAV全基因组克隆及序列分析
根据先前获得的Rep和Cap基因片段序列设计两对引物,分别用PCR扩增约1.9kb的Rep-Cap基因片段以及约2.1kb的Cap-ITR-Rep基因片段,分别克隆入质粒载体后,对除ITR序列以外的基因组序列进行序列测定。同时从纯化病毒提取病毒核酸,经体外变性和退火获得双链病毒基因组DNA,经凝胶电泳分离后,切胶回收约4.7kb的AAAV双股基因组DNA,用Taq酶在基因组DNA的3′端添加“A”碱基后,用TA克隆法克隆入pCR2.1载体,获得了含AAAV全基因组的重组质粒pAAAV并进行序列测定。将两种克隆方法获得的基因组序列进行比对,结果序列完全一致。序列测定结果显示,全基因组全长度为4684个碱基,与AAAV VR-865株和DA-1株核苷酸序列同源性分别为95.0%和92.1%;ITR长度为119核苷酸,可形成典型的回文结构,D区由22个碱基组成,含4个串连GAGY重复序列的Rcp蛋白结合元件(RBE),末端裂解位点(TRS)序列为TGGCCA;左侧Rep78阅读框由1995nt组成,编码664个氨基酸,与AAAV DA-1株和VR-865株的核苷酸同源性分别为96.6%和95.2%,氨基酸序列同源性分别为99.2%和95.6%;右侧最大的阅读框编码VP1蛋白,由2217个碱基组成,编码738个氨基酸,与AAAV DA-1株和VR-865株的核苷酸同源性分别为94.1%和89.9%,氨基酸序列同源性分别为95.3%和88.6%;编码VP3的阅读框由1608个碱基组成,编码535个氨基酸,与AAAV DA-1株和VR-865株的氨基酸序列同源性分别为94.2%和91.6%。
为了进一步阐明AAAV与其它AAV的遗传进化关系,将AAAV YZ-1株、DA-1株和VR-865株全基因组序列与其它9株AAV以及鹅细小病毒B株(GPV-B)基因组序列进行同源性比较,并构建遗传进化树。结果显示3株AAAV与人及其他哺乳动物AAV分离株的核苷酸同源性在55.0%～59.7%之间(与人源AAV-2的同源性最高,与牛源AAV的同源性最低),与GPV-B株的同源性在51.4%～52.2%。YZ-1株、DA-1株和VR-865株处于遗传进化树的一个独特分支上。结果表明,禽源AAV与人及哺乳动物源AAV以及属于细小病毒属的GPV遗传关系较远。
三、AAAV蛋白的表达与鉴定
为了制备针对AAAV Rep和Cap蛋白的特异抗血清,分别将AAAV的Rep78基因和VP3基因克隆入原核表达载体pET-47b,转化BL21(DE3)大肠杆菌,经IPTG诱导后进行SDS-PAGE分析,结果显示表达的Rep78蛋白分子量约为82kDa,VP3蛋白分子量约为56kDa;Western blot分析显示,表达的两种蛋白均能与AAAV抗血清反应;将目的蛋白切胶免疫BALB/c小鼠,分别制备了针对两种蛋白的多克隆抗血清,与AAAV抗原呈间接免疫荧光试验(IFA)阳性反应,与鸡胚致死孤儿病毒(CELO)呈阴性反应;Western blot分析显示,VP3蛋白抗血清能特异识别AAAV的三种结构蛋白VP1、VP2、VP3;将Rep-Cap阅读框插入真核表达质粒pcDNA3.0,用获得的重组质粒pcDNA-Rep-Cap转染293T细胞,分别以Rep78和VP3抗血清为一抗进行IFA检测,结果均为阳性;对转染细胞裂解产物进行Western blot分析,VP3抗血清可识别VP1、VP2、VP3三种结构蛋白,Rep78抗血清可识别Rep78和Rep52两种非结构蛋白。这些试验结果表明,pcDNA-Rep-Cap中的两个阅读框均能正确表达,可作为制备重组AAAV的包装质粒。
四、感染性AAAV的拯救
为了探明克隆的AAAV YZ-1株全基因组序列是否能拯救出感染性病毒,用5′端ITR缺失96nt的重组质粒pSM525转染CELO病毒感染的鸡胚肝(CEL)细胞系,将1:100稀释的转染细胞裂解上清在CEL细胞上传5代,用PCR对细胞裂解上清进行检测,可扩增出特异的450bp AAAV Cap基因片段;取细胞裂解上清进行电镜检查,可以观察到预期的20～25nm病毒粒子;Western blot分析结果显示,拯救病毒的三种结构蛋白分子量正确。将pSM525质粒与表达AAV-5 E2a、E4和VA RNA基因的辅助质粒pAd12共转染293细胞,细胞裂解上清经电镜检查,可以观察到典型的AAAV病毒粒子;细胞裂解上清经DNA酶Ⅰ处理后,与CELO病毒共接种SPF鸡胚,致死的鸡胚尿囊液用PCR检测,可以扩增到预期的450bp和1.9kb的AAAV特异片段。这些试验结果说明,含人腺病毒5型辅助基因的pAd12质粒同样可以支持pSM525质粒的拯救。
上述试验结果表明,用含AAAV YZ-1株全基因组的重组质粒能够拯救出感染性病毒,重组质粒包含与AAAV复制和包装所需的所有关键序列,而且ITR区的部分碱基缺失不影响感染性病毒的拯救,为深入研究AAAV复制、基因表达以及重组载体构建奠定了基础。
Adeno-associated viruses(AAV) are members of dependvirus genus of the family of parvoviridae.AAV virions are approximately 20 to 25 nm in diameter and are composed of VP1,VP2 and VP3 structural proteins that encapsidate a linear 4.7-kb single-stranded DNA of plus or minus polarity.For efficient replication,AAV requires adenovirus or herpes virus as a helper.In the absence of helper virus,however,AAV-2 remains latent within the human cells and integrates its genome into the sequence-specific site AAVS1 on 19q13.3-qter of human chromosome.As gene transfer vectors,AAVs have the advantages of infecting both dividing and nondividing cells,long-term transgene expression and lack of pathogenicity,which make them attractive for use in gene therapy