表达HIV-1 gag和env基因的多载体疫苗在动物体内免疫原性研究
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摘要
艾滋病对人类医学提出了空前的挑战,在过去20多年里,科学家已经做了大量尝试来研究预防性疫苗,但还没有任何一个临床方案获得成功。随着对HIV感染的深入研究以及免疫学的发展,有越来越多的研究表明细胞免疫应答尤其是Gag特异性的细胞免疫应答与疾病的缓慢进展有着很强的关联。因此用疫苗诱导HIV-1特异性的细胞免疫应答可能会在降低感染后的病毒载量以及延缓疾病进展方面发挥作用。而且治疗性疫苗可以通过较小规模的临床试验,在较短时间内得到效果评价的数据,能为预防性疫苗的研究提供免疫保护机理方面的依据。本研究的目的是以Gag为主要抗原诱导HIV-1特异性的细胞免疫应答,研制适合在中国应用的治疗性HIV-1疫苗。
本文首先将来源于疫苗计划应用地区(河南省)有偿献血HIV-1感染者的gag基因构建到几种不同的载体上,包括质粒DNA、重组F基因缺失型仙台病毒载体(rSeV)、重组腺病毒5型载体(rAd5)和重组腺相关病毒1型和2型嵌合载体(rAAV2/1),在小鼠体内比较了不同载体携带相同抗原Gag在小鼠体内的细胞和体液反应特点。结果显示,各候选疫苗单独免疫小鼠时所诱导的Gag特异性免疫应答水平依次为:rAd5＞rSeV＞DNA,且细胞免疫应答较强的疫苗所诱导的抗体反应也较强,而rAAV2/1载体与其他载体不同,能诱导很强而持久的Gag特异性抗体应答,而细胞免疫应答却很弱。而且用rAAV2/1载体疫苗初免,再用其他疫苗(包括rAd5和rAd5/F35疫苗)加强对细胞免疫应答有着一定程度的减弱作用,以上结果提示rAAV2/1载体很可能具有与其他载体不同的特性,具体机制需要进一步研究。
基于以上对各载体免疫应答特点的了解,我们选择了表达gag基因的DNA、rSeV和rAd5载体疫苗作为诱导Gag特异性细胞免疫应答的主要疫苗并对这些载体的联合免疫效果进行了研究,结果发现DNA、rSeV和rAd5载体采用两两联合免疫所诱导的细胞和体液免疫应答明显比单独免疫强。而这三种载体联合应用,所诱导的细胞免疫应答比两种载体联合免疫提高2～5倍,在抗体应答方面也大大提高。
随后,我们选择了在小鼠体内细胞和体液免疫应答最强的三种载体联合应用(DNA/rSeV/rAd5和DNA/rAd5/rSeV)的免疫方案,在恒河猴体内进行了实验。结果表明,所有接种疫苗的恒河猴均产生了Gag特异性细胞和体液免疫应答。在每一次用重组病毒载体疫苗加强免疫后均可出现一个反应高峰,持续2～4周后逐渐下降,并稳定在一个相对较高的水平,此时疫苗免疫动物的特异性免疫反应水平仍然远远高于对照组。三种载体联合免疫还能诱导高水平的Gag特异性抗体反应,且长期维持在较高水平。
综合以上结果,我们认为将DNA、rSeV和rAd5三种疫苗联合免疫动物可以诱导很好的Gag特异性细胞和体液免疫反应。这种多载体联合免疫的方案可以克服针对载体的免疫应答对疫苗反复应用的限制,多次诱导针对HIV-1的高水平免疫应答。
本文还对表达gp120基因的rAAV2/1疫苗在小鼠和恒河猴体内的免疫原性进行了研究,结果显示在小鼠体内的Gp120特异性细胞免疫应答水平很弱,IgG结合抗体水平较高,但没有中和活性;在恒河猴体内的细胞和抗体应答都很弱,没有中和抗体的产生,提示需要对膜蛋白基因进行改造,提高其免疫原性。
The global HIV epidemic continues to expand,exceeding previous predictions and causing tremendous suffering.At the same time,a rapid increase of HIV infection was also found in China in recent years.The cumulative reported cases living with HIV/AIDS were 223,501 by the end of Oct 2007.Therefore,developing HIV vaccines targeting the prevalent strains in China is one of the most important tasks of Chinese HIV/AIDS therapy and prevention.Subtype B is found to be prevalent in several epidemic regions where paid blood donors are mainly affected population.HIV-1 Subtype B isolates in these epidemic regions are relatively conserved,so the prevalent strains isolated from these regions were used as vaccine strain.The purpose of this study is developing therapeutic vaccines using multiple vectors in combination with HAART treatment for enhancing the host specific immunity.The study in untreated HIV-1 infected cohort and HIV-2 long-term non-progressors indicated that only Gag-specific responses were associated with lowering viremia and may play an important role in controlling viral load during chronic infection.Therefore,we made DNA,adenovirus type 5(rAd5), adenoassociated virus type 1(rAAV2/1) and Sendai virus(rSeV) vectors expressing gag gene of the prevalent Subtype B strains in China as candidate vaccine strategies.
