Goldschmidt Valérie, Bleiber Gabriela, May Margaret, Martinez Raquel, Ortiz Millàn, Telenti Amalio
Institute of Microbiology and University Hospital, University of Lausanne, Switzerland.
Retrovirology. 2006 Aug 22;3:54. doi: 10.1186/1742-4690-3-54.
The retroviral restriction factor tripartite motif protein (TRIM)5alpha, is characterized by marked amino acid diversity among primates, including specific clusters of residues under positive selection. The identification of multiple non-synonymous changes in humans suggests that TRIM5alpha variants might be relevant to retroviral pathogenesis. Previous studies have shown that such variants are unlikely to modify susceptibility to HIV-1 infection, or the course of early infection. However, the longterm effect of carrying Trim5alpha variants on disease progression in individuals infected with HIV-1 has not previously been investigated.
In a cohort of 979 untreated individuals infected with HIV-1 with median follow up 3.2 years and 9,828 CD4 T cell measurements, we analysed common amino acid variations: H43Y, V112F, R136Q, G249D, and H419Y. The rate of CD4 T cell decline before treatment was used as the phenotype. In addition, we extended previous work on the in vitro susceptibility of purified donor CD4 T cells (n = 125) to HIV-1 infection, and on the susceptibility of HeLa cells that were stably transduced with the different TRIM5 variants. Haplotypes were analysed according to the most parsimonious evolutionary structure, where two main human TRIM5alpha groups can be defined according to the residue at amino acid 136. Humans present both Q136 and R136 at similar frequency, and additional TRIM5alpha amino acid variants are almost exclusively derived from R136-carrying haplotypes.
We observed modest differences in disease progression for evolutionary branches carrying R136-derived haplotypes, and with the non-synonymous polymorphisms G249D and H419Y. In vitro analysis of susceptibility of donor CD4 T cells, and of the various transduced HeLa cell lines supported the absence of significant differential restriction of HIV-1 infection by the various huTRIM5alpha alleles.
Common human variants of TRIM5alpha have no effect or modest effect on HIV-1 disease progression. These variants occur at sites conserved throughout evolution, and are remote from clusters of positive selection in the primate lineage. The evolutionary value of the substitutions remains unclear.
逆转录病毒限制因子三聚体基序蛋白（TRIM）5α的特点是在灵长类动物中存在显著的氨基酸多样性，包括处于正选择下的特定残基簇。人类中多个非同义变化的发现表明，TRIM5α变体可能与逆转录病毒发病机制相关。先前的研究表明，此类变体不太可能改变对HIV-1感染的易感性或早期感染的进程。然而，携带Trim5α变体对HIV-1感染个体疾病进展的长期影响此前尚未得到研究。
在一个由979名未接受治疗的HIV-1感染者组成的队列中，中位随访时间为3.2年，进行了9828次CD4 T细胞测量，我们分析了常见的氨基酸变异：H43Y、V112F、R136Q、G249D和H419Y。治疗前CD4 T细胞下降率用作表型。此外，我们扩展了先前关于纯化供体CD4 T细胞（n = 125）对HIV-1感染的体外易感性以及用不同TRIM5变体稳定转导的HeLa细胞易感性的研究。根据最简约的进化结构分析单倍型，根据氨基酸136处的残基可定义两个主要的人类TRIM5α组。人类中Q136和R136出现的频率相似，其他TRIM5α氨基酸变体几乎完全源自携带R136的单倍型。
我们观察到携带R136衍生单倍型以及非同义多态性G249D和H419Y的进化分支在疾病进展方面存在适度差异。对供体CD4 T细胞和各种转导的HeLa细胞系的体外易感性分析支持各种huTRIM5α等位基因对HIV-1感染不存在显著的差异限制。
TRIM5α的常见人类变体对HIV-1疾病进展没有影响或影响较小。这些变体出现在整个进化过程中保守的位点，并且远离灵长类谱系中的正选择簇。这些替代的进化价值仍不清楚。