applications.Previous studies have showed that avian adeno-associated virus(AAAV) had the similar genome organizations with its primate counterparts,suggesting that AAAV can be used as the gene transfer vector for gene expression studies in avian cells and for development of recombinant vaccines against avian diseases.In this study,a AAAV isolate was isolated by co-inoculating embryonating eggs with filtered fecal samples from healthy chickens and CELO virus.The complete genome was cloned and characterized by sequence analysis,expression of the viral genes in E.coli and immunological methods,which laid a solid foundation for generation of recombinant AAAV for gene expression studies in avian cells.
1.Isolation and identification of AAAV
A total of 10 rectum swab samples were obtained from 7-week-old healthy chickens from a local chicken farm.After aseptic treatment,the filtrates were co-inoculated with the type 1 fowl adenovirus(CELO) into 11-day-old embryonated eggs of SPF chickens.Their allantoic fluids were harvested at different time points of post-inoculation and submitted to PCR amplification using primes designed according to the Rep and Cap genes of the reference AAAV VR-865 strain.The results showed that two expected gene fragments of about 480bp and 450bp were detected from the allantoic fluid of the chicken embryos inoculated with one fecal sample.The PCR products were purified by agarose gel electrophoresis for direct sequencing.The sequence analysis showed that the two gene fragments were 97.1%and 94.6%identical to the Rep and Cap genes of the AAAV VR-865 strain.The isolated virus was successfully passed in embryonated SPF eggs based on PCR detection of their egg allantoic fluids.Electron microscopy showed that purified AAAV particles had a diameter of 20 to 25nm.Agarose gel electrophoresis showed that the AAAV genome extracted from the purified particles had an expected size of 4.7kb.These results confirmed the identity of AAAV isolated from healthy chickens.
2.Genome cloning and sequencing of AAAV
Two different strategies were used to clone the genome of AAAV YZ-1 isolate.First, based on the abtained rep and cap sequences,one pair of primers were used to amplify the 1.9-kb rep-cap fragment and another pair of primers were used to amplify the 2.1-kb cap-ITR-rep fragment,both of which were subcloned into TA cloning vector for sequence analysis.Second,AAAV particles were isolated from the allantoic fluids of the co-inoculated eggs by ultracentrifugation and the viral DNA was extracted by SDS-proteinase K digestion followed by phenol-chloroform extraction.After annealing and agarose gel separation,the double-stranded genomic DNA was gel-purified and blunt-ended with Taq DNA polymerase.The viral genomic DNA was then cloned into pCR 2.1 vector and six clones with 4.7-kb insert were subjected to sequencing.