Firstly,we examined the potency of vaccine regimens of DNA,rAd5-gag, rAAV2/1-gag and rSeV-gag for inducing specific immune responses.The Gag-specific cellular immune responses were detected by intracellular cytokine staining(ICS), ELISPOT and in vivo CTL,and humoral immune resposes were detected by ELISA.In Balb/C mice,the immunogenecity of candidate vaccines were rAd5>rSeV>DNA and stronger cellular immune reponses companied with stronger humoral responses.However, it's different from the immunogenecity of rAAV2/1 vacccine,rAAV2/1 vaccine induced potent and long lasting Gag-specific antibody responses but very moderate cellular immune responses.Moreover,rAAV2/1-gag impaired the Gag-specific immune responses induced by follwing rAd vaccines(rAd5-gag and rAd5/F35-gag) boosting.The same results were observed in rAAV2/1 and rAd5 vaccines expressing HIV-1 gp120 gene.It indicates that the different immunogenicity is vector dependent and independent of the nature of antigen.Then the potency of DNA,rAd5-gag and rSeV-gag to induce HIV-1 cellular responses were tested in combined modality.The results showed that combination of these vectors induced higher Gag-specific cellular immune response than any regimen using single vector alone.Commonly,vaccination protocols require multiple immunizations to achieve robust,protective and sustained immune responses.However, the immunity against viral vectors has limited the repeated use of same candidate vaccine. Most researches have focused on vaccination protocols based on one or two candidates.In this study we addressed the magnitude,sustain and breadth of HIV-1 Gag-specific immune responses induced by prime-boost-boost scheme with combination of triple heterologous vectors.The prime-boost-boost regimen consisting of the triple heterologous vectors(i.e. DNA,adenovirus and SeV) induced Gag-specific T-cell responses the most efficiently as well as humoral response.
In rhesus macaques,the prime-boost-boost regimen induced potent Gag-specific cellular immune responses as well as long lasting humoral immune response,and each boosting resulted in rapid and efficient expansion of Gag-specific T cells.These results indicate that this prime-boost-boost regimen using triple heterologous vectors is a promising AIDS vaccine candidate for efficiently inducing HIV-1-specific cellular and humoral immune responses.Its further studies as a promising scheme for prophylactic and/or therapeutic HIV-1 vaccines should be grounded.
Based on the results of strong and long lasting humoral responses induced by rAAV2/1-gp120 in Balb/C mice,the potency of rAAV2/1-gpl20 to induce Env-specific humoral responses was also tested in rhesus macaques.However,only moderate Env-specific IgG were induced.Gene optimization may be necessary to induce high level of Env-specific humoral responses and neutralizing antibody.
本文首先将来源于疫苗计划应用地区(河南省)有偿献血HIV-1感染者的gag基因构建到几种不同的载体上,包括质粒DNA、重组F基因缺失型仙台病毒载体(rSeV)、重组腺病毒5型载体(rAd5)和重组腺相关病毒1型和2型嵌合载体(rAAV2/1),在小鼠体内比较了不同载体携带相同抗原Gag在小鼠体内的细胞和体液反应特点。结果显示,各候选疫苗单独免疫小鼠时所诱导的Gag特异性免疫应答水平依次为:rAd5＞rSeV＞DNA,且细胞免疫应答较强的疫苗所诱导的抗体反应也较强,而rAAV2/1载体与其他载体不同,能诱导很强而持久的Gag特异性抗体应答,而细胞免疫应答却很弱。而且用rAAV2/1载体疫苗初免,再用其他疫苗(包括rAd5和rAd5/F35疫苗)加强对细胞免疫应答有着一定程度的减弱作用,以上结果提示rAAV2/1载体很可能具有与其他载体不同的特性,具体机制需要进一步研究。
基于以上对各载体免疫应答特点的了解,我们选择了表达gag基因的DNA、rSeV和rAd5载体疫苗作为诱导Gag特异性细胞免疫应答的主要疫苗并对这些载体的联合免疫效果进行了研究,结果发现DNA、rSeV和rAd5载体采用两两联合免疫所诱导的细胞和体液免疫应答明显比单独免疫强。而这三种载体联合应用,所诱导的细胞免疫应答比两种载体联合免疫提高2～5倍,在抗体应答方面也大大提高。
随后,我们选择了在小鼠体内细胞和体液免疫应答最强的三种载体联合应用(DNA/rSeV/rAd5和DNA/rAd5/rSeV)的免疫方案,在恒河猴体内进行了实验。结果表明,所有接种疫苗的恒河猴均产生了Gag特异性细胞和体液免疫应答。在每一次用重组病毒载体疫苗加强免疫后均可出现一个反应高峰,持续2～4周后逐渐下降,并稳定在一个相对较高的水平,此时疫苗免疫动物的特异性免疫反应水平仍然远远高于对照组。三种载体联合免疫还能诱导高水平的Gag特异性抗体反应,且长期维持在较高水平。
综合以上结果,我们认为将DNA、rSeV和rAd5三种疫苗联合免疫动物可以诱导很好的Gag特异性细胞和体液免疫反应。这种多载体联合免疫的方案可以克服针对载体的免疫应答对疫苗反复应用的限制,多次诱导针对HIV-1的高水平免疫应答。
本文还对表达gp120基因的rAAV2/1疫苗在小鼠和恒河猴体内的免疫原性进行了研究,结果显示在小鼠体内的Gp120特异性细胞免疫应答水平很弱,IgG结合抗体水平较高,但没有中和活性;在恒河猴体内的细胞和抗体应答都很弱,没有中和抗体的产生,提示需要对膜蛋白基因进行改造,提高其免疫原性。
