中国静脉吸毒人群TRIM5α基因多态性与HIV-1 易感性研究
文献类型：学位论文
| 作者 | 刘丰亮 |
| 学位类别 | 博士 |
| 答辩日期 | 2011-05 |
| 授予单位 | 中国科学院研究生院 |
| 授予地点 | 北京 |
| 导师 | 郑永唐 |
| 关键词 | HIV-1 静脉吸毒者 TRIM5α 基因多态性 易感性 中国 |
| 其他题名 | An Association Study between TRIM5alpha Polymorphism and HIV-1 Infection among Chinese Intravenous Drug Users |
| 学位专业 | 细胞生物学 |
| 中文摘要 | 细胞限制因子TRIM5a(Tripartite motif protein 5a)具有物种特异的限制活性，它可以限制包括HIV-1在内的很多逆转录病毒。由于大多数灵长类动物都表达TRIM5a蛋白，所以大部分灵长类动物都不会感染HIV-1。人虽然也表达TRIM5a蛋白，但是人TRIM5a的HIV-1限制能力很弱以至于不能像大部分的灵长类动物一样可以限制HIV-1的感染。之前国外的研究表明，人TRIM5a基因中的某些位点的变异会影响人的HIV-1易感性和感染HIV后AIDS(Acquired immune deficiency syndrome)疾病进程，但是这些位点对于HIV-1易感性和AIDS疾病进程的影响在不同人种中并不一致。 由于之前国外关于TRIM5a基因多态性研究的结论不一致，以及目前尚欠缺关于中国人群TRIM5a基因多态性的研究。本论文对中国云南省境内的静脉吸毒人群的TRIM5a基因多态性与HIV-1易感性进行研究。我们从云南省募集了1523名静脉吸毒者，并对他们的TRIM5基因2号外显子和8号外显子的编码区进行了重测序，结果共发现13个基因位点变异，但仅有4个单核苷酸多态性(Single Nucleotide Polymorphisms, SNPs)位点的分布频率高于0.05，对这4个常见SNPs进行分析后发现43YY纯合子在HIV-1血清阴性静脉吸毒者中的分布频率明显高于HIV-1血清阳性静脉吸毒者，并且在进行汉族和傣族的分层分析后这一显著差异依然存在，这就提示H43Y有可能是导致中国静脉吸毒者具有一定HIV-1抗性的原因。 我们对认为会影响中国静脉吸毒者HIV-1易感性的H43Y和2个首次发现的罕见基因位点变异——R97C和G110R进行体外功能研究。结果发现这3个基因位点变异都会减弱人TRIM5a的HIV-1限制能力，但是它们对人TRIM5a功能的影响程度不同，其中H43Y造成人TRIM5a完全丧失HIV-1限制能力，而R97C和G110R虽然降低了人TRIM5a的HIV-1限制能力，但是基因突变的人TRIM5a还具有一定的HIV-1限制能力。 综上所述，我们认为在中国静脉吸毒人群中H43Y不是通过增强人TRIM5a的HIV-1限制能力，而极有可能是通过影响机体的免疫反应来降低HIV-1的易感性。 |
| 英文摘要 | TRIM5a has species-specific restriction activity against replication of many retroviruses, including HIV-1. Most primates express TRIM5a protein so that they can not be infected by HIV-1. Though human also express TRIM5a protein, it is less potent in suppressing infection of HIV-1 than most orthologs of other nonhuman primates. Previous studies suggested that polymorphisms in human TRIM5a gene might influence HIV-1 susceptibility and AIDS progress, but the potential role of human TRIM5a nucleotide variants on HIV-1 susceptibility and AIDS progress was not consistent among different population. Because there were lack of consistent conclusion about TRIM5a gene polymorphism and study among Chinese population, we perform an association study between TRIM5a polymorphism and HIV-1 infection among Chinese Intravenous Drug Users (IDUs). We resequenced TRIM5 exon2 and exon8 coding region from genomic DNA of 1523 IDUs, who are all recruited from Yunnan Province. Though we identified a total of 13 different nucleotide variants, only 4 single nucleotide polymorphisms (SNPs) were not observed at low frequencies [minor allele frequency (MAF) > 0.05]. We observed that the frequency of 43Y homozygote in seronegative IDUs was significantly higher than that in the HIV-1 infected IDUs, and the stratified analysis of H43Y SNP between Han and Dai ethnicity again confirmed the significant difference, which suggested H43Y might account for the HIV-1 resistance due to TRIM5a gene in Chinese IDUs. We performed in vitro experiment to assay the contribution of H43Y and two novel rare gene variants R97C and G110R in the TRIM5a protein to anti-HIV-1 activity. We found all 3 gene variants weakened the anti-HIV-1 activities of human TRIM5a: H43Y impairs human TRIM5a restriction of HIV-1, while R97C and G110R result in modest effects on anti-HIV-1 potency. We concluded that the effect of H43Y on HIV-1 susceptibility among Chinese IDUs might be not caused by enhanced the anti-HIV-1 activity of human TRIM5a protein, but caused by influencing immune response. |
| 语种 | 中文 |
| 公开日期 | 2011-09-20 |
| 源URL | [http://159.226.149.42:8088/handle/353002/6796]  |
| 专题 | 昆明动物研究所_分子免疫药理学 |
| 推荐引用方式 GB/T 7714 | 刘丰亮. 中国静脉吸毒人群TRIM5α基因多态性与HIV-1 易感性研究[D]. 北京. 中国科学院研究生院. 2011. |
入库方式： OAI收割
来源：昆明动物研究所
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