Sequencing analysis showed that the YZ-1 AAAV genome cloned using two different strategies had a high agreement,which was 4684-nt long and had similar gene organization to other AAVs.The first 119 nucleotides of the 141-nt ITR formed a typical T-shaped palindromic structure and the remaining 22 nucleotides corresponded to the D region of ITR.The putative Rep-binding element(RBE) were tandem repeats of (GAGY)_4 and the putative terminal resolution site(TRS) was TGGCCA.
Sequence alignment showed that the YZ-1 AAAV was 95.0%or 92.2%identical to AAAV strain DA-1 or VR-865 at nucleotide sequence level.The Rep78 of the YZ-1 isolate was 99.2%to the DA-1 strain or 95.6%identical to the VR-865 strain at amino acid sequence level.The left Rep78 ORF was 1995nt long,encoding 664 amino acids. The right VP1 ORF was 2217nt long,encoding 738 amino acids,which was 95.3%or 88.6%identical to the DA-1 or VR-865 strain at the amino acid sequence level.The VP3 ORF encoded 535 amino acids with an identity of 94.2%or 91.6%to the DA-1 or VR-865 strain.
The whole genome sequences of three AAAV strains were aligned with that of other AAVs and goose parvovirus B strain(GPV-B) and identities ranged from 55.0%to 59.7%to mammalian AAVs were identified with a highest identity of 59.7%to AAV-2 and the lowest identity 55.0%to bovine adeno-associated virus(BAAV).The percent identity between the YZ-1 AAAV and GPV was 52.2%.
3.Expression and characterization of AAAV proteins
Both nonstructural protein Rep78 gene and structural protein VP3 gene were separately amplified by PCR and subcloned into prokaryotic expression vector pET-47b. After transformation into BL21(DE3) E.coli and induction with IPTG,expected proteins of 82 kDa and 56 kDa were revealed by SDS-PAGE,both of which could be recognized by anti-AAAV serum in Western blotting assay.The expressed proteins were eluted from SDS-PAGE gel and injected into BALB/c mice for antiserum production.Indirect immunofluorescence showed that the antisera reacted positively to viral antigens in AAAV-infected CEF cells,but not to CELO virus antigens.Western blotting of AAAV particles showed the three structural proteins VP1,VP2 and VP3 using the VP3-specific antibody as the probe.
The rep and cap ORFs of the AAAV YZ-1 isolate was subcloned as a single fragment into the eukaryotic expression vector pcDNA3.0 and transfected into 293T cells. Correct expression of the Rep and Cap proteins were analyzed by IFA using Rep78- or VP3-specific antiserum.Western blotting of the transfected 293T cells detected the three capsid proteins VP1,VP2 and VP3 using VP3-specific antiserum and two nonstructural proteins Rep78 and Rep52 using Rep78-specific antiserum.
4.Rescuing of infectious AAAV
To rescue infectious AAAV,the recombinant plasmid pSM525 containing the YZ-1 genome with a 96-nt deletion in the 5' ITR was co-transfected into chicken embryo live (CEL) cells with CELO virus and passed on CEL cells for five passages.A 450-bp cap gene fragment could be amplified by PCR using viral DNA extracted from the cell lysate. After co-transfection of the pSM525 vector into 293T cells with the helper vector pAd12 containing the E2,E4 and VA RNA gene of Ad5,typical AAAV particles of 20-25nm in diameter were revealed by electron microscopy.The rescued virus was passed in 11-day-old SPF embryonated eggs with CELO virus and its infectivity was confirmed by PCR.