The global HIV epidemic continues to expand,exceeding previous predictions and causing tremendous suffering.At the same time,a rapid increase of HIV infection was also found in China in recent years.The cumulative reported cases living with HIV/AIDS were 223,501 by the end of Oct 2007.Therefore,developing HIV vaccines targeting the prevalent strains in China is one of the most important tasks of Chinese HIV/AIDS therapy and prevention.Subtype B is found to be prevalent in several epidemic regions where paid blood donors are mainly affected population.HIV-1 Subtype B isolates in these epidemic regions are relatively conserved,so the prevalent strains isolated from these regions were used as vaccine strain.The purpose of this study is developing therapeutic vaccines using multiple vectors in combination with HAART treatment for enhancing the host specific immunity.The study in untreated HIV-1 infected cohort and HIV-2 long-term non-progressors indicated that only Gag-specific responses were associated with lowering viremia and may play an important role in controlling viral load during chronic infection.Therefore,we made DNA,adenovirus type 5(rAd5), adenoassociated virus type 1(rAAV2/1) and Sendai virus(rSeV) vectors expressing gag gene of the prevalent Subtype B strains in China as candidate vaccine strategies.
Firstly,we examined the potency of vaccine regimens of DNA,rAd5-gag, rAAV2/1-gag and rSeV-gag for inducing specific immune responses.The Gag-specific cellular immune responses were detected by intracellular cytokine staining(ICS), ELISPOT and in vivo CTL,and humoral immune resposes were detected by ELISA.In Balb/C mice,the immunogenecity of candidate vaccines were rAd5>rSeV>DNA and stronger cellular immune reponses companied with stronger humoral responses.However, it's different from the immunogenecity of rAAV2/1 vacccine,rAAV2/1 vaccine induced potent and long lasting Gag-specific antibody responses but very moderate cellular immune responses.Moreover,rAAV2/1-gag impaired the Gag-specific immune responses induced by follwing rAd vaccines(rAd5-gag and rAd5/F35-gag) boosting.The same results were observed in rAAV2/1 and rAd5 vaccines expressing HIV-1 gp120 gene.It indicates that the different immunogenicity is vector dependent and independent of the nature of antigen.Then the potency of DNA,rAd5-gag and rSeV-gag to induce HIV-1 cellular responses were tested in combined modality.The results showed that combination of these vectors induced higher Gag-specific cellular immune response than any regimen using single vector alone.Commonly,vaccination protocols require multiple immunizations to achieve robust,protective and sustained immune responses.However, the immunity against viral vectors has limited the repeated use of same candidate vaccine. Most researches have focused on vaccination protocols based on one or two candidates.In this study we addressed the magnitude,sustain and breadth of HIV-1 Gag-specific immune responses induced by prime-boost-boost scheme with combination of triple heterologous vectors.The prime-boost-boost regimen consisting of the triple heterologous vectors(i.e. DNA,adenovirus and SeV) induced Gag-specific T-cell responses the most efficiently as well as humoral response.
In rhesus macaques,the prime-boost-boost regimen induced potent Gag-specific cellular immune responses as well as long lasting humoral immune response,and each boosting resulted in rapid and efficient expansion of Gag-specific T cells.These results indicate that this prime-boost-boost regimen using triple heterologous vectors is a promising AIDS vaccine candidate for efficiently inducing HIV-1-specific cellular and humoral immune responses.Its further studies as a promising scheme for prophylactic and/or therapeutic HIV-1 vaccines should be grounded.
Based on the results of strong and long lasting humoral responses induced by rAAV2/1-gp120 in Balb/C mice,the potency of rAAV2/1-gpl20 to induce Env-specific humoral responses was also tested in rhesus macaques.However,only moderate Env-specific IgG were induced.Gene optimization may be necessary to induce high level of Env-specific humoral responses and neutralizing antibody.
引文
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