近日，中国科学院昆明动物研究所动物模型与人类疾病机理重点实验室郑永唐研究员指导的博士研究生况轶群等人开展了中国云南境内北平顶猴TRIM5基因和HIV-1感染的相关性进行了研究。

研究发现：中国云南境内北平顶猴都存在CypA假基因的cDNA通过逆转座机制插入至TRIM5基因座的3’-UTR区域的现象，形成了一个不同于鹰猴TRIM5-CypA的新型融合基因npmTRIMCyp。npmTRIMCyp融合基因转录本中外显子7和8均被剪切掉。外显子7剪接丢失机制源于TRIM5第6内含子内3’剪接位点的G/T突变。同时发现，北平顶猴外周血单个核细胞(PBMC)对HIV-1易感，不限制HIV-1在细胞内的复制。npmTRIMCyp融合蛋白可以有效地限制HIV-2ROD的复制，对SIVmac239只有十分微弱的限制活性。在北平顶猴npmTRIMCyp中可能识别逆转录病毒衣壳的区域存在较高的多态性。

理想的动物模型对艾滋病的发病机制、抗HIV药物及疫苗等研究具有特别重要的作用。但至今国际上尚未建立理想的动物模型，非人灵长类动物是目前公认较理想的艾滋病模型动物。在灵长类动物中，TRIM5α蛋白限制了HIV-1等逆转录病毒的复制。平顶猴是唯一可以感染HIV-1的旧大陆猴，但其确切机制有待探索。郑永唐学科组和宿兵学科组合作的前期研究首先发现，在平顶猴TRIM5基因座中插入了亲环蛋白A (Cyclophilin A)基因，形成TRIM5-CypA融合模式，该融合基因产物不能限制HIV-1的复制，这可能是平顶猴成为旧大陆猴中唯一易感HIV-1的重要分子基础。

根据现行的灵长类动物分类学，2001年动物分类学家将原属平顶猴群体(M. nemestrina group)三个亚种的灵长类动物被分类为猕猴属的三个不同种： 巽他平顶猴(Sunda pig-tailed macaque，M. nemestrina)，北平顶猴(Northern pig-tailed macaque，M. leonine)和明打威猴(Mentawai macaque，M. pagensis)。北平顶猴仅分布于我国云南南部和西藏东南部、缅甸、泰国和印度北部地区。

该研究结果进一步阐明了天然免疫分子TRIM5α限制HIV-1感染和复制的作用机制，在细胞和分子水平上支持了北平顶猴是较理想和合适的艾滋病模型动物，为建立基于北平顶猴的艾滋病灵长类动物模型提供了重要思路和科学依据。相关研究成果已发表在国际知名杂志《逆转录病毒学》(Retrovirology, 2009, 6:58)上。

推荐原始出处：

Retrovirology 2009, 6:58doi:10.1186/1742-4690-6-58

Genotyping of TRIM5 locus in northern pig-tailed macaques (Macaca leonina), a primate species susceptible to Human Immunodeficiency Virus type 1 infection

Yi-Qun Kuang1,4 , Xia Tang1,4 , Feng-Liang Liu1,4 , Xue-Long Jiang2 , Ya-Ping Zhang2 , Guangxia Gao3  and Yong-Tang Zheng1

1Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, PR China
2State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, PR China
3Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, PR China
4Graduate School of Chinese Academy of Sciences, Beijing 100039, PR China

Background

The pig-tailed macaques are the only Old World monkeys known to be susceptible to human immunodeficiency virus type 1 (HIV-1) infection. We have previously reported that the TRIM5-Cyclophilin A (TRIMCyp) fusion in pig-tailed macaques (Macaca nemestrina) is dysfunctional in restricting HIV-1, which may explain why pig-tailed macaques are susceptible to HIV-1 infection. Similar results have also been reported by other groups. However, according to the current primate taxonomy, the previously reported M. nemestrina are further classified into three species, which all belong to the Macaca spp. This calls for the need to look into the previous studies in more details.

Results

The local species Northern pig-tailed macaque (M. leonina) was analyzed for the correlation of TRIM5 structure and HIV-1 infection. Eleven M. leonina animals were analyzed, and all of them were found to possess TRIM5-CypA fusion at the TRIM5 locus. The transcripts encoding the dysfunctional TRIM5-CypA should result from the G-to-T mutation in the 3'-splicing site of intron 6. Polymorphism in the putative TRIMCyp recognition domain was observed. The peripheral blood mononuclear cells (PBMCs) of M. leonina were susceptible to HIV-1 infection. Consistent with the previous results, expression of the M. leonina TRIMCyp in HeLa-T4 cells rendered the cells resistant to HIV-2ROD but not to SIVmac239 infection.

Conclusion

The susceptibility of M. leonina to HIV-1 infection is due to the dysfunctional TRIM5-CypA fusion in the TRIM5 locus. This finding should broaden our perspective in developing better HIV/AIDS non-human primate animal models.