一、AAAV的分离与鉴定
从某健康鸡群采集泄殖腔棉拭样本10份,将无菌处理的粪便滤液与禽腺病毒1型鸡胚致死孤儿病毒(CELO)共接种11日龄SPF鸡胚,收集接种后72～120h死亡鸡胚尿囊液。根据已发表AAAV VR-865株Rep和Cap基因序列设计引物,用PCR对致死鸡胚尿囊液进行检测,结果从1份样品接种的鸡胚尿囊液中扩增到预期大小的Rep和Cap基因片段。将电泳分离的PCR产物切胶回收,序列测定结果显示与AAAV VR-865株Rep和Cap基因的核苷酸序列同源性分别为97.1%和94.6%。将PCR检测阳性尿囊液进行鸡胚传代,用PCR对不同代次死亡鸡胚尿囊液进行连续检测,结果均能扩增到预期大小的基因片段。从死亡鸡胚尿囊液中纯化病毒,经磷钨酸负染后在电子显微镜下观察,可见典型的AAAV病毒颗粒。用差速和超速离心分离病毒,提取的核酸电泳分析显示预期大小的4.7kb基因组DNA。这些结果表明,从1份健康鸡粪便样品中分离的病毒为AAAV,定名为YZ-1株。
二、AAAV全基因组克隆及序列分析
根据先前获得的Rep和Cap基因片段序列设计两对引物,分别用PCR扩增约1.9kb的Rep-Cap基因片段以及约2.1kb的Cap-ITR-Rep基因片段,分别克隆入质粒载体后,对除ITR序列以外的基因组序列进行序列测定。同时从纯化病毒提取病毒核酸,经体外变性和退火获得双链病毒基因组DNA,经凝胶电泳分离后,切胶回收约4.7kb的AAAV双股基因组DNA,用Taq酶在基因组DNA的3′端添加“A”碱基后,用TA克隆法克隆入pCR2.1载体,获得了含AAAV全基因组的重组质粒pAAAV并进行序列测定。将两种克隆方法获得的基因组序列进行比对,结果序列完全一致。序列测定结果显示,全基因组全长度为4684个碱基,与AAAV VR-865株和DA-1株核苷酸序列同源性分别为95.0%和92.1%;ITR长度为119核苷酸,可形成典型的回文结构,D区由22个碱基组成,含4个串连GAGY重复序列的Rcp蛋白结合元件(RBE),末端裂解位点(TRS)序列为TGGCCA;左侧Rep78阅读框由1995nt组成,编码664个氨基酸,与AAAV DA-1株和VR-865株的核苷酸同源性分别为96.6%和95.2%,氨基酸序列同源性分别为99.2%和95.6%;右侧最大的阅读框编码VP1蛋白,由2217个碱基组成,编码738个氨基酸,与AAAV DA-1株和VR-865株的核苷酸同源性分别为94.1%和89.9%,氨基酸序列同源性分别为95.3%和88.6%;编码VP3的阅读框由1608个碱基组成,编码535个氨基酸,与AAAV DA-1株和VR-865株的氨基酸序列同源性分别为94.2%和91.6%。
为了进一步阐明AAAV与其它AAV的遗传进化关系,将AAAV YZ-1株、DA-1株和VR-865株全基因组序列与其它9株AAV以及鹅细小病毒B株(GPV-B)基因组序列进行同源性比较,并构建遗传进化树。结果显示3株AAAV与人及其他哺乳动物AAV分离株的核苷酸同源性在55.0%～59.7%之间(与人源AAV-2的同源性最高,与牛源AAV的同源性最低),与GPV-B株的同源性在51.4%～52.2%。YZ-1株、DA-1株和VR-865株处于遗传进化树的一个独特分支上。结果表明,禽源AAV与人及哺乳动物源AAV以及属于细小病毒属的GPV遗传关系较远。
三、AAAV蛋白的表达与鉴定
为了制备针对AAAV Rep和Cap蛋白的特异抗血清,分别将AAAV的Rep78基因和VP3基因克隆入原核表达载体pET-47b,转化BL21(DE3)大肠杆菌,经IPTG诱导后进行SDS-PAGE分析,结果显示表达的Rep78蛋白分子量约为82kDa,VP3蛋白分子量约为56kDa;Western blot分析显示,表达的两种蛋白均能与AAAV抗血清反应;将目的蛋白切胶免疫BALB/c小鼠,分别制备了针对两种蛋白的多克隆抗血清,与AAAV抗原呈间接免疫荧光试验(IFA)阳性反应,与鸡胚致死孤儿病毒(CELO)呈阴性反应;Western blot分析显示,VP3蛋白抗血清能特异识别AAAV的三种结构蛋白VP1、VP2、VP3;将Rep-Cap阅读框插入真核表达质粒pcDNA3.0,用获得的重组质粒pcDNA-Rep-Cap转染293T细胞,分别以Rep78和VP3抗血清为一抗进行IFA检测,结果均为阳性;对转染细胞裂解产物进行Western blot分析,VP3抗血清可识别VP1、VP2、VP3三种结构蛋白,Rep78抗血清可识别Rep78和Rep52两种非结构蛋白。这些试验结果表明,pcDNA-Rep-Cap中的两个阅读框均能正确表达,可作为制备重组AAAV的包装质粒。
四、感染性AAAV的拯救
为了探明克隆的AAAV YZ-1株全基因组序列是否能拯救出感染性病毒,用5′端ITR缺失96nt的重组质粒pSM525转染CELO病毒感染的鸡胚肝(CEL)细胞系,将1:100稀释的转染细胞裂解上清在CEL细胞上传5代,用PCR对细胞裂解上清进行检测,可扩增出特异的450bp AAAV Cap基因片段;取细胞裂解上清进行电镜检查,可以观察到预期的20～25nm病毒粒子;Western blot分析结果显示,拯救病毒的三种结构蛋白分子量正确。将pSM525质粒与表达AAV-5 E2a、E4和VA RNA基因的辅助质粒pAd12共转染293细胞,细胞裂解上清经电镜检查,可以观察到典型的AAAV病毒粒子;细胞裂解上清经DNA酶Ⅰ处理后,与CELO病毒共接种SPF鸡胚,致死的鸡胚尿囊液用PCR检测,可以扩增到预期的450bp和1.9kb的AAAV特异片段。这些试验结果说明,含人腺病毒5型辅助基因的pAd12质粒同样可以支持pSM525质粒的拯救。
上述试验结果表明,用含AAAV YZ-1株全基因组的重组质粒能够拯救出感染性病毒,重组质粒包含与AAAV复制和包装所需的所有关键序列,而且ITR区的部分碱基缺失不影响感染性病毒的拯救,为深入研究AAAV复制、基因表达以及重组载体构建奠定了基础。
