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SIV辅助调控蛋白在小鼠模型中对SIV结构蛋白Gag,Pol和Env免疫原性的影响
Alternative TitleImpact on immunogenicity of SIV structural proteins by SIV
张寅峰
Subtype硕士
Thesis Advisor陈凌
2011-07-29
Degree Grantor中国科学院研究生院
Place of Conferral广州生物院
Degree Name硕士
Degree Discipline生物化学与分子生物学
Keyword非结构蛋白 HIV/SIV疫苗 免疫原性
Abstract虽然人类在二十多年前就已发现HIV-1病毒,但到目前为止,仍有数以千万计的病人被该病毒感染。在发展有效的针对HIV病毒的疫苗道路上充满了曲折,至今仍没有取得非常令人满意的结果;人们甚至现在都还无法确认哪些免疫反应可以控制病毒。除了传统的以诱发中和抗体为主的疫苗策略外,基于T细胞免疫反应的疫苗一度被认为十分具有潜力。然而,Merck公司宣布其STEP疫苗计划失败后,人们对这种策略失败的原因进行了深入的探索:其中一种解释是STEP疫苗所引发的免疫反应的广度十分有限。为了拓宽疫苗的免疫反应广度,除了传统的作为疫苗主要靶标的HIV结构蛋白(Gag,Pol 和Env)外,辅助调控蛋白(非结构蛋白) 也越来越受到人们的重视而成为疫苗的新组分。然而,辅助调控蛋白与结构蛋白之间的相互影响,尤其是其免疫原性间的影响目前还不为人们所了解,因此本研究比较了结构蛋白单独免疫与非结构蛋白联合免疫后其免疫原性的变化。研究中首先构建了一系列携带不同SIVmac239病毒结构蛋白和非结构蛋白基因的质粒和5型重组腺病毒载体;然后在小鼠体内进行了DNA疫苗初免/腺病毒疫苗加强的免疫实验,并测定了相关免疫反应指标;最后,又通过两次腺病毒免疫的策略重复了相关实验。我们的实验数据表明,当Gag,Pol和Env等结构蛋白分别与辅助调控蛋白一起免疫时,相对于各个结构蛋白单独免疫而言,针对Gag抗原的CD8+ T 细胞反应强度会升高,而针对Pol和Env抗原的免疫反应强度却会显著下降;CD4+ T细胞的免疫反应中并没有观察到同样的现象。此外Gag,Env抗原与辅助调控蛋白一同免疫后,可以更有效的引发针对SIV病毒颗粒的抗体。这些新发现将对HIV/SIV疫苗的研发提供一些有益的提示。
Other AbstractTo date, hundreds of millions of individuals have been infected by the HIV-1 virus which was discovered more than 20 years ago. Development of an effective vaccine is fraught with difficulty, and thus far, a satisfactory outcome has yet to be achieved. Currently, even the precise correlation between the immune response and viral protection remains unknown. In addition to the classical vaccine based on neutralizing antibodies, T-cell based vaccines were considered very promising。After the announcement of Merck’s frustrating failure of their STEP trial,the reason to the defeat has been explored thoroughly: The limited breadth of the induced immune response is thought to be one potential explanation. In order to broaden the breath of immune response,accessory and regulatory proteins (nonstructural proteins) have received increasing attention as components in novel HIV/SIV vaccine design besides the structural proteins (Gag, Pol and Env), which have traditionally been the major targets. However, the complicated interactions between nonstructural proteins and structural proteins remain poorly understood, especially their effect on immunogenicity. In this study, the immunogenicity of structural proteins with and without nonstructural proteins was compared. First, a series of recombinant plasmids and adenoviral vectors carrying various SIVmac239 nonstructural and structural genes were constructed. Then mice were primed with DNA plasmids and boosted with corresponding Ad5 vectors, and the resulting immune responses were measured. At last, immunizations of Ad5 vectors were performed twice to ensure the results. Our results demonstrated that when the individual Gag, Pol or Env gene products were co-immunized with the whole repertoire of nonstructural proteins, the Gag-specific CD8+ T response was enhanced, while the Env and Pol-specific CD8+ T responses were significantly reduced; the same pattern was not observed in CD4+ T cell responses. Antibody responses against the SIVmac239 virus were elicited more effectively when Gag and Env proteins were immunized together with nonstructural antigens. These findings may provide helpful insights in the development of novel HIV/SIV vaccines.
Subject Area生物化学与分子生物学
Pages101
Language中文
Document Type学位论文
Identifierhttp://ir.foo.ac.cn/handle/2SETSVCV/964
Collection中国科学院广州生物医药与健康研究院
Affiliation中国科学院广州生物医药与健康研究院
First Author AffilicationGUANGZHOU INSTITUTES OF BIOMEDICINE AND HEALTH,CHINESE ACADEMY OF SCIENCES
Recommended Citation
GB/T 7714
张寅峰. SIV辅助调控蛋白在小鼠模型中对SIV结构蛋白Gag,Pol和Env免疫原性的影响[D]. 广州生物院. 中国科学院研究生院,2011.
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