Adeno-associated viruses(AAV) are members of dependvirus genus of the family of parvoviridae.AAV virions are approximately 20 to 25 nm in diameter and are composed of VP1,VP2 and VP3 structural proteins that encapsidate a linear 4.7-kb single-stranded DNA of plus or minus polarity.For efficient replication,AAV requires adenovirus or herpes virus as a helper.In the absence of helper virus,however,AAV-2 remains latent within the human cells and integrates its genome into the sequence-specific site AAVS1 on 19q13.3-qter of human chromosome.As gene transfer vectors,AAVs have the advantages of infecting both dividing and nondividing cells,long-term transgene expression and lack of pathogenicity,which make them attractive for use in gene therapy applications.Previous studies have showed that avian adeno-associated virus(AAAV) had the similar genome organizations with its primate counterparts,suggesting that AAAV can be used as the gene transfer vector for gene expression studies in avian cells and for development of recombinant vaccines against avian diseases.In this study,a AAAV isolate was isolated by co-inoculating embryonating eggs with filtered fecal samples from healthy chickens and CELO virus.The complete genome was cloned and characterized by sequence analysis,expression of the viral genes in E.coli and immunological methods,which laid a solid foundation for generation of recombinant AAAV for gene expression studies in avian cells.
1.Isolation and identification of AAAV
A total of 10 rectum swab samples were obtained from 7-week-old healthy chickens from a local chicken farm.After aseptic treatment,the filtrates were co-inoculated with the type 1 fowl adenovirus(CELO) into 11-day-old embryonated eggs of SPF chickens.Their allantoic fluids were harvested at different time points of post-inoculation and submitted to PCR amplification using primes designed according to the Rep and Cap genes of the reference AAAV VR-865 strain.The results showed that two expected gene fragments of about 480bp and 450bp were detected from the allantoic fluid of the chicken embryos inoculated with one fecal sample.The PCR products were purified by agarose gel electrophoresis for direct sequencing.The sequence analysis showed that the two gene fragments were 97.1%and 94.6%identical to the Rep and Cap genes of the AAAV VR-865 strain.The isolated virus was successfully passed in embryonated SPF eggs based on PCR detection of their egg allantoic fluids.Electron microscopy showed that purified AAAV particles had a diameter of 20 to 25nm.Agarose gel electrophoresis showed that the AAAV genome extracted from the purified particles had an expected size of 4.7kb.These results confirmed the identity of AAAV isolated from healthy chickens.
2.Genome cloning and sequencing of AAAV
Two different strategies were used to clone the genome of AAAV YZ-1 isolate.First, based on the abtained rep and cap sequences,one pair of primers were used to amplify the 1.9-kb rep-cap fragment and another pair of primers were used to amplify the 2.1-kb cap-ITR-rep fragment,both of which were subcloned into TA cloning vector for sequence analysis.Second,AAAV particles were isolated from the allantoic fluids of the co-inoculated eggs by ultracentrifugation and the viral DNA was extracted by SDS-proteinase K digestion followed by phenol-chloroform extraction.After annealing and agarose gel separation,the double-stranded genomic DNA was gel-purified and blunt-ended with Taq DNA polymerase.The viral genomic DNA was then cloned into pCR 2.1 vector and six clones with 4.7-kb insert were subjected to sequencing.
Sequencing analysis showed that the YZ-1 AAAV genome cloned using two different strategies had a high agreement,which was 4684-nt long and had similar gene organization to other AAVs.The first 119 nucleotides of the 141-nt ITR formed a typical T-shaped palindromic structure and the remaining 22 nucleotides corresponded to the D region of ITR.The putative Rep-binding element(RBE) were tandem repeats of (GAGY)_4 and the putative terminal resolution site(TRS) was TGGCCA.
Sequence alignment showed that the YZ-1 AAAV was 95.0%or 92.2%identical to AAAV strain DA-1 or VR-865 at nucleotide sequence level.The Rep78 of the YZ-1 isolate was 99.2%to the DA-1 strain or 95.6%identical to the VR-865 strain at amino acid sequence level.The left Rep78 ORF was 1995nt long,encoding 664 amino acids. The right VP1 ORF was 2217nt long,encoding 738 amino acids,which was 95.3%or 88.6%identical to the DA-1 or VR-865 strain at the amino acid sequence level.The VP3 ORF encoded 535 amino acids with an identity of 94.2%or 91.6%to the DA-1 or VR-865 strain.
The whole genome sequences of three AAAV strains were aligned with that of other AAVs and goose parvovirus B strain(GPV-B) and identities ranged from 55.0%to 59.7%to mammalian AAVs were identified with a highest identity of 59.7%to AAV-2 and the lowest identity 55.0%to bovine adeno-associated virus(BAAV).The percent identity between the YZ-1 AAAV and GPV was 52.2%.
3.Expression and characterization of AAAV proteins
Both nonstructural protein Rep78 gene and structural protein VP3 gene were separately amplified by PCR and subcloned into prokaryotic expression vector pET-47b. After transformation into BL21(DE3) E.coli and induction with IPTG,expected proteins of 82 kDa and 56 kDa were revealed by SDS-PAGE,both of which could be recognized by anti-AAAV serum in Western blotting assay.The expressed proteins were eluted from SDS-PAGE gel and injected into BALB/c mice for antiserum production.Indirect immunofluorescence showed that the antisera reacted positively to viral antigens in AAAV-infected CEF cells,but not to CELO virus antigens.Western blotting of AAAV particles showed the three structural proteins VP1,VP2 and VP3 using the VP3-specific antibody as the probe.
The rep and cap ORFs of the AAAV YZ-1 isolate was subcloned as a single fragment into the eukaryotic expression vector pcDNA3.0 and transfected into 293T cells. Correct expression of the Rep and Cap proteins were analyzed by IFA using Rep78- or VP3-specific antiserum.Western blotting of the transfected 293T cells detected the three capsid proteins VP1,VP2 and VP3 using VP3-specific antiserum and two nonstructural proteins Rep78 and Rep52 using Rep78-specific antiserum.
4.Rescuing of infectious AAAV
To rescue infectious AAAV,the recombinant plasmid pSM525 containing the YZ-1 genome with a 96-nt deletion in the 5' ITR was co-transfected into chicken embryo live (CEL) cells with CELO virus and passed on CEL cells for five passages.A 450-bp cap gene fragment could be amplified by PCR using viral DNA extracted from the cell lysate. After co-transfection of the pSM525 vector into 293T cells with the helper vector pAd12 containing the E2,E4 and VA RNA gene of Ad5,typical AAAV particles of 20-25nm in diameter were revealed by electron microscopy.The rescued virus was passed in 11-day-old SPF embryonated eggs with CELO virus and its infectivity was confirmed by PCR.
引